Displaying One Session

Poster Fri, Sep 11, 2020
Session Type
Poster
Date
Fri, Sep 11, 2020
Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0287 - Alemtuzumab induces changes in the innate immune system in patients with relapsing-remitting multiple sclerosis (ID 722)

Speakers
Presentation Number
P0287
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

Alemtuzumab is a humanized monoclonal antibody specific for CD52 and has been shown to be an efficient treatment for patients with relapsing-remitting multiple sclerosis (RRMS). CD52 is present at high expression levels on the surface of B- and T-lymphocytes and at low levels on monocytes and NK-cells. Recent evidence has emerged that the innate immune system might also undergo reorganization contributing to the long-lasting immunomodulatory properties of alemtuzumab.

Objectives

To better understand the effect of alemtuzumab on the innate immune system we longitudinally assessed the function of innate immune cells in a cohort of alemtuzumab treated RRMS patients. We particularly focused on distinguished monocyte and macrophage phenotypes to identify specific cellular activational patterns that are modulated during alemtuzumab treatment.

Methods

Peripheral mononuclear blood cells (PBMCs) and plasma were collected from RRMS patients before and every two months after alemtuzumab treatment for 12 months. PBMC surface marker (CD14, CD16, CD23, CD206, CD163, CD86, CCR7, HLA-DR) were assessed by flow cytometry. Monocyte function (phagocytosis of latex beads, ROS production) was examined by in vivo assays. Plasma cytokine levels were analyzed using ELISA.

Results

We observed an increase in the expression of anti-inflammatory surface markers such as CD206 and CD23 on the overall monocyte population. While the distribution of different monocyte phenotypes (classical, intermediate, and non-classical monocytes) did not change significantly after alemtuzumab treatment, several surface marker expressions within the individual phenotypes showed alterations. The CD16+ intermediate and non-classical monocytes showed an increase in anti-inflammatory CD23+, whereas the CD16- population displayed an elevation of pro-inflammatory CCR7 and CD86, 2 months post alemtuzumab treatment and a return to baseline levels later on. Furthermore, CD163+ monocytes, showing phagocytic activity were increased 6 months post-treatment and were still slightly elevated after 12 months, while phagocytosing B-cells showed an increase 12 months post alemtuzumab treatment

Conclusions

Alemtuzumab treatment goes along with complex alterations of the immune system including innate immunity mechanisms. In the peripheral blood compartment, PBMC display an increase in phagocytotic activity.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0288 - Analysis of CD3 T lymphocyte count in patients under treatment with Ocrelizumab regarding development of infections (ID 1840)

Presentation Number
P0288
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

Ocrelizumab is a monoclonal antibody approved for relapsing-remitting primary progressive multiple sclerosis (MS) acting against B lymphocytes that expresses CD20. The CD 20 antigen is a cell surface antigen found on pre-B lymphocytes, mature B lymphocytes, memory B lymphocytes, and a T cell subtype (CD3+ CD20+) that also expresses CD20. Clinical trials have shown that the use of this drug can produce a reduction in immunoglobulin levels which might be related to infections; however, there is little data about the influence of this immunomodulatory treatment on CD3+ T lymphocytes.

Objectives

To analyze differences in CD3+ T lymphocyte counts in patients under treatment with Ocrelizumab and their relationship with the development of infections.

Methods

We performed an observational retrospective case-control study nested in a cohort of MS patients under treatment with Ocrelizumab. Cases were patients who developed infections and controls were patients who did not develop any type of infection during treatment.

Results

We included 33 patients, mean age 39 years old (SD:9.6), mean MS duration 9 years (SD:5.8), 66.7% women, 38.7% developed infections during treatment. Mean CD3+ T lymphocytes count was 1157.6 (SD:498) at baseline, 1373 (SD:621.9) CD3+ T lymphocytes at 3 months, 1221 (SD:439) CD3+ T lymphocytes at 6 months and 1405 (SD:836) at 12 months. We did not find statistical differences between groups, although there was a tendency towards a higher mean CD3+ T lymphocyte count at three months (1781.2;SD:399.9) in patients who did not develop infections as compared to the mean CD3+ T lymphocytes count at three months (1047.1; SD: 595.1) in patients who developed infections (p=0.064).

Conclusions

Our preliminary data did reveal statistical differences in the total CD3+ T lymphocyte count between patients under Ocrelizumab treatment, although there was a tendency towards a higher count at 3 months in patients who did not develop infections. Weather the putative effect of Ocrelizumab on T cell subtype (CD3+ CD20+) might be related to the development of infections needs further research.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0290 - Anti-CD20 therapy interferes with the immune response to the Hepatitis B virus vaccine in MS patients (ID 1515)

Speakers
Presentation Number
P0290
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

The highly effective therapies for multiple sclerosis (MS) could potentially interfere in the immune response against novel antigens, but evidence is lacking.

Objectives

To evaluate the immunogenicity to the hepatitis B virus vaccine (HBV-v) in MS patients who are candidate to highly effective therapies.

Methods

This is an observational retrospective cohort study. MS patients were eligible if they had a complete HBV-v primo-vaccination course (40 mcg or adjuvated 20 mcg HBV-v at months 0, 1, 2 and 6-12) and a post-vaccination serology at least 1 month after the last dose, to assess the response to the vaccine. Seroprotection status (VHB surface antigen antibody titers of at least 10 UI/L) and geometric mean antibody titers were evaluated taking into account the time of vaccination in relation to the specific MS disease-modifying therapies (DMT). We considered the DMT received at baseline (onset of vaccination) as well as, the possible treatment change over the course of vaccination.

Results

153 patients were included, with mean age 48 (SD 8.6) years, of which 68% were female. Mean disease duration was 13.8 (SD 9.4) years. Median EDSS was 4 (IQR 3). 78 patients (51%) were under DMT at the onset of vaccination and 115 (75.2%) patients changed their DMT during the course of vaccination. The global seroprotection rate was 66.7% (IC 95% 58.6-74.1). The highest seroprotection rate was observed in non-treated patients (N=17; 94.1% 95%CI 71.3-99.0) and in those treated with injectables, dimethyl fumarate, teriflunomide or natalizumab (N=31; 96.8% 95%CI 83.3%-99.9%). Starting anti-CD20 therapy during the course of vaccination reduced the seroprotection rate regardless of the preceding therapeutic situation: 1) non-treated patients (N=40; 52.5% 95%CI 36.1%-68.5%), 2) treated with injectables, dimethylfumarate, teriflunomide or natalizumab (N=33; 48.5% 95%CI 30.8%-66.5%) and 3) treated with fingolimod (N=11; 18.2% 95%CI 23%-51.8%). Onset of AntiCD20 also resulted in a significant decrease in the antibody titers (p<0.001) compared to those without AntiCD20. There was a dose-gradient effect in the achieved seroprotection with the number of vaccine doses administered before the onset of the anti-CD20 therapy (16.7%, 30%, 66.7% and 92.9% with one, two, three and four doses, respectively).

Conclusions

MS patients on anti-CD20 therapy mount deficient immune responses to VHB vaccination and therefore, vaccination should be completed in advance of treatment onset.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0291 - Association of Headache with B-cell Targeted Therapies in Multiple Sclerosis patients. (ID 1796)

Speakers
Presentation Number
P0291
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Patients with Multiple Sclerosis (MS) have an increased incidence of headache, whereas the mechanism and the various co-factors are poorly understood. Among them, MS therapies are considered to play a role. Nonetheless, there is not enough data that correlate MS therapies with headache.

Objectives

The aim of the present study is to conduct a systematical review of the current literature towards identifying any possible association between B-cell MS therapies and increased headache incidence.

Methods

Systematic literature search was conducted using PubMed/MEDLINE database, clinicaltrials.gov and clinicaltrialsregister.eu searching clinical trials of B-cell depleting therapies in MS (i.e. ofatumumab, ocrelizumab, rituximab, ublituximab, cladribine) and investigating a possible role in the incidence of headache in MS patients. PRISMA guidelines for systematic reviews were applied. Risk of bias was evaluated using the Cochrane Risk of Bias tool. Relative risk (RR) and confidence intervals (CI) were calculated.

Results

In total, 9 randomized-control trials with 3785 patients were included in this study. The overall pooled relative risk of headaches in MS patients receiving B-cell depleting therapies was estimated to 1.12; p=0.15 (95% CI: 0.96 – 1.30; I2=9.32%; Q=7.42 [p=0.49]). Subgroup analysis of the studies in which cladribine was given as B-cell targeted therapy, showed a statistically significant higher increased risk of headache with a risk ratio of 1.19; p=0.04 (95% CI 1.01 – 1.42; I2=0%; Q=1.07 [p=0.59]).

Conclusions

B-cell targeted MS therapies do not correlate with increased incidence of headache as an adverse effect, even though a trend is shown. Further sub-analysis revealed that cladribine alone is associated with increased incidence of headache. More research is needed to elucidate the pathogenetic mechanism of headache induction, as well as, to identify headache prevention strategies.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0292 - Associations between treatment satisfaction, medication beliefs, and adherence to DMT in MS patients: Saudi Tertiary Care Center Experience (ID 112)

Speakers
Authors
Presentation Number
P0292
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Multiple sclerosis (MS) considered as one of the most common Neuro-immune diseases that leads to major disabilities in an affected patient with a significant burden and consequences to patients and their families. Even though till these days there is no available cure for MS, however, the last two decades witnessed a promising future for MS treatments drugs precisely disease-modifying therapies (DMTs) to reduce MS relapse and delay disability.
Adherence to DMTs has a significant impact on treatment outcomes and is considered a critical factor in succeeding therapeutic success. Accordingly, the need to examine this issue in Saudi Arabia stands.

Objectives

To identify the factors associated with adherence to DMTs medications among MS patients in Saudi Arabia.

To evaluate the relationship between treatment satisfaction, medication beliefs, and DMTs adherence, and other factors

Methods

A survey was conducted in 2019 in neurology clinics in King Fahad Medical City (KFMC) in Riyadh. Patients were sampled from the KFMC’s Data Base with population size of 387 patients. The survey measured self-reported DMT adherence (doses taken divided by doses prescribed during previous 2-week period—adherence ≥0.80), DMT satisfaction using the Treat­ment Satisfaction Questionnaire for Medication version II, medication beliefs using the Beliefs About Medicines Questionnaire, and demographic and clinical covariates. Relationships between variables were examined using multivariate logistic regression.

Results

Final analyses included 239 usable surveys. Mean ± SD participant age was 35.07 ± 9.7 years. Most respondents were female (74.9%)), taking an injectable DMT (49%), and adher­ent to DMT (64.4%). Significant predictors of DMT adherence were DMT Experience (naive vs. experienced (odds ratio [OR], 3.722; 95% CI, 1.487 - 9.316; P = .005), DMT Rout (oral vs. injectable; OR, 0.974; 95% CI, 0.952 - 0.995; P = .017), and Global Satisfaction; OR, 0.950; 95% CI, 0.926 - 0.975; P = <0.001)

Conclusions

In patients with MS sampled from KFMC’s Data Base, medication beliefs was not significantly associated with DMT adherence while the Global satisfaction was significantly associated with DMT adherence. Based on significant predictors, patients taking injectable DMTs, and patients with previous experience with another DMT(s) are at higher risk for no adherence. Future research is warranted to assess relationships between variables in more diverse MS populations.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0294 - Autoinmunity secondary to alemtuzumab in clinical practice: 5 years of RWE (ID 1424)

Presentation Number
P0294
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Aletuzumab(ALZ) is an approved drug for the treatment of active recurrent-remitting multiple sclerosis (RRMS), with proved efficacy and safety in clinical trials. Among its most frequent adverse effects are autoinmune disorders related to secondary autoinmunity (SA) phenomena.

Objectives

We analyze and characterize secondary autoinmunity in our multiple sclerosis unit after more than five years of clinical experience.

Methods

Retrospective observational descriptive study of RRMS patients treated with ALZ in our center, characterizing SA phenomena after more than 5 years of experience

Results

n=131(77% women), with a mean age of 40,2 years (SD±9,1) and a mean time of disease of 13.8 years (SD±7,1). The mean pre-treatment EDSS was 4,5 (DS±1,6) with an prior annualized relapse rate of 1.48 (SD±0,83). SA was found in 42 patients (32%), most of them with thyroid disease (81% with 73,5% hyperthyroidism, asymptomatic majority) with aggresive treatment (surgical, radiotherapy) in 20%. Hematological SA was found in 0.01% (autoinmune thrombopenia, with monophasic course and excellent response to pharmacological treatment) and cutaneous SA in 0.05% (most of them vitiligo and well-controlled alopecia areata and one patient with chronic urticaria). Currently one patient is under study for nephropathy (0.01%). Like the available evidence, we detected an increase in SA around third year.

Conclusions

In our experience ALZ is emerging as a drug with a safety profile similar to available evidence regarding SA, although some complications have been described in other body systems, and it requires an adequate patient selection and close clinical control.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0295 - Autologous Hematopoietic Stem Cell Transplantation in Multiple Sclerosis (aHSCT-in-MS): The Zurich Experience 24 Months after Approval (ID 1828)

Speakers
Presentation Number
P0295
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Autologous hematopoietic stem cell transplantation (aHSCT) is used for highly active relapsing-remitting or progressive forms of multiple sclerosis (MS) since 1995. Based on increasing evidence regarding efficacy and improved safety of aHSCT in MS, the Swiss Federal Office of Public Health (FOPH) granted approval in June 2018 with the requirement that patients participate in a prospective registry study at our institution (“aHSCT-in-MS”) to assess clinical, radiological, laboratory and safety measures for 5 years after transplantation.

Objectives

We here report adverse events (AEs) and severe AEs after hematopoietic stem cell mobilization and aHSCT for MS in Zurich, Switzerland.

Methods

All data is collected systematically using RedCap. Hematopoietic stem cells are mobilized with 2 days of cyclophosphamide 2g/m2/d and granulocyte-colony stimulating factor. Conditioning high-dose chemotherapy comprises BEAM-ATG, i.e. BCNU, etoposide, cytarabine, melphalan before- and ATG (d+1 and +2: 3.75 mg/kg/d) after stem cell re-transfusion (d0).

Results

26 MS patients (13 females, 13 males) with a mean age of 40.8±7.8 years, mean disease duration of 8.9±4.8 years and a mean expanded disease status scale (EDSS) score of 5.0±1.2 have been treated with aHSCT. 10/26 (38.5%) patients had relapsing-remitting MS, 9/26 (34.6%) secondary-progressive MS and 7/26 (26.9%) primary-progressive MS. aHSCT was indicated because 8/26 (30.8%) patients had clinical activity (i.e. relapses), 13/26 (50.0%) had radiological activity (i.e. new or contrast-enhancing CNS lesions) and 16/26 (61.5%) had clinical progression – despite conventional highly effective immunomodulatory therapy. We observed infectious AEs in the majority of patients, i.e. mucositis, pharyngitis and/or enteritis (24/26), upper airway (9/26) and urinary (8/26) infection, symptomatic reactivation of CMV (4/26), HSV (5/26), VZV (2/26) and BKV (3/26). Other AEs included Uhthoff’s phenomenon (14/26), hypotension (3/26), epistaxis and cholecystolithiasis (each 1/26). Severe AEs included 4 cases with neutropenic fever, 2 symptomatic CMV reactivations, each 1 urosepsis, hemorrhagic cystitis, gastroenteritis with ileus, laryngitis, pharyngitis, cervical abscess, pulmonary embolism, gastrointestinal bleeding, manic episode, depressive reaction and emesis. Although a substantial proportion of patients reported improvements of neurological functions and less fatigue, follow-up is too short to comment on long-term outcomes.

Conclusions

The safety profile of aHSCT-in-MS is acceptable, but requires vigilant monitoring and optimized antibacterial and antiviral prophylactic care. Regarding the increased risk of CMV reactivation (4/7 CMV-seropositive patients) and herpes zoster (2/26), we decided to establish prophylaxis with the CMV inhibitor letermovir in CMV-seropositive patients and to vaccinate all patients with Shingrix® after transplantation.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0296 - Automated extraction of multiple sclerosis treatment timelines (ID 1859)

Speakers
Presentation Number
P0296
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Background: The treatment information stored in free-text electronic health records has remarkable potential for use in a variety of research applications, including pharmacogenomic studies investigating genetic variants associated with adverse drug reactions to multiple sclerosis (MS) medications. However, utilization of this data typically requires extensive manual curation.

Objectives

Objectives: To determine the feasibiity of extracting glatiramer acetate (GA) treatment timelines in an automated manner from electroni health records, to increase datasets available for MS treatment research.

Methods

Methods: We identified 7,000 patients with MS from a de-identified electronic health record database from Vanderbilt University Medical Center. After extraction of the medication recoreds, we developed a rule-based algorithm using Python and Sequel for GA that 1) classifies free-text notes mentioning GA based on patient treatment status and 2) aggregates note classifications into complete GA treatment periods.

Results

Results: For notes indicating GA initiation, continuation, and discontinuance, the algorithm achieved sensitivities of 0.79, 0.83, and 0.79, respectively. For these same groups, precision was 0.92, 0.97, and 0.65, respectively. Subsequently, the algorithm correctly identified 72% of treatment period beginnings (precision = 0.75) and 70% of treatment period ends (precision = 0.73). The algorithm correctly determined 86% of days during which patients were on GA (precision = 0.79). A conservative method of treatment period generation was developed that extracted fewer periods (per day sensitivity = 0.40) but maintained extremely high fidelity (per day precision = 0.98).

Conclusions

Conclusions: Automated extraction of MS treatment timelines is feasilbe with high accuracy. Among other applications, the treatment data extracted by the algorithm can facilitate pharmacogenetic research either as direct input in analyses or by significantly reducing the time demands of manual curation. Application of algorithms such as the one we have developed will increase the ability to study MS treatments in real world populations.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0297 - Autonomic nervous system abnormalities may predict cardiovascular changes after initiation of siponimod in the treatment of SPMS (ID 1451)

Speakers
Presentation Number
P0297
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

The aim of this study was to identify whether autonomic nervous system (ANS) dysfunction identified prior treatment initiation can predict siponimod related decrease in HR after treatment initiation.

Objectives

Primary outcome was to identify whether HRV parameters identified prior treatment initiation can predict decrease in HR after taking the first dose of the drug.

Secondary outcomes were to identify whether HRV parameters identified prior treatment initiation can predict changes in sBP and dBP after taking the first dose of the drug.

Methods

In 26 people with secondary progressive multiple sclerosis (SPMS) (16 females, mean age 50.96±9.48, median EDSS 6.0, range 3.0-6.5) the following ANS testing protocol was applied: 10-min supine resting position, Valsalva maneuver, deep breathing test, 10 min tilt-up table test, 5-min supine resting period, ingestion of siponimod, followed by 180-min supine resting period recordings. Heart rate variability (HRV) parameters were investigated as possible predictors of decrease in heart rate HR (ΔHR) after treatment initiation. According to pharmacokinetic properties of siponimod, average values after 1 hour of siponimod ingestion were compared to the values prior to siponimod ingestion.

Results

After treatment initiation, there was a statistically significant drop in HR (71.1±9.2 to 66.3±8.1, p<0.001) and elevation of systolic blood pressure (sBP) (113.2±12.4 to 117.1±10.8, p=0.04). Values of the diastolic BP (dBP) followed similar trend as did sBP, however not reaching statistically significance (72.8±9.6 to 74.9±8.3, p=0.13). In a multivariable regression model, disease duration and standard deviation of NN intervals (SDNN) were identified as independent predictors for ΔHR, where increase in SDNN and longer disease duration predict smaller ΔHR. Normalized high frequency (HFnu) component was identified as negative predictor of increase in sBP and dBP.

Conclusions

ANS abnormalities may predict cardiovascular abnormalities associated with treatment initiation with siponimod.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0298 - Azathioprine as a disease-modifying therapy for multiple sclerosis.  Experience of department of Neurology: HASSAN II UHC of Fez; Morocco (ID 1012)

Speakers
Presentation Number
P0298
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

The therapeutic arsenal in the disease-modifying therapy of Multiple Sclerosis (MS), especially in its relapsing-remitting form, is becoming richer, particulary with new oral medications. In many countries, azathioprine is still used as a first-line treatment for MS, mainly for its low cost, but also for its tolerance and its effectiveness.

Objectives

Report the experience of the neurology department of the University Hospital in Fez in the management of multiple sclerosis by the use of Azathioprine as first line disease-modifying therapy.

Methods

Retrospective study collecting 78 patients followed in the neurology department of Hassan II UHC of Fez for MS and who were treated with Azathioprine, from 2010 until May 2020.

Results

Since 2010, a total of 78 MS patients followed in the Neurology department have been receiving Azathioprine as a disease-modifying therapy. The average age of the patients was 44 years, predominantly female. 83% of patients had relapsing-remitting MS while 17% had a progressive form. The duration of treatment varies between 1and 10 years. The mean EDSS at starting Azathioprine was 3.5. Hematological complications was noted in 14 %, such as lymphopenia in 7 cases, neutropenia in 2 cases, and pancytopenia in 2 cases. Only one patient, after 3 years of treatment with azathioprine, developed a serious adverse event "Macrophage activation syndrome". One patient presented with a moderate disturbance of the hepatic balance and another presented banal digestive disorders. Only 3 cases changed their disease-modifying therapy because of the side effects. The progress of patients taking Azathioprine was marked by clinical and radiological stability in 76%, while 14% developed relapses and 10% progressed. Therapeutic escalation was towards Rituximab for 9 patients and cyclophosphamide for 1 case.

Conclusions

Azathioprine is an appropriate treatment for MS, and a good alternative in low-income countries. But its use requires vigilance to avoid complications including the long-term risk of malignancy.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0299 - Balo’s concentric sclerosis successfully treated with Alemtuzumab (ID 683)

Speakers
Presentation Number
P0299
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

Balo’s concentric sclerosis is often regarded as a rare variant of multiple sclerosis (MS) and is characterised by concentrically multi-layered ring-like lesions in the cerebral white matter. Despite pathological overlap with MS, the effect of disease modifying therapies is unclear.

The only existing case report of Alemtuzumab in Balo’s concentric sclerosis described a lack of clinical response in a patient with Balo’s concentric sclerosis who had previously not responded to corticosteroids, plasma exchange and cyclophosphamide. The authors did speculate that Alemtuzumab may have been more effective if started earlier in the disease process.

Objectives

We present the imaging and clinical outcomes of a patient with Balo’s concentric sclerosis who was successfully treated with Alemtuzumab over a period of 3 years.

Methods

A 54 year old nurse with no prior history of neurological symptoms presented with a 2 day history of expressive dysphasia and subacute onset of right hemiplegia. MRI of the brain revealed a large enhancing lesion in the white matter of the posterior temporal lobe measuring 29.5mm in maximal diameter with a complex layered enhancement pattern. There were also non-enhancing lesions present in the periventricular and deep white matter with an appearance typical of demyelination due to multiple sclerosis. CSF examination revealed positive oligoclonal bands. Anti-aquaporin-4 IgG and MOG-IgG were negative. A diagnosis of Balo’s concentric sclerosis was made, and she was treated with intravenous and oral steroids, followed by Alemtuzumab.

Results

Clinically her speech and weakness gradually improved and she is now symptom free. She has had no further relapses. Radiologically the Balo’s lesion ceased to enhance and reduced in size and T2 hyperintensity gradually. She has had no new or enlarging T2 lesions.

Conclusions

We present the second case report of the use of Alemtuzumab in Balo’s concentric sclerosis. Our patient has enjoyed a good outcome with resolution of symptoms, and a period of freedom from relapse and radiological activity. Alemtuzumab may be effective in the treatment of Balo’s concentric sclerosis if started early.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0300 - Baseline features in DISCOntinuation of disease modifying therapies in Multiple Sclerosis (DISCOMS) (ID 791)

Speakers
Presentation Number
P0300
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

New relapses and magnetic resonance imaging (MRI) abnormalities diminish as people age with multiple sclerosis (MS). Data supporting use of disease modifying therapies (DMTs), from studies with typical inclusion ages of 18-55, suggest diminished benefit in older compared with younger individuals. Whether it is beneficial to continue, or safe to discontinue, DMTs as people age beyond 55 remains unknown. Retrospective studies show those at greatest risk of new inflammatory disease activity upon DMT discontinuation are younger and had recent new relapse and/or MRI scan activity.

Objectives

Present the design and baseline data in our study evaluating whether older individuals with MS who discontinue their DMT have no worse risk of new disease activity compared to those who remain on DMT.

Methods

This is a randomized (1:1), controlled, rater-blinded study in which 260 MS participants aged 55 and older and continuously taking DMTs (at least 5 years, minimum 2 years on current DMT) were enrolled at 19 sites in the United States. They have no evidence of MS relapse for 5+ years or new MRI lesion for 3+ years, and will be followed for up to 2 years, with study visits every 6 months. Primary outcome is either a new MS relapse or T2 brain MRI lesion. Secondary outcomes are 6-month confirmed increase in Extended Disability Status Scores (EDSS), and worsening of Symbol Digit Modality Test or patient-reported outcomes.

Results

Mean age of participants is 63 ± 5 years, and 83.7% are female. Racial/ethnic breakdown is 89.2% White, 9.2% Black or African American, 0.8% Hispanic/Latino, and 0.8% Other. Participants average 22.3 ± 10.5 years since symptom onset, and 13.5 ± 7 years since last relapse. Most have Relapsing-Remitting MS (83.7%), with 13.1% Secondary Progressive and 3.2% Primary Progressive MS. At enrollment, 42.6% were on an interferon, 30.3% on glatiramer acetate, 15.1% dimethyl fumarate, 6.4% fingolimod, 3.2% teriflunomide, 1.6% natalizumab, and 0.8% ocrelizumab. EDSS scores average 3.3 ± 1.8, and 77.8% of participants rate their treatment satisfaction as Satisfied or Very Satisfied at enrollment.

Conclusions

The DISCOMS study is the first controlled trial to address whether it is safe to discontinue DMTs in MS. Enrolled participants represent a unique cohort of stable, older MS patients with relatively low disability. Upon completion, the study will increase our understanding of the utility of MS DMTs throughout the lifespan of MS.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0301 - Beyond pivotal trials inclusion criteria: real world clinical profile of multiple sclerosis patients under disease modifying treatment in Argentina. (ID 851)

Abstract

Background

Background: In multiple sclerosis (MS), randomized controlled trials (RCT) have provided relevant information about the efficacy and safety in ideal scenarios. While RCT are powerful tools for developing scientific evidence based on their high internal validity, there is always uncertainty about the generalizability, especially since the populations enrolled in such studies may differ in significant ways from those seen in clinical practice.

Objectives

Objective: to describe the frequency and clinical profile of MS patients under disease modifying treatment in Argentina that would have not fulfilled inclusion criteria in RCT.

Methods

Methods: MS patients included in the Argentinean MS and NMOSD registry (RelevarEM, NCT 03375177) were analyzed. RelevarEM is a longitudinal, strictly observational MS and NMOSD registry in Argentina. From May 2018 to March 2020, the centers and principal investigators were contacted and incorporated into the Registry. All patients with definite MS and receiving DMT at 31 December 2019 were screened, those with EDSS >6, phenotypes secondary progressive (SP) and primary progressive (PP)(with other DMT than ocrelizumab) and age <18 and >55 years old were included in the analysis.

Results

Results: A total of 1782 patients with MS receiving DMT were screened, of whom 465 (26%)would not have been included in a pivotal trial. From the 465,218 had and EDSS >6, 67 had phenotype SP and 19 PP; 292 were patients with <18 and >55 years of age (2 under 18 years old). Most prescribed DMT among patients with EDSS >6 was fingolimod (31%), among age >55 was beta interferon (35%), phenotype SP fingolimod (30%) and PP fingolimod and glatiramer acetate (each 26%).

Conclusions

Conclusion: in our registry, we found a significant number of MS patients who would have not been included in pivotal trials, receiving DMT. Real life evidence is highly relevant to assess effectiveness as well as safety of DMT in this subset of patients.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0302 - Bruton tyrosine kinase inhibitor suppresses disease progression in Thieler’s Murine Enchephalomyelitis Virus mouse model of multiple sclerosis (ID 1429)

Speakers
Presentation Number
P0302
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

Ibrutinib is a Bruton Tyrosine Kinase inhibitor (iBTK) treatment which binds with target protein to arrest B cell development and decrease microglia activation. The Theiler’s Murine Encephalomyelitis Virus (TMEV) infection induces an immune-mediated chronic multiple sclerosis (MS) like disease of the central nervous system. Hence, we hypothesized that iBTK treatment will suppress the TMEV pathology.

Objectives

We studied clinical disability, motor learning and spinal cord lesion load in TMEV-infected animals in response to iBTK (ibrutinib) treatment. Our goal was to assess the effect of iBTK on TMEV induced disease pathology and disability.

Methods

Twenty six 8-11 week old mice were bilaterally, intra-cerebrally injected with TMEV and equally divided into iBTK (n=13) or vehicle control (n=13) treatment groups. Daily treatment with iBTK at 6 mg/kg started at 1 month post induction (mPI). Clinical disability score (CDS) on a 5 point scale, body weight and rotarod performance were recorded at 1 to 5 mPI. Half of the study animals were sacrificed at 3 mPI and their spinal cord tissue lesion load was analyzed with Iba1 microglia staining. TMEV infection was confirmed using ELISA on blood plasma. CD19 expressing B cell fraction of peripheral blood mono-nuclear cells was measured.

Results

ELISA confirmed that all TMEV injected mice produced anti-TMEV antibodies. Furthermore, CD19 expressing B cell fraction was significantly reduced in iBTK treated mice (6.65±1.92%) relative to vehicle treated mice (12.51±2.34%) (p = 0.0428, T test). IBTK significantly improved longitudinal changes in CDS (p<0.001), body weights (p = 0.033) and rotarod latency measures (p=0.0477) in treated TMEV mice (repeated measures ANOVA). Additionally, Iba1 staining showed that TMEV animal spinal cord lesion area was significantly lower in white matter regions (p = 0.016, T test) and was trending lower in grey matter regions (p = 0.107, T test) in iBTK treated animals relative to vehicle treated mice.

Conclusions

BTK inhibition decreased B cell fraction and microglia activation in treated TMEV mice, resulting in lower lesion load of spinal cord tissue. Consequently, iBTK restricted TMEV disease induced clinical disability, body weight loss and motor dysfunction. To further characterize the impact of iBTK on MS disease pathology, future studies will assess neuro-degenerative immune cells and immune cell infiltration using neuroimaging.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0303 - Calculated steroid dose needed for multiple scleroses relapses (ID 1456)

Speakers
Presentation Number
P0303
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Glucocorticoid (GC) pulse therapy is used for Multiple Sclerosis (MS) relapse treatment. At the same time GC resistance often mandates timely introduction of plasma exchange (PLEX). There are yet no well established predictors for the GC dose needed to treat MS relapses.

Objectives

The aim of this study is to establish a predictive model basing on clinical data to support clinicians in estimating the maximum GC dose above which no additional therapeutic value can be expected.

Methods

We retrospectively screened clinical registries at University Hospital Bern and Ruhr University Hospital Bochum for MS patients treated with GC. We performed a multivariate regression analysis with GC dose as dependent variable and Vitamin D (25D) level, sex, age, expanded disability status scale (EDSS), contrast enhancement on cranial and/or spinal MRI, immunotherapy and clinical involvement of optic nerve as independent variables.

Results

In this explorative cohort, 113 MS patients were included (Bern/Bochum: n = 63/47). Our model in total significantly predicted GC dose, however within the independent variables only 25D serum concentration and presence of optic neuritis were independent predictors of the GC dose needed to treat the present MS relapse ([25D]: -25.95 (95% CI: -47.40 - -4.49), p=0.018; optic neuritis: 2040.51 (95% CI: 584.64 – 3496.36), p=0.006).

Conclusions

Considering that GC dosing appears to be individual with several response-influencing factors, we established a predictive model, which supports clinicians to estimate GC dose needed to treat MS relapses. A second validation cohort is needed to proof our analysis.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0304 - Can the induction of thyroid autoimmune antibodies after alemtuzumab treatment predict secondary autoimmune thyroid disorder? (ID 663)

Speakers
Presentation Number
P0304
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Alemtuzumab (ALZ) belongs to the immune reconstitution therapies for relapsing-remitting multiple sclerosis (RRMS). ALZ therapy is associated with an increased risk for secondary autoimmune diseases (SAD), in particular autoimmune thyroid disorders (AITD).

Objectives

To investigate if the occurrence of thyroid auto-antibodies (Ab), after initiating ALZ treatment, could predict the development of AITD.

Methods

All RRMS patients in Sweden initiating ALZ (n=124, 74 females) 2014-2019, were consecutively included in this prospective observational study. Plasma samples were obtained prior to ALZ and at 6, 12 and 24 months of follow-up for analyses of thyroglobulin Ab (TgAb), thyroperoxidase Ab (TPOAb) and thyrotropin receptor Ab (TRAb). Monthly serum samples for free thyroxin and thyroid stimulating hormone, as well as clinical symptoms were followed to detect AITD.

Results

At mean follow-up of 4.5 (SD 1.6) years 50 patients (40%) had developed AITD (43 Graves’ disease). Mean time from baseline to AITD was 2.1 (SD 1.6) years, in 62 % the development of thyroid Ab preceded AITD. At baseline 5% (n=6/114) patients had positive TRAb, 3% (n=3/115) positive TgAb, and 3% (n=3/115) positive TPOAb. Corresponding values at 6 months were 3% (n=2/78), 6% (n=5/85), 5% (n=4/86), at 12 months 14% (n=14/102), 15% (n=15/102), 18% (n=18/102), and at 24 months 22% (n=16/73), 19% (n=15/78), 23% (n=18/78). No treatment was given for AITD in 4% (n=2/50), 14% (n=7/50) had levothyroxine (L-T4) only, 36% (n=18/50) high dose anti-thyroid drug (ATD) with L-T4, 34% (n=17/50) thyroidectomy, 4% (n=2/50) ATD alone, 2% (n=1/50) radioactive iodine and for 6% (n=3/50) data were missing. Mean time from detection of auto-Ab to diagnosis of AITD was 4 (SD 11.3) months. At baseline 9 patients had thyroid Ab, but only those with TRAb (n=3) developed AITD. The OR for AITD was 1.51 given TRAb compared to those with no TRAb at baseline. At 24 months, 27 patients were positive for either of the thyroid Ab, 93% (25/27) of these developed AITD. In contrast, only, 30% (15/51) of those thyroid Ab negative developed AITD (p<0.0001 x2- test).

Conclusions

AITD was developed in 40% of ALZ treated patients, at 24 months 21% had AITD which was similar with that reported from the pivotal studies of ALZ. Thyroid Ab preceded AITD in 62 % of cases. In contrast, the risk of AITD was low in cases without thyroid Ab. Although, monitoring thyroid Ab may be useful identifying patients at high risk for AITD, this has not so far had any therapeutic incentives.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0305 - Can We Predict Ocrelizumab Super Responder Status in Relapsing Remitting Multiple Sclerosis Patients? (ID 1903)

Speakers
Presentation Number
P0305
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Ocrelizumab (OCR), an anti-CD20 humanized monoclonal antibody, was approved by the FDA for treatment of relapsing-remitting multiple sclerosis (RRMS) in March 2017. We hypothesize that due to inherent biological variability present in individuals, patients’ response to OCR therapy will vary, with a subset appearing to be super responders (SR) when compared to the remaining population (RP).

Objectives

To categorize the response of patients after initiation of OCR therapy into SR or RP based on the following criteria: 1) rapid improvement in symptom profiles, including mobility, and/or neurological exam findings, 2) relapse free disease course, and 3) MRI stabilization throughout treatment. The SR will be characterized to determine if certain covariates distinguish this group from the RP.

Methods

A retrospective chart review was conducted of patients who had completed at least two courses of OCR therapy by July 2019. Eligible subjects were identified using the electronic health record. Patient demographics and medical history including disease duration and prior disease modifying therapy were collected. Patients were categorized into groups (SR vs RP) based on neurological findings, MRIs, and relapse rates as described above. Covariates including patient demographics and lab values (IgG, IgM, IgA, CD3, CD4, CD8) from the initiation of OCR through duration of treatment were analyzed.

Results

Of the 135 eligible patients, 13 (9.6%) were classified as SR. Of the covariates examined, SR exhibited significantly higher mean IgG levels when initiating OCR (p = 0.0448) and maintained higher IgG levels throughout their treatment (Course 1 p = 0.011, Course 2 p = 0.018). SR were younger, median age of 42 years, compared to the RP, median age of 51 years (p =0.14). SR maintained greater stability in IgM levels than the RP (p = <0.0001). SR were more likely to have been crossed-over over from oral therapies than infusions or injectables (p = 0.02).

Conclusions

At a single site, OCR SR tended to be younger with higher baseline IgG and greater IgG resiliency throughout therapy. Consideration of these factors may be of assistance when assessing a patient for OCR therapy.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0306 - Cardiovascular monitoring during alemtuzumab infusion in Multiple Sclerosis patients (ID 1880)

Speakers
Presentation Number
P0306
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Alemtuzumab (AL) is a monoclonal antibody approved for Relapsing Remitting Multiple Sclerosis (RRMS). Infusion adverse events (AEs) are common during AL administration. AL administration protocol was revised in 2019 by regulatory agencies due to serious cardiovascular (CV) AEs. The new recommendations included at least hourly measurement of vital signs (VS) during infusion, daily electrocardiogram (EKG) before infusion, and contraindication in patients with previous CV comorbidities.

Objectives

To describe changes in VS and EKGs recordings in a cohort of RRMS patients during the first AL cycle treated at the same MS Center.

Methods

Since 2015, when AL was approved for MS in Italy, we consecutively monitored our patients for VS before and every 30 minutes during AL administration lasting at least 5 hours; EKGs were recorded daily before premedication. Methylprednisolone, chlorphenamine, acetaminophen, were given as premedication with ranitidine or omeprazole. We collected heart rate (HR), systolic (SBP) and diastolic blood pressure (DBP) after premedication, before AL infusion and every 60 minutes thereafter up to hospital discharge. Bradycardia was defined as HR<60 bpm or HR<20% if patient had bradycardia at day 1 admission. HR<45 bpm was the cut-off for clinically relevant bradycardia. Data about clinical history, comorbidities, and concomitant medications were collected.

Results

From June 2015 to November 2019, 47 (31 female) RRMS patients received the first AL course. At baseline mean age was 20.1(±8.1) years, disease duration 5.5(±5.5) years and EDSS 2 (0-4.5). 4 patients had CV comorbidities (2 hypertension, 2 premature ventricular contraction). A total of 153 EKGs were analyzed. We observed 30 non-specific repolarization abnormalities and 18 inverted T waves. Bradycardia was reported in 24 EKGs (20/24 at day 4 and 5). Bradycardia was recorded in 45/229 infusions. 24 patients showed at least 1 episode of bradycardia, 16/47 had clinically relevant bradycardia. SBP showed an increasing trend starting from the third day, but still within normal limits.

Conclusions

Our data support the need for accurate monitoring of AL infusion. AL administration was rarely associated with clinically relevant CV. Nevertheless, bradycardia was frequently recorded even though usually asymptomatic. Careful monitoring should be continued for the whole protocol of AL infusion since CV events can be observed independently from the expected early infusion-related reactions likely associated to cytokine release.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0307 - Changes in immune blood cells in patients on teriflunomide treatment (ID 1041)

Presentation Number
P0307
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

Teriflunomide, is an approved treatment for relapsing-remitting multiple sclerosis (RRMS) . The mechanism of action is not fully elucidated yet.

Objectives

The main goal of this study was to identify the changes in blood immune cells in clinical practice that can predict a better response to treatment.

Methods

RRMS patients who initiated teriflunomide treatment were included in the study. We studied peripheral blood cells obtained before and 6 months after treatment initiation.

Patients were classified in two groups: no evidence of disease activity (NEDA) or ongoing disease activity (ODA) after a year of follow-up.

Wilcoxon matched pair tests were used to assess differences between basal and 6 months after treatment results. Correlations were assessed by Mann–Whitney test. P-values below 0.05 were considered as significant.

Results

A total of 51 RRMS patients (31 females and 20 males) were included in this study. The mean age at the start of teriflunomide was 41 years. Baseline EDSS was 1.80. 18 patients were treatment naive, 15 switched from interferon-β, 15 from glatiramer acetate and 3 from experimental treatments. After a year on teriflunomide treatment, 35 patients showed NEDA and 16 ODA.

We studied changes between basal and 6-month sample. We observed a decreases for the lymphocytes, 75% for ODA (p = 0.004) and 57.14% for NEDA (p= 0.034). They showed a clear decrease for leukocytes 75% for ODA (p = 0.021) and 71.43% for NEDA (p= 0.047). We observed a moderate increase of monocytes in NEDA patiens 40% (p =0.314) and mild increase of monocytes in ODA patients 25% (p = 0.755).

Conclusions

We observe that teriflunomide induces changes in blood immune cells. It was shown a decrease in leukocytes and lymphocytes in both groups and a moderate increase in monocytes in patients with NEDA that we did not find in ongoing disease activity patients.

We did not find a statistically significant correlation between analytical values ​​and response to treatment.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0308 - Changing patterns of first line and first switch ocrelizumab use in the United States: Analysis of subtype, gender, age, and disability (ID 558)

Speakers
Presentation Number
P0308
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

Use of disease-modifying therapies (DMTs) for the treatment of multiple sclerosis (MS) is driven by many factors that are not well understood. In March 2017, ocrelizumab (OCR), an intravenous humanized anti-CD20 monoclonal antibody (mAb), was approved in the United States for the treatment of relapsing-remitting MS (RRMS) and primary progressive MS (PPMS).

Objectives

To examine whether the type of MS patient being treated with OCR first line or as a first switch is changing over time in the United States.

Methods

Cross-sectional MS patient-level data were collected once-yearly from practicing United States neurologists from 2017 to 2020. Contributed chart review data were from MS patients either initiating their first DMT (2017 n=1,033; 2018 n=1,059; 2019 n=1,006) or switching to a new DMT (2018 n=1,035; 2019 n=1,003; 2020 n=1,009) within the prior three months. Analyses focused on new OCR starts (2017 n=70; 2018 n=107; 2019 n=102) and first switches to OCR (2018 n=60; 2019 n=85; 2020 n=90). Relapsing forms of MS (RMS) is defined as clinically isolated syndrome and RRMS.

Results

Overall use of OCR in treatment-naïve MS individuals has increased since 2017, with a decrease in PPMS offset by an increase in RMS. By 2019, OCR was the initial DMT choice in 7% of RMS individuals, while use decreased from 63% in 2017 to 35% of PPMS. Of all new OCR DMT starts evaluated in 2019, RMS made up 58% and PPMS 31%. OCR starts are increasingly female, with 65% of 2019 new start use among female MS patients. This pattern is seen for both RMS and PPMS, although is more marked for PPMS. Mean age of MS patients initiating OCR has decreased by 4.6 years since 2017. OCR use in those aged ≥56 years has fallen to 12% compared to 31% in 2017. Mean Expanded Disability Status Scale (EDSS) score decreased in the PPMS cohort who initiate OCR therapy, but increased in the RMS cohort.

Among MS individuals who made a first switch to OCR in 2018-2020, more switches were among RMS patients compared to PPMS. Switches to OCR are now most likely from first-line glatiramer acetate (GA; 39%), followed by dimethyl fumarate (18%). Switches from interferon beta have decreased from 33% to 17%. In PPMS, the second most common switch is from another mAb therapy to OCR (accounting for 24% of 2020 switches up from 11% of 2018 switches). First switches to OCR are increasingly among female MS patients (2020: 64% vs. 2018: 50%), especially among PPMS patients. Mean age and EDSS score have not changed significantly over time when assessed by total, MS subtype, or gender.

Conclusions

OCR initiation as a first-line agent is on the rise, driven by increased use among RMS patients, and is being used in younger MS individuals. First-line OCR use in females with PPMS has increased over time. Initial switches to OCR are increasingly coming from GA. The usage pattern of OCR in the United States is evolving and changing over time.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0309 - Cladribine is a safe and effective treatment for highly active relapsing-remitting multiple sclerosis (ID 423)

Speakers
Presentation Number
P0309
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Cladribine is a novel disease-modifying therapy (DMT) that has recently been licensed for the treatment of highly active relapsing-remitting multiple sclerosis (rrMS) in Scotland. Lymphocytopaenia (LLC) was reported as the main side-effect of this treatment, in clinical trials.

Objectives

1. Determining the real-world incidence of adverse effects of cladribine

2. Assessing the temporo-spatial likelihood of adverse effects

3. Commenting on current practice for monitoring and managing adverse incidents.

Methods

A retrospective cohort analysis of 120 patients prescribed cladribine, over four health boards in Scotland, assessed the incidence of adverse effects at 1 and 2 year intervals, by examination of patient notes, documented self-reported patient comments and follow-up blood monitoring results.

Results

It is affirmed that LLC is the main adverse effect of cladribine, occurring in around 68% of patients following receipt of the first treatment cycle and 75% following receipt of the second. Mild to moderate LLC (Grades 0-2) was present in 84% of LLC patients within treatment year 1, but only 58% of LLC patients after year 2. The average lag to peak LLC is noted to be two to four months after first treatment (n patients = 75%) and similarly after the second (n = 66%), indicating the optimal time frame for routine follow-up screening.

Other adverse effects were noted in 25 patients (21%), most commonly fatigue (incidence = 0.07), hair loss (incidence = 0.05) and nausea (incidence = 0.03). Allergic-type reactions were also observed in 2% of patients, but these were mild and treatable, without interruption to therapy. All patients in this cohort had adequate V. zoster pre-screening and prophylaxis. Treatment continuation was disrupted in 31% of patients due to COVID-19.

Conclusions

Adequate infection prophylaxis and counselling are noted to be key aspects of preassessment. Treatment is interrupted where no adequate protection can be provided. It is essential to ensure adequate lymphocyte populations, via routine screening and follow-up monitoring, before treatment initiation or progression. Shielding of cladribine patients from COVID-19 or similar may be indicated for up to 6 months after treatment, covering the nadir of LLC.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0310 - Cladribine tablets in patients with RRMS and active SPMS after suboptimal response to prior DMD (MASTER-2 and CLICK-MS): initial baseline demographics (ID 129)

Speakers
Presentation Number
P0310
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

Although the efficacy and safety of cladribine tablets (CT) 10 mg (3.5 mg/kg cumulative dose over 2 years [yrs]) have been shown in patients (pts) with relapsing forms of multiple sclerosis (MS) in Phase 3 trials, real world data are limited.

Objectives

To examine real-world effectiveness, safety, and pt reported outcomes (PROs) in pts with relapsing-remitting MS (RRMS) and active secondary progressive MS (SPMS) who transition to CT after suboptimal response to prior disease-modifying drugs (DMDs).

Methods

MASTER-2 and CLICK-MS are single arm, observational, 30-month (mo), Phase 4 trials in the US (Timeline: 2019–2023). Eligible pts are adults with RRMS or active SPMS, with suboptimal response to an oral/infusion (MASTER-2) or injectable (CLICK-MS) DMD, meeting criteria for CT 3.5 mg/kg treatment (US Prescribing Information). The primary outcome is 24-mo annualized relapse rate (ARR). Key secondary outcomes are PROs, treatment adherence and satisfaction, ARR in prior 24 mos, MS treatment pattern prior to transition and follow-up if CT are discontinued, and adverse events (AEs). Planned enrollment per study is 200 pts across 50 sites.

Results

Pt enrollment is ongoing for both trials. As of May 2020, 52 pts (mean [standard deviation {SD}] age: 50 [10.6] yrs; 75% female) have baseline data available in MASTER-2 (data not shown for CLICK-MS). Mean (SD) time since diagnosis was 11.8 (7.71) yrs. Most recent DMDs used included teriflunomide (23.1%), dimethyl fumarate (23.1%), fingolimod (19.2%), ocrelizumab (13.5%), natalizumab (9.6%) and alemtuzumab (1.9%). Sixteen pts had 21 relapses within 24 mos prior to enrollment (mean [SD] ARR: 0.21 [0.351]). Mean (SD) baseline PRO scores before starting CT were 50.7 (25.11) for 14-Item Treatment Satisfaction Questionnaire for Medication (Global Satisfaction), 50.0 (9.57) and 41.4 (11.56) for 36-Item Short Form Health Survey (mental and physical component summaries, respectively), 1.4 (1.71) for Beck-Depression Inventory-Fast Screen, 8.9 (4.79) for the Fatigue Impact Scale, and 2.7 (2.31) for Patient Determined Disability Steps scale. Thirty-six treatment emergent AEs (2 serious, but unrelated) were seen in 12 pts in 9.97 pt-yrs to date. Additional MASTER-2 and CLICK-MS pt baseline data will be shown in the presentation.

Conclusions

These studies will report real-world effectiveness and safety data of cladribine tablets in pts with RRMS and active SPMS with suboptimal response to prior oral, infusion, or injectable DMDs.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0311 - Decoding Bruton’s tyrosine kinase signalling in neuroinflammation (ID 1381)

Speakers
Presentation Number
P0311
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

Neuroinflammation in the brain and spinal cord, driven largely by CNS-resident microglia, has been proposed as a significant contributor to disability accumulation in patients living with multiple sclerosis (MS). Bruton’s tyrosine kinase (BTK) is expressed in microglia, as well as in B lymphocytes and monocytes/macrophages found in the periphery. In B cells, this kinase is an essential component of the B-cell receptor signalling pathway regulating proliferation, maturation, antigen presentation, and production of secreted immunoglobulins. We hypothesize that in addition to its role in B cells, BTK regulates microglial deleterious inflammatory signalling; therefore, inhibiting BTK with a brain-penetrant inhibitor may provide therapeutic benefit within the CNS by targeting innate immunity associated with disease progression in MS.

Objectives

To assess the role of BTK signalling in modulating inflammatory processes in microglial cells both in vitro and in vivo.

Methods

Immunohistochemistry, Western blotting, and RNA sequencing monitored BTK or phospho-BTK in primary mouse microglial cells, the rodent model of cuprizone-mediated demyelination, and post-mortem MS brain tissues.

Results

Basal activity of BTK in murine microglial cells in vitro was enhanced by stimulation with immune complexes and silenced with a BTK inhibitor. Transcriptome analysis was used to generate a BTK-dependent transcriptional signature in microglia. In tissue derived from autopsy specimens, immunohistochemistry studies and single-nucleus RNA sequencing demonstrated that BTK was expressed in B cells as well as in microglial cells, with increased levels in MS lesion samples. To further explore the role of BTK in vivo, we identified a BTK-dependent transcriptional profile in brains from cuprizone-treated mice. Oral administration of a brain-penetrant BTK inhibitor downregulated the BTK-dependent gene expression signature in the cuprizone-treated mouse brain. Finally, using post-mortem tissue, we evaluated BTK-dependent activation signatures derived from mouse models in MS samples.

Conclusions

Using the cuprizone-induced toxicity model, we extend our previous findings on the role of BTK in microglia to show that BTK-dependent inflammatory signalling in these cells can be modulated using brain-penetrant BTK inhibitors in vivo, which could abrogate microglia-driven neuroinflammation implicated in disease progression in MS.

STUDY SUPPORT: Sanofi.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0312 - Differential effects of dimethyl fumarate, monomethyl fumarate and cannabidiol in the activation of transcription factor Nrf2 in neurons and microglia (ID 361)

Speakers
Presentation Number
P0312
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

The Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that promotes the expression of antioxidant genes, protecting cells against oxidative stress and it also exerts immunomodulatory properties. The activation of Nrf2 is one of the proposed mechanisms of action of dimethyl fumarate (DMF), an approved drug for Multiple Sclerosis (MS).

DMF is rapidly metabolized into its active metabolite monomethyl fumarate (MMF) in the intestine. However, there is a lack of studies comparing the effects of both compounds. The combination of other Nrf2 activators could be relevant as adjuvants for DMF in neuroinflammation. Cannabidiol (CBD), a cannabinoid that attenuates MS in murine models, is known to have antioxidant properties, although there are no studies on Nrf2 activation by CBD.

Objectives

The aim of this study was to evaluate the in vitro effects of DMF, MMF and CBD on the activation of Nrf2 in neurons and microglia.

Methods

Primary hippocampal neurons and the microglial cell line BV-2 were treated for 4 hours with either vehicle, DMF (1-30 µM), MMF (1-30 µM) or CBD (1-10 μM). Cells were fixed, permeabilized and stained with a Nrf2 antibody. Activation of Nrf2 was considered as nuclear translocation, measured by confocal microscopy as the mean density of nuclear fluorescence. Five fields were taken from each condition in 3 experiments. One-way ANOVA test was used, considering p<0.05 statistically significant.

Results

DMF induced Nrf2 translocation in both neurons and microglia. However, Nrf2 translocation in neurons needed a higher dose (30 µM) than microglia (10 µM), and the induction was lower in neurons (four-fold increase) than in microglia (eight-fold increase). We did not find activation of Nrf2 with MMF in neither neurons nor microglia. CBD induced a dose-dependent Nrf2 activation in neurons, statistically significant at 6 and 7 μM, with a higher increase than that of DMF (8 and 12-fold compared to vehicle, respectively). CBD did not produce any effect on Nrf2 activation in microglia.

Conclusions

Our results support the idea that DMF acts as a neuroprotective and immunomodulatory drug through the activation of the Nrf2 pathway in neurons and microglia. We also demonstrate that DMF and MMF differ in their mechanisms of action, as we did not see Nrf2 activation with MMF. CBD could be relevant in neuroprotection as an adjuvant to DMF, as it induces a higher Nrf2 activation than DMF. CBD’s mechanism of action differs between neurons and microglia.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0313 - Dimethyl fumarate-induced changes in lymphocyte subpopulations could identify "NEDA" patients (ID 1433)

Presentation Number
P0313
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

The optimal response to dimethyl fumarate (DMF) is mediated by a shift to antiinflammatory and immunoregulatory profile. In a preliminary study of 22 patients with multiple sclerosis (MS) followed for 12 months, we observed that, at 3 months of treatment, patients with "No evidence of disease activity (NEDA)" had a decrease in the Th1-like Th17 effector memory subpopulation.

Objectives

To analyze the long-term effect of DMF on the lymphocyte subpopulations of MS patients and its relationship with the activity of the disease.

Methods

Ongoing longitudinal prospective study in MS patients undergoing DMF treatment. A panel of T and B lymphocyte subpopulations in peripheral blood is analyzed by flow cytometry. Patients with a complete follow-up of more than 1 year are classified as: NEDA, MEDA (minimal clinical or radiological activity) or EDA.

Results

To date, 48 patients have been analyzed. After a 2.66 (1-5) years follow-up, we find 39.6% in NEDA, 25% in MEDA, and 16.7% in EDA.

The changes induced on the subpopulations (increase T [CD4 and CD8] and B naïve, and decrease T central memory (CM) and effector memory (EfM), and B memory) remain stable in the long term (> 2 years), being most prominent in NEDA patients. In these, lower percentages of Th1 CM and EfM pre-treatment (p = 0.009, p = 0.002), as well as of Th1, Th17 and Th1-like Th17 CM (p <0.001, p = 0.002, p = 0.012) and Th1 and Th17 EfM (p <0.001, p = 0.034) during the first 12 months of treatment are found. MEDA patients appear to behave like EDA patients in changes in Th1/Th17/Th1-like Th17.

Conclusions

The changes induced by DMF on the lymphocyte subpopulations remain stable over time. NEDA patients have an immunophenotype that seems to identify them. Immunomonitoring detects the true biological effect of the treatments.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0314 - Dimethyl fumarate-induced lymphocyte count drop is related to clinical effectiveness in relapsing-remitting multiple sclerosis (ID 853)

Speakers
Presentation Number
P0314
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

Dimethyl fumarate (DMF) is an effective treatment for relapsing-remitting multiple sclerosis (RRMS) patients. Besides a partially known mechanism of action involving both neuroprotective and antioxidant effects, it causes a mean lymphocyte count drop of approximately 30%, typically occurring within the first year of treatment. Several studies investigated the relationship between this reduction and DMF effectiveness, with heterogeneous methods, obtaining contradictory results.

Objectives

To investigate if absolute lymphocyte count (ALC) decrease during DMF treatment is associated with drug effectiveness on clinical and MRI disease activity in a real-life cohort of patients treated with DMF for at least 6 months. Secondary aims were to evaluate ALC variations over time and the impact of baseline demographic and clinical factors on DMF-induced lymphopenia.

Methods

Demographic, laboratory, clinical and MRI data were collected in this retrospective, observational multicentre study, conducted on RRMS patients attending nine MS centers of Emilia-Romagna region (Northern Italy). Multivariate Cox models were performed to evaluate the impact of six month-ALC drop on time to NEDA-3 (“no evidence of disease activity”) status loss and Kaplan-Meier curves were generated to display the results. Multivariate logistic regression was carried out to analyse possible predictors of lymphopenia.

Results

476 patients (312 females, age at DMF start 38.4 ± 9.97 years) were analysed during a mean follow-up time of 29 months (range 6-61 months). A greater lymphocyte decrease was associated with a longer NEDA-3 status (HR 0.87, p = 0.01), relapse-free (HR 0.85, p = 0.03) and MRI activity-free survival (HR 0.80, p < 0.0001). A higher risk of NEDA-3 status loss (p=0.008) was observed in tertile with lower ALC drop (< 11.5%), compared with other tertiles (11.5-40.5% and >40.5% ALC drop, respectively). A shorter activity-free survival was also influenced by younger age at DMF start (HR 0.98, p = 0.03). The nadir of mean ALC drop (-33.6%) and 35% of grade III lymphopenia cases occurred after 12 months of treatment. An older age at DMF start (OR 1.03, 95% CI 1.00-1.06, p = 0.009) and lower ALC at baseline (OR 1.69, 95% CI 1.34-2.14, p < 0.0001) predicted higher risk of lymphopenia.

Conclusions

A higher lymphocyte count drop at six months is related to better outcomes in DMF-treated patients. A careful ALC monitoring should be pursued up to 24 months of treatment.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0315 - Disease modifying therapies in patients with aggressive MS (ID 1510)

Speakers
Presentation Number
P0315
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

There is a growing need to identify the course of aggressive multiple sclerosis (agMS) at an early stage so that affected patients can be treated with suitable disease modifying drugs (DMD). Investigations of treatment patterns in agMS and non-agMS patients are of interest, particularly in the context of the multitude of agMS definitions.

Objectives

We aimed to determine characteristics of DMDs at baseline for comparative analyses of agMS patients and non-agMS patients.

Methods

We included patients from the German Multiple Sclerosis registry who started DMD use between 2010 and 2020 and were assessable on whether they are agMS patients according to a commonly used criterium of reaching EDSS ≥6.0, or by a criterium for highly active MS, i.e. ≥2 relapses during 12 months, or gd+ lesions on MRI. Both were assessed within the first 5 years of disease duration.

Results

7249 patients fulfilled the inclusion criteria. Of these, 860 were identified as agMS. In agMS patients, Interferons (INFs) were the most frequently used DMDs with 34.8% followed by Glatiramer acetate (GLAT, 24.0%), Dimethyl fumarate (DMF, 15.8%), Teriflunomide (TRF, 7.6%), Natalizumab (NTZ, 5.4%), Fingolimod (FTY, 3.9%), Ocrelizumab (OCR, 3.2%), Steroids (STE, 1.8%), and others (3.5%). Regarding patients with non-agMS, INFs were also most frequent with 30.5% followed by GLAT (18.1%), DMF (13.2%), FTY (8.1%), NTZ (7.7%), TRF (7.5%), OCR (5.9%), STE (2.3%), and others (6.7%).

Within 5 years of disease duration, switches to another DMD were observed for 51% of agMS patients whereas only 17% of non-agMS switched to a second DMD. The average time spent on the first DMD was 1.3 (±1.1) years for agMS patients and 3.4 (±3.6) years for non-agMS patients (p<0.001; Mann-Whitney test). With regard to DMD use, significant differences between agMS and non-agMS patients were detected (p<0.001; χ2-test): INFs (p=0.009), GLAT (p<0.001) and DMF (p=0.03) were used significantly more often by agMS patients while FTY (p<0.001), NTZ (p=0.02) and OCR (p=0.002) were used more often by non-agMS patients.

Conclusions

Our analysis showed that in line with the (national) guidelines, the new immunomodulatory treatments are accessible to all MS patients. The patients classified as agMS spent less time on the first DMD than non-agMS patients did. To investigate causal factors in the connection between DMD preference and resulting disease progression, Marginal Structural Models are required, adjusting for relevant time-varying confounders such as patient demography, clinical visit details, MRI, and relapse parameters.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0316 - Dose-dependent tolerability of intravenous and subcutaneous ofatumumab in clinical studies (ID 1585)

Speakers
Presentation Number
P0316
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Ofatumumab, a fully human anti-CD20 monoclonal antibody with monthly 20 mg subcutaneous (s.c.) dosing regimen, demonstrated superior efficacy vs teriflunomide and a favorable safety profile in relapsing MS (RMS) patients in the Phase 3 ASCLEPIOS I/II trials. Prior studies evaluated the effect of >20 mg ofatumumab doses, s.c. and intravenous (i.v.), in both MS and rheumatoid arthritis (RA) patients. Injection/infusion-related reactions (IRRs) were the most frequently reported adverse events in these studies.

Objectives

To assess the dose-dependent tolerability of different ofatumumab doses (s.c. and i.v.) in both patients with MS and with RA.

Methods

For MS, data were pooled from ASCLEPIOS I/II, APLIOS (s.c. ofatumumab 20 mg, N=1873 including long-term data), Phase 2 dose-finding (i.v. ofatumumab 100 mg, N=12; 300 mg, N=15; 700 mg, N=11) and MIRROR studies (s.c. ofatumumab every 12 weeks [q12w]: 3 mg, N=34; 30 mg, N=32; 60 mg, N=34; 60 mg every 4 weeks [q4w], N=64). For RA, data were pooled from Phase 1/2/3 studies administered with atleast 1 dose of i.v. ofatumumab (300 mg, N=70; 700 mg, N=282; 1000 mg, N=64) up to Week 24. IRRs were reported within 24 hours of dose administration. Tolerability was measured as IRR-related drug interruption, discontinuation, severity and seriousness.

Results

In MS patients, the incidence of IRRs was lowest with s.c. 20 mg (23.2%) vs all other effective doses. The majority (99.8%) of IRRs with s.c. 20 mg were Grade 1/2 in severity. Grade 3 IRRs were lower with s.c. 20 mg (0.2%) vs all other doses (1.6–18.2%). No drug interruptions were observed across s.c. doses while the drug was interrupted (paused and restarted) in 41.7–72.7% patients with i.v. doses. A lower proportion of patients withdrew treatment with s.c. 20 mg (0.1%) vs other doses (1.6–6.7%). Serious IRRs were low with s.c. 20 mg (0.1%) vs 60 mg doses (q12w, 2.9%; q4w, 3.1%); none were reported with all other doses. Two serious IRRs (of 1873 patients) with s.c. 20 mg occurred at first injection, resolved without treatment withdrawal and with no recurrences. Cytokine release syndrome was reported in 3 patients (s.c. 60 mg q12w, n=1 [hospitalized for observation]; i.v. 300 mg, n=2 [non-serious]). In RA patients, the incidence of IRRs was higher with i.v. 1000 mg (at first infusion: 71.9%), vs 300 mg (55.7%) and 700 mg (36.9%). The majority of IRRs were Grade 1/2 in severity (95.2%), non-serious (96.9%) and subsided with treatment; 8.4% discontinued treatment due to IRRs.

Conclusions

Ofatumumab 20 mg s.c. was well tolerated compared to higher s.c. and i.v. doses. IRRs were predominant with first injection and similar to matching-placebo with subsequent injections. Most IRRs were non-serious and mild-to-moderate in severity. The IRRs were manageable with low withdrawal rate and recovered with symptomatic treatment, even in absence of premedication. For MS, low dose s.c. injections have a better tolerability profile with higher compliance.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0317 - Dual mode of action of siponimod in secondary progressive multiple sclerosis: A hypothesis based on the relevance of pharmacological properties (ID 1380)

Speakers
Presentation Number
P0317
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

Siponimod, a potent and selective sphingosine 1-phosphate (S1P1,5) receptor modulator, is the first oral disease-modifying therapy shown to reduce disability progression, cognitive decline, and total brain volume loss in secondary progressive multiple sclerosis (SPMS) patients. Recently presented data further suggest a favorable impact on more specific measures of neurodegeneration such as gray matter atrophy and myelin density assessed by magnetization transfer ratio. New preclinical insights further substantiate the dual mode of action (MoA) of siponimod demonstrating peripheral and central action targeting both inflammation and neurodegeneration.

Objectives

To propose a working hypothesis of a dual MoA for siponimod based on its unique specific pharmacological profile versus other S1P modulators.

Methods

Recent preclinical results with siponimod in pharmacokinetic/pharmacodynamic (PK/PD), mechanistic, and disease models were reviewed and placed in perspective.

Results

Preclinical data demonstrate that siponimod triggers S1P1-dependent anti-inflammatory effects on pathogenic lymphocytes and glial cells in the central nervous system (CNS), and S1P5-dependent promyelination effects on oligodendrocytes. Concomitant optimal S1P1- and S1P5-dependent effects are therefore required, in both blood and CNS compartments, for translation into clinical efficacy. Preclinical data indicate that the S1P1- and S1P5-dependent CNS effects follow non-classical pharmacology (“bell-shaped”), resulting in lowering of efficacy for agonists at supramaximal doses. This suggests an overall particularly complex drug dose-effect relationship. Recent preclinical PK/PD studies show that a CNS/blood drug exposure ratio (CNS/bloodDER) of ~6 allows siponimod to approach the top nadir of both S1P1- and S1P5-dependent dose-response curves in the blood and CNS compartments.

Hence, the CNS/bloodDER might be a key factor impacting therapeutic efficacy of an S1P-modulator. Fingolimod-phosphate has a higher CNS/bloodDER of 20–30, which might result in a potential therapeutic disadvantage compared to siponimod regarding S1P1- and S1P5-mediated CNS effects.

Conclusions

Preclinical findings show that siponimod has the pharmacological characteristics required for its dual S1P1/S1P5 MoA in both blood and CNS compartments, which may be of relevance for its clinical efficacy in SPMS. Translational and clinical studies are warranted to further validate this hypothesis.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0318 - Early monitoring of B cells on ocrelizumab may help to identify those at risk of adverse effects (ID 923)

Presentation Number
P0318
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Ocrelizumab (OCR) is a humanized anti-CD20 monoclonal antibody used in the treatment of MS. The drug targets CD20 and acts to reduce circulating B cells. Infection is a known adverse effect of treatment. It is not a requirement of the licence to monitor the effect of OCR on B cells counts and the relationship between B cell count and adverse effects is unknown.

Objectives

We aimed to assess the impact of OCR infusions on B cell counts in our patient group and whether there is a relationship between B cell count & adverse events such as infusion reactions or infections

Methods

Lymphocyte subsets were measured for each patient at baseline and before each subsequent infusion. Patients who had received OCR were identified from hospital records & lymphocyte subset results obtained from pathology reports. Date of infusions were noted and B cell data was correlated to determine average counts before or after each dose. Patient records were examined retrospectively to identify reports of adverse events including infection. These were then related to the degree of B cell suppression.

Results

170 people with MS (pwMS) received infusions of ocrelizumab from Sept 2018 to March 2020. Baseline B cell subsets were collected on 145 of these. The mean count ±SD was 279mm3 ±175 (range 44-1290) . Sampling was performed on average 92±62 days prior to dosing. 136 individual pwMS had sampling performed after the first infusion (194 samples in total). In 101 pwMS, between the first and second infusion, the mean B cell counts were 15mm3 ±32.6 . Samples were performed 171±40 days after the first infusion. In 32 pwMS sampled between second and third infusions, mean cell B counts were 13.9mm3 ±29.6 . Samples were performed 353±63 days after the 2nd infusion. In the naïve subgroup (n=10 vs n=71 not naive) there was a more significant drop in B cells 7.7 vs 18.6 (p=0.038) with treatment. However they did not experience more adverse effects. Adverse effects were seen in 54/83 subjects. 21/54 had infusion related reactions. 43 reported infections including herpes (1), cellulitis (1), gastroenteritis (6), upper (18) or lower respiratory tract (7), urinary tract infections (22) or other infection (8). In those who had adverse effects there was no difference in the B cell counts at baseline. However, those who developed infections had a significant reduction in B cells (infection 6mm3 vs no adverse effects 28mm3, p=0.045). This difference persisted after the second dose (infection 5mm3 vs no adverse effects 27mm3, p=0.19). There was however no difference in the absolute lymphocyte counts (p=0.8) , CD8 or NK cells.

Conclusions

This data suggests that regular monitoring of B cell counts, rather than absolute lymphocyte counts, may be a method of identifying those patients at risk of adverse effects, such as infection, following ocrelizumab.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0319 - Early Real-World Safety, Tolerability, and Efficacy of Cladribine Tablets: A Single Center Experience (ID 369)

Speakers
Presentation Number
P0319
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Cladribine tablets were recently approved for the treatment of RRMS based on evidence from Phase III trials. However, the real-world efficacy and safety of cladribine is unclear.

Objectives

To assess the early real-world safety, tolerability, and efficacy of cladribine tablets in relapsing-remitting multiple sclerosis (RRMS).

Methods

A retrospective chart review was performed to identify RRMS patients who initiated cladribine tablets prior to June 2019 at the MS Clinic in Toronto, Canada. Clinical features, reported side effects, lymphocyte nadir, and clinical/MRI disease activity after treatment initiation were collected.

Results

111 RRMS patients who initiated cladribine tablets were identified, of which 14%(n=16) completed the two annual treatment courses. The median follow-up time after cladribine initiation was 284 days (range 41-512). All patients were previously treated with DMTs with 51%, 25%, 24% on 1, 2, or >3 prior DMTs respectively. The most common reasons prompting the switch to cladribine were: persistent relapses or MRI activity (57%, n=63), intolerance to prior DMT/patient choice (19, n=21) or AE related to prior DMT (13%, n=14). At a mean of 2.3 months after cladribine initiation, 10% (n=11) had one or more relapse. 65% (n=72) of patients showed evidence of lymphopenia at any time point after cladribine initiation: 16%(n=18) were grade 3 and 2%(n=2) demonstrated grade 4 lymphopenia. The mean time to lymphocyte nadir was 3.6 months. The most commonly reported side effects within 3 months of cladribine initiation were: flu/cold-like symptoms (8%) and nausea (6%). Three cases of herpes zoster infection were reported. There have been no treatment discontinuations to date.

Conclusions

Our early real-world experience demonstrates that cladribine tablets are generally well-tolerated and safe, with observed adverse effects consistent with what was reported in clinical trials. Prospective follow-up of this cohort will enable an assessment of the on-going safety and efficacy of cladribine in the real-world.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0320 - Effect of age on effectiveness and discontinuation of subcutaneous interferon beta-1a, and healthcare utilization, in patients with multiple sclerosis (ID 391)

Speakers
Presentation Number
P0320
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Subcutaneous interferon beta-1a (sc IFNβ-1a) is a well-established multiple sclerosis (MS) therapy with cumulative exposure of approximately 1,766,525 patient-years. Previous clinical trials demonstrate that patient age does not impact the efficacy of such therapy for treatment of MS.

Objectives

Using real-world data, we evaluated the effect of age on the effectiveness and discontinuation of sc IFNβ-1a, and healthcare utilization, in patients with MS.

Methods

This cohort study using MarketScan© Databases included adult patients with MS newly initiated with sc IFNß-1a between Jul2010-Dec2015, with at least 6 months’ patient history before initiation (index date), and a recorded diagnosis of MS over the 6 months before or at initiation. Follow-up was until end of study period, end of insurance, or treatment discontinuation. Incidence rate (IR) per 100 person-years was used for discontinuation. Hazard ratio (HR) and 95% confidence internal (CI) were used to compare time to first relapse and discontinuation.

Results

Among 5,340 patients included, 14.5% were aged 18-30y, 27.5% 31-40y, 30.5% 41-50y, and 27.5% were 51+y. Relapse-free probability at 2-y ranged from 91.44% in 18-30y to 92.82% in 51+y. Compared with 18-30y, the HRs for relapse at 2-y (95%CI) were 31-40y: 1.00 (0.70, 1.43), 41-50y: 0.79 (0.55, 1.12), and 51+y: 0.86 (0.60, 1.24). In all age groups, hospitalizations due to MS were ≤0.01 and neurology visits were 0.2 patient per-month (PPM) over 2-y. Mean number (95%CI) of magnetic resonance imaging (MRI) scans performed PPM over 2-y ranged from 0.25 (0.16, 0.34) in 18-30y to 0.14 (0.12, 0.16) in 51y+ and outpatients visits due to MS from 0.68 (0.57, 0.78) to 0.75 (0.67, 0.82). Discontinuation IR at 2-y was 72.06 (65.12, 79.52) in 18-30y and 57.95 (53.76, 62.38) in 51+y. Compared to 18-30y, the HR of discontinuation decreased from 0.89 (0.79, 1.01) in 31-40y to 0.86 (0.76, 0.97) in 51+y.

Conclusions

Data suggest no effect of age on the effectiveness of sc IFNß-1a in the real-world setting, while treatment discontinuation decreased with increasing age. Older MS patients initiating sc IFNß-1a appear to have less active disease, reflected in lower relapses, and undergo MRI scanning less frequently than younger patients.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0321 - Effect of anti-CD20 antibody-induced B-cell depletion on the susceptibility to Streptococcus pneumoniae infections (ID 1575)

Speakers
Presentation Number
P0321
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

Treatment with rituximab, an anti-CD20 chimeric monoclonal antibody, rapidly depletes >95% of CD20+ B cells from circulation. However, immunosuppression induced by B-cell depletion therapy is associated with an increased risk of respiratory tract infections.

Objectives

To investigate the effect of B-cell depletion on the antibody-mediated immunity to Streptococcus pneumoniae in mice.

Methods

B cells were depleted in 6-week-old CD57/BL6 female mice (n=6/group) by intravenously injecting the anti-CD20 SA271G2 antibody (50 µg/mouse) for evaluating the effect of B-cell depletion on S.pneumoniae colonization and vaccination. After depletion, mice were either colonized by intranasal administration of the S.pneumoniae 6B strain (10 µL/dose, 1×107 bacteria, Day 3) or vaccinated by intraperitoneal injections of two doses of Prevnar (20 µL/dose, Days 3 and 13). Intravenous (i.v.) and subcutaneous (s.c.) routes of administration of B-cell therapy were also compared by injecting anti-CD20 mIgG1 (50 µg/mouse) followed by Prevnar vaccinations (n=8/group). For both studies, B-cell repertoire and S.pneumoniae-specific IgG levels were measured using the whole-cell enzyme-linked immunosorbent assay (ELISA) and flow cytometry antibody-binding assay.

Results

B-cell depletion did not increase susceptibility to S.pneumoniae in naïve mice, indicating limited functional effects on natural IgM. When administered before colonization/vaccination, the treatment caused a significant decrease in circulating IgG levels to S.pneumoniae. Following the pneumonia challenge model, a decreased level of protection induced by these immunizations was also observed in the B-cell depleted mice. In contrast, vaccination-induced protection was preserved in the depleted group when treatment was administered after vaccination. Both i.v. and s.c. administration of the anti-CD20 antibody using an identical dose induced a large decrease in splenic follicular B cells, with relative preservation of marginal zone B cells.

Conclusions

The timing of B-cell depletion by anti-CD20 therapy critically affects the development of antibody-mediated immunity to S.pneumoniae. Clinical studies further confirm the negative effects of B-cell depletion on antibody responses to S.pneumoniae in patients treated with rituximab.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0322 - Effect of anti-CD20 antibody-mediated B-cell depletion on susceptibility to a Pneumocystis infection in mice (ID 1579)

Speakers
Presentation Number
P0322
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

Pneumocystis species are heterogeneous atypical microscopic fungi. Immune response against Pneumocystis infections is thought to be mediated by B and T cells.

Objectives

To investigate the effect of subcutaneous (s.c.) anti-CD20 antibody-induced B-cell depletion on T-cell responses and antibody generation against primary and secondary Pneumocystis infection in mice.

Methods

C57BL/6 female mice were administered with the s.c. anti-CD20 antibody or control 3 days prior to a pulmonary challenge with Pneumocystis murina (2×105 cysts, primary infection) and continued weekly for up to 4 weeks. In another group, mice were infected with P. murina and allowed to clear the infection. Six weeks later, mice were administered with the anti-CD20 antibody or control and then re-infected with P. murina after 3 days (secondary infection) to determine if the anti-CD20 antibody affected the pre-existing anti-fungal antibody. Administration of the anti-CD20 antibody or control was continued weekly. In both cohorts, T- and B-cells in the lung were assayed by flow cytometry at Day 14 and Day 28 after infection, and lung fungal burden was determined by quantitative polymerase chain reaction (PCR). Serum immunoglobulin (IgG, IgE and IgM) levels were measured by the enzyme-linked immunosorbent assay (ELISA).

Results

In mice with primary Pneumocystis infection, anti-CD20 antibody treatment depleted both CD19+ and CD27+CD19+ cells, but not T cells, in the lung at Days 14 and 28. Although the anti-CD20 antibody treatment impaired fungal clearance at Day 14 post-infection, fungal burden in the lungs was substantially reduced at Day 28 in both depleted and control mice. Anti-CD20 antibody treatment did not alter antigen-specific serum immunoglobulin levels compared with control mice, and there were no significant differences in the numbers of lung interferon gamma (IFNg)+CD4+, interleukin (IL-4)+CD4+, IL-5+CD4+ and IL-17A+CD4+ cells between depleted and control mice after infection. In mice with secondary Pneumocystis infection, the lung fungal burden was comparable between depleted and control mice 14 days after re-infection.

Conclusions

Subcutaneous anti-CD20 antibody treatment may delay fungal clearance but it does not impair the ability of the host to clear a Pneumocystis infection, irrespective of primary or secondary infection.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0323 - Effect of neutralizing antibodies on pharmacodynamic biomarkers of subcutaneous interferon β-1a in REFLEX and REFLEXION (ID 959)

Speakers
Presentation Number
P0323
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

Several pharmacodynamic (PD) biomarkers have been described in patients (pts) with multiple sclerosis (MS) treated with interferon β (IFNβ), each with variable degrees of evidence. Non-responders to IFNβ often produce neutralizing antibodies (NAbs), which are expected to diminish PD biomarker response to treatment (tx). In the REFLEX and REFLEXION trials, around 15% of subcutaneous (sc) IFNβ-1a treated pts developed NAbs.

Objectives

To evaluate the effect of NAbs on candidate pharmacodynamic biomarkers of long-term scIFNβ-1a therapy in a large pt cohort.

Methods

Biomarkers (neopterin, 2’5’-oligoadenylate synthetase [2’5’OAS], soluble TNF-related apoptosis-inducing ligand [TRAIL], interferon-γ inducible protein [IP-10], interleukin-1 receptor antagonist [IL-1RA]) were measured in serum samples using validated assays with appropriate quality standards applied. Samples from 448 clinically isolated syndrome (CIS) pts who received scIFNβ-1a 44 μg once (ow) or three (tiw) times weekly, or placebo (PBO) in REFLEX were collected at baseline (month[M]0), M6, M12, M18, M24. Whole-blood Myxovirus protein A (MxA) gene expression measured at M0, M24. In the extension trial, REFLEXION, 302 pts with CIS or who converted to MS were followed up to 5 yrs; neopterin, IP-10, TRAIL serum levels analysed every 6 months. The PD effect of each biomarker was tested upon scIFNβ-1a tx using linear mixed effect models (independent variable:biomarker expression; fixed effects:baseline biomarker expression, tx arm, gender, time; random effect:subject). Serum NAb levels were analyzed in pts from REFLEX and REFLEXION; PD data stratified by pt NAb status (NAb-positive[≥20 neutralizing units/mL]/NAb-negative).

Results

In REFLEX (M0-24) and REFLEXION (M24-60), levels of all assessed biomarkers in NAb-positive pts were similar to those measured for PBO in REFLEX. In NAb-negative pts, all biomarkers were significantly upregulated in response to scIFNβ-1a tx vs M0 of REFLEX. No changes were seen in PBO pts. The greatest changes were observed with scIFNβ-1a tiw; intermediate changes with scIFNβ-1a ow. In REFLEXION, a modest dose-dependent biomarker response to scIFNβ-1a tx was observed.

Conclusions

It is known that classical IFN-responsive PD genes do not predict clinical response to IFNβ. In this study, PD biomarkers were upregulated by scIFNβ-1a in the 85% of pts NAb-negative. Reduced PD biomarker expression in NAb-positive pts was consistent with the concept that NAbs reduce PD activity of scIFNβ-1a.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0324 - Effect of ocrelizumab treatment in peripheral blood leukocyte subsets of Primary Progressive Multiple Sclerosis patients (ID 1613)

Abstract

Background

Ocrelizumab is the first drug approved as disease modifying treatment for primary progressive (PP) multiple sclerosis (MS). As a humanized monoclonal antibody targeting CD20 cells, it is widely known that ocrelizumab treatment results in B cells depletion, but less is known about the effects of this drug in other blood leukocyte subsets of PPMS patients.

Objectives

To explore the changes induced by ocrelizumab in blood immune cells of PPMS patients to further understand their effects in the abnormal inflammatory response.

Methods

Multi-centre prospective longitudinal study including fifty‐three PPMS patients who initiated ocrelizumab treatment. Effector, memory, and regulatory cells were analyzed by flow cytometry at baseline and after 6 months of treatment. To assess differences between baseline and after 6 months, Wilcoxon matched paired tests were used and p values were corrected using Bonferroni test.

Results

Ocrelizumab decreased numbers of naïve and memory B cells (p<0.0001) and those of B cells producing interleukin (IL)-6, IL-10, granulocyte-macrophage colony-stimulating factor and tumor necrosis factor-alpha (p<0.0001 in all cases). A reduction of CD20+ T cell numbers (p=0.02) and percentages (p<0.0001) was also observed. We also detected a clear remodelation of the T cell compartment characterized by relative increases of the naïve/effector ratio in CD4+ (p=0.002) and CD8+ (p=0.002) T cells, and relative decreases of CD4+ (p=0.03) and CD8+ (p=0.004) T cells producing interferon-gamma. Total monocyte numbers increased (p=0.002), with no changes in those producing inflammatory cytokines. All these changes resulted in a reduction of serum neurofilament light chain (sNfL) levels (p=0.009).

Conclusions

Effector B cell depletion by ocrelizumab treatment induces changes in the T cell response of PPMS patients towards a low inflammatory profile. This resulted in a decrease of sNfL levels.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0325 - Effect of ozanimod on proportions of leukocyte subsets in patients with relapsing multiple sclerosis (ID 979)

Speakers
Presentation Number
P0325
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

Ozanimod is a sphingosine 1-phosphate receptor 1 and 5 modulator that blocks the capacity of lymphocytes to egress from lymphoid tissue, reducing the number of lymphocytes in peripheral blood. The mechanism by which ozanimod exerts therapeutic effects in multiple sclerosis is unknown, but may involve reduction of lymphocyte migration into the central nervous system.

Objectives

To characterize the phenotype of circulating leukocytes in relapsing multiple sclerosis (RMS) in participants treated with ozanimod.

Methods

In a phase 1, open-label, pharmacokinetic/pharmacodynamic study, 24 participants with RMS were randomized to oral ozanimod 0.46 (n=13) or 0.92 mg/d (n=11) [equivalent to ozanimod HCl 0.5 or 1 mg] for ~12 weeks, including an initial 7-d dose escalation (0.23 mg/d x 4d + 0.46 mg/d x 3d). Key exclusion criteria were active infection, history of chronic infections or immunodeficiency, recent live vaccination, previous lymphocyte-depleting or immunosuppressant therapy, and absolute lymphocyte count <1.0 × 109/L. Exploratory analyses used flow cytometry to characterize proportional changes from baseline in leukocyte subsets on days 28, 56, and 85 in total peripheral blood mononuclear cells (PBMC) and total T cells. Proportional change from baseline is reported using descriptive statistics.

Results

Ozanimod was associated with dose-dependent decreases in absolute numbers of CD4+ and CD8+ T cells. Within the PBMC population, ozanimod was associated with a minimal increase in the proportion of CD8+ TEMRA cells (ozanimod 0.92 mg only) and no change in CD8+ effector memory T (TEM) cells. A decrease in the proportion of CD4+ and CD8+ naive and central memory T (TCM) cells and CD4+ TEM cells was evident. Within the total T cell population, ozanimod was associated with an increase in the proportion of CD4+ TEM cells (ozanimod 0.92 mg only) and CD8+ TEM and TEMRA cells. A decrease in the proportion of CD4+ naive (ozanimod 0.92 mg only) and CD8+ naive cells was observed; CD4+ and CD8+ TCM cells were minimally affected. Changes from baseline were more pronounced with ozanimod 0.92 mg than with ozanimod 0.46 mg.

Conclusions

During ozanimod treatment, the relative frequencies of circulating cell types within total PBMCs and within the remaining T cell population were altered. These shifts in circulating leukocyte proportions support the hypothesis that although ozanimod inhibits trafficking of some subsets of lymphocytes, the remaining circulating cells are still poised to provide immune surveillance.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0326 - Effect of Teriflunomide on Epstein-Barr Virus Shedding in Relapsing-Remitting Multiple Sclerosis Patients: Outcomes From a Real-world Cohort Study (ID 787)

Speakers
Presentation Number
P0326
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

The role of Epstein-Barr virus (EBV) in relapsing-remitting multiple sclerosis (MS) pathogenesis is poorly understood. Options for inhibiting EBV are limited except for possibly teriflunomide, which has been associated with inhibitory activity against EBV and other viruses (Mei-Jiao G, et al. Biomed Pharmacother 2019). Inhibition of EBV activity could contribute to teriflunomide’s efficacy in MS. The most direct method of quantitatively measuring EBV activity in vivo is to measure EBV shedding in saliva.

Objectives

To quantify EBV in the saliva of teriflunomide-treated MS patients, compared with 3 control cohorts of patients with MS.

Methods

Patients stable on teriflunomide for ≥3 months were prospectively recruited from 2 large MS practices in Australia. Saliva was collected at home each week for 3 months, per a standardized protocol. Saliva specimens were stored in patients’ home freezers for 6 weeks, then shipped to Queen Mary University of London for quantitative measurements of EBV DNA. EBV shedding was defined as >5.8 copies/µL. Results were compared with samples from 3 separate reference cohorts of MS patients not taking teriflunomide, which served as controls; all samples were analyzed using the same lab and assay.

Results

Over 3 months, EBV DNA was detected in 11/19 (58%) teriflunomide-treated patients; 5 (26%) had EBV shedding detected in ≥1 samples. In control cohorts, EBV DNA was detected in 61%−70% of patients, with EBV shedding present in ≥1 samples in 37%−45% of patients (P=not significant vs teriflunomide). However, when looking at 211 saliva samples from the teriflunomide-treated patients, 20% had detectable EBV DNA and 9.5% had EBV shedding. Samples from control cohorts had significantly higher proportions with detectable EBV DNA (38%−41%) and shedding (21%−24%) versus those from teriflunomide-treated patients (all P<0.0001). The number of samples positive for EBV detection and shedding in the teriflunomide-treated group was mainly driven by 2 patients with consistent shedding, whereas positive samples were spread evenly in the control cohorts.

Conclusions

Of 19 teriflunomide-treated patients, only 2 had consistent EBV shedding in saliva, suggesting teriflunomide may inhibit EBV shedding. Future studies could confirm this relationship by quantifying EBV shedding before and after teriflunomide initiation. Longer-term studies comparing the clinical courses of EBV shedders and nonshedders may help determine the role of EBV in MS.

STUDY SUPPORT: Sanofi.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0327 - Effectiveness and safety profile of the Natalizumab extended interval dosing in a Spanish cohort (ID 1815)

Presentation Number
P0327
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Previous Biogen analyses of the US TOUCH Registry showed that the risk of developing natalizumab-associated progressive multifocal leukoencephalopathy (PML) among anti-JCV antibody positive natalizumab-treated patients was significantly lower with extended interval dosing (EID) compared with standard interval dosing (SID). However, the efficacy of EID was not evaluated in these analyses. Real-world studies and modelling data suggest that a patient population stable on natalizumab SID who is then switched to EID is more likely to maintain efficacy with EID as compared to a population who initiates natalizumab on EID.

Objectives

The main objective of the study is to evaluate the effectiveness (measured by the annualized relapse rate - ARR) of natalizumab EID in subjects who have been previously treated with natalizumab SID during the 12-month list, in relation to continuous SID treatment.

Methods

Observational, open-label study with retrospective analysis of a prospective cohort of patients with relapsing-remitting multiple sclerosis (RRMS) treated at Hospital Ramón y Cajal (Madrid) with natalizumab for 12 months using SID (Infusion every month). All patients were transferred after a period of initial treatment at standard interval doses to a 6-week EID, according to hospital protocol, eliminating a potential selection bias for assigning less active patients to the EID group Demographic, clinical, radiological and immunological variables were collected.

Results

61 patients were included, 33 (54%) women, with a median (range) age at treatment initiation of 35 (17-55) years. Median (range) treatment duration was 5,2 years (2-11,3), 3,47 years (1,4-7,8) in SID, 1,7 years (0,5-4,1) in EID. There was no difference in ARR, mean [95% confidence interval (CI)], (SID: 0.05 [0,01-0,1]; EID: 0.02 [0,02-0,05]; P=0.558), or EDSS (SID: 2,35 [1,9-2,7], EID: 2,67 [2,2-3,9]; p=0,42).

Conclusions

This study does not demonstrate significant differences in relapse outcomes between SID and EID periods of patients who switched to EID from natalizumab after ≥1 year on SID. These results are consistent with previous analyzes without comparison that concluded that efficacy is maintained after switching to EID. Consistent MRI and EDSS results will be shown in the final poster. An ongoing prospective randomized trial of EID versus SID will provide a more complete understanding of the effectiveness of natalizumab EID.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0328 - Effectiveness of cladribine in multiple sclerosis – clinical experience of two tertiary centers (ID 1498)

Speakers
Presentation Number
P0328
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

Cladribine is a selective and oral immunological reconstitution treatment, approved in Europe in 2017 and in Portugal in 2018 for very active multiple sclerosis (MS) with relapses. Its safety and efficacy profile were assessed in phase III CLARITY (2005-2009) trial. Post-commercialization studies in real life conditions, are essential to confirm this profile.

Objectives

To assess the efectiveness of cladribine in multiple sclerosis patients a real-world clinical setting, during treatment follow-up.

Methods

Observational, multicentric, prospective study. Consecutive MS patients treated with cladribine were included in two tertiary hospitals in Lisbon and followed during treatment. Demographic and clinical aspects, EDSS, previous disease-modifying drugs (DMD) and annual relapse rate (ARR) were recorded, as well as laboratory and imaging monitoring during treatment

Results

Eighty-five included patients, 54 (63.5%) female, mean age 42±12 years old, mean disease duration 9±7 years. Seventy-seven (90.6%) had relapsing-remitting MS, and the remaining had secondary progressive MS. Median pre-treatment EDSS was 2,0 (1,5-4,0), and 40 (47.1%) patients had at least one relapse in previous year. Most (65.9%) patients had been submitted to more than one DMD before, 43 (51.2%) with first-line therapies and 9 (10.7%) were naïve. Cladribine was started in 57 (68.7%) patients due to inefficacy of previous drug. Mean follow-up time was 13±6 months, and 54 (63.5%) completed first year of treatment. Second year of treatment was delayed in some patients due to global COVID-19 pandemic. Fifteen relapses were registered in 12 patients. Five (5.9%) stopped treatment because of disease activity in the first year. After 12 months of follow-up (n=54), no difference was found between previous and 12-month EDSS medians (2 (IQR 1,5-4,0) vs 2 (IQR 1,25-4) p=0.606). Mean 12-month ARR (0,1±0,4) was significantly inferior to previous year ARR (0,6±1,0), p<0.001.

Conclusions

At pivot trial, the efficacy of cladribine was proved after two annual treatment cycles. In this population, short follow-up period is a limitation, but after mean follow-up of one year, clinical estabilization was found in MS patients treated with cladribine.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0329 - Effects of adrenocorticotropic hormone on melanocortin receptors, regulatory immune cells, and MRI in MS (ID 1915)

Speakers
Presentation Number
P0329
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

Background: Adrenocorticotropic hormone (ACTH) is an alternative to corticosteroid therapy to treat relapses in Multiple Sclerosis. ACTH stimulate low levels of corticosteroid release from the adrenal glands, but it also works through the melanocortin system to induce anti-inflammatory, neuroprotective, osteoprotective, and analgesic effects specific to ACTH by binding to melanocortin receptors (MCR). Although cortisol and cortisol receptor levels have been examined extensively in MS, ACTH effects on MCR expression and on regulatory immune cells have not been examined, particularly in patients undergoing MRI-confirmed MS relapses.

Objectives

Objectives: To elucidate if ACTHAR administration causes changes in MRI scans, modifies expression of MCR acutely and long-term in MS, or changes regulatory subsets, acutely or long-term.

Methods

Methods: Six MS patients with acute clinical exacerbations and active contrast-enhancing lesions were given a 10-day course of subcutaneous ACTHAR (80 units/day). Blood was drawn from patients at baseline, 10 days, and 1, 3, 6, and 12 months post ACTHAR injections. MRIs were performed at baseline and months 3, 6, and 12. Mononuclear cells (MNCs) were isolated from the blood using Lympholyte FICOL gradient separation and frozen. MNC were stained for MCRs 1,3, and 5 with newly-developed assays, and for CD8+CD28- and CD4+FOXP3+ regulatory T cells (Tregs) for flow cytometry with a Fortessa 4-15 analyzer.

Results

Results: MCRs, 3>1>5 (%) and 1>3>5 (expression) on MNC at baseline, were highly variable after depot ACTH. CD8 Tregs as % of lymphocytes did not change acutely or long-term. However, CD8+CD28+ cytolytic cells (CTL) decreased at 1 month (8.15%) compared to baseline (14.6%; p=0.046, paired t-test, n = 5). 3/6 patients also had a new T2 and/or contrast-enhancing MRI lesions at month 1.

Conclusions

Conclusions: ACTHAR may decrease potentially MS-toxic CD8 CTLs at 1 month post-administration, due to direct effects or to induction of corticosteroids. There were no clear changes in MCRs and T regulatory populations. A 10-day course of ACTHAR was not enough to completely suppress MRI activity in some of patients at month 1. A longer duration of ACTHAR treatment is probably required for further suppression of MRI activity and greater control of immune cell activity.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0330 - Effects of cladribine on proliferation, survival and cytokine release of human astrocytes (ID 1581)

Speakers
Presentation Number
P0330
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

Cladribine is a synthetic purine nucleoside analogue with immunosuppressive functions that has demonstrated beneficial effects in patients with relapsing-remitting multiple sclerosis (MS) and that may also regulate the immune function as an analogue of adenosine receptors. Although the effect of cladribine is well studied on immune cells, it remains unveiled how it affects the immune function of glial populations of the central nervous system.

Objectives

In the context of MS, we aimed to test the effect of cladribine on proliferation, survival and cytokine release of human astrocytes.

Methods

To assess the effect of cladribine on cell survival and proliferation, primary human astrocytes were cultured with cladribine at high concentrations (2µM, 0.2µM), at the mean estimated brain exposure of the drug (0.02µM) and at a low concentration (0.002µM) for 72h. The percentages of dead and proliferating cells were determined by flow cytometry. To assess the effect of cladribine on cytokine release, human astrocytes were stimulated for 6h with 20ng/ml IL1-β and TNF-α. The stimulus was withdrawn and cells were cultured for additional 18h. Cladribine was added for the whole 24h of culture. Supernatants were harvested to quantify IL1-β, IL6, TNF-α and GM-CSF release by Luminex. To assess the effect of cladribine independently of deoxycytidine kinase (DCK), deoxycytidine was also added to human astrocytes.

Results

Only high concentrations of cladribine induced death on human astrocytes (2µM: 35.89%±7.62 or 0.2µM: 7.27%±3.12 vs control: 3.17%1.84±; p<0.0001 and p=0.156, respectively) and inhibited their proliferative capacity (2µM: 0.96%±1.14 or 0.2µM: 14.06%±5.44 vs control: 33.06%±1.42; both p-values<0.0001). Additionally, the percentage of proliferating cells in the 2µM and 0.2µM conditions presented a limited capacity of proliferation (measured as the Relative Intensity of Proliferation Staining respect to basal; 2µM: 0.24±0.04 and 0.2µM: 0.55±0.22, both p-values<0.0001). When DCK activity was blocked by deoxycytidine, cell death and proliferation were reversed to control condition values. We are currently determining the effect of cladribine on pro-inflammatory cytokine release by human astrocytes.

Conclusions

The mean estimated brain exposure to cladribine does not influence cell survival or proliferation of human astrocytes neither in a DCK-dependent nor in a DCK-independent manner, suggesting that cladribine does not affect the normal astrocyte function in MS patients.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0331 - Efficacy and safety in patients treated with Natalizumab for at least 10 years - Real-world data from a Swedish national surveillance study (IMSE 1) (ID 673)

Speakers
Presentation Number
P0331
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Natalizumab (NTZ) is a highly effective disease modulatory treatment for relapsing-remitting multiple sclerosis (RRMS). Post-marketing surveillance is important for evaluation of long-term safety and effectiveness in a real-world setting. To this end, the “Immunomodulation and Multiple Sclerosis Epidemiology Study” (IMSE 1) was initiated upon NTZ launch in Sweden (August 2006).

Objectives

To follow-up the long-term effectiveness and safety of NTZ in a real-world setting, with focus on patients treated at least 10 years.

Methods

IMSE 1 includes patients starting NTZ treatment and data is collected from the nationwide Swedish Neuro Registry (NeuroReg). Adverse events (AEs), JC-virus status (JCV) and clinical effectiveness measures are registered in NeuroReg prospectively. Effectiveness measures were assessed using the Wilcoxon Signed Rank Test.

Results

A total of 3291 patients were included in the IMSE 1 study from August 2006 until June 2020 (72% female; mean age 36 years; 80% RRMS; mean treatment duration 50 months). 171/3291 patients (5%) had been treated for at least 120 months (73% female; men age 36 years; 87% RRMS; mean treatment duration 139 months). A total of 64% (110/171) were treated with interferons or glatiramer acetate prior to NTZ treatment. Over the duration of follow-up discontinued 21% (35/171) their NTZ treatment of which 46% (16/35) discontinued due to JCV positive (JCV+). In total, 27% (46/171) of these patients were JCV+ with a mean JCV index of 1.2±1.0 (4% missing data). The mean number of relapses were reduced from 0.84 one year before NTZ treatment start to 0.00 during the first treatment year (12% missing data). All clinical effectiveness measures (Extended Disability Status Scale (EDSS), Multiple Sclerosis Severity Scale (MSSS), Multiple Sclerosis Impact Scale (MSIS-29) and Symbol Digit Modalities Test (SDMT)) showed improvement in mean between baseline and 120 months. However, only MSSS, MSIS-29 psychological and SDMT were statistically significant. Over the entire observation time, 114 Serious AEs had been reported to the Swedish Medical Product Agency and included nine cases (2 fatal) of progressive multifocal leukoencephalopathy (PML) of which eight between year 2008 and 2012, and one in 2018. 17 patients died during or within 6 months of last NTZ infusion. None were judged to be directly associated with NTZ.

Conclusions

NTZ is generally well tolerated with sustained effectiveness regarding cognitive, physical and psychological measures, as well as relapse-control.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0332 - Evaluating the Efficacy and Safety of Transitioning Patients from Natalizumab to Ocrelizumab (OCTAVE) (ID 439)

Speakers
Presentation Number
P0332
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Natalizumab (NTZ) is an effective therapy for patients with relapsing MS (RMS). However, it is associated with a risk of progressive multifocal leukoencephalopathy (PML) in patients infected with John Cunningham virus (JCV). Ocrelizumab (OCR) has demonstrated efficacy, yet its safety in patients previously treated with NTZ is unclear.

Objectives

To present interim data from OCTAVE, a prospective, observational study to evaluate the efficacy and safety of OCR in RMS patients previously treated with NTZ.

Methods

Clinically and radiologically stable RMS patients, aged 18-65 treated with a stable dose of NTZ for ≥ 12 months, were started on OCR 4-6 weeks after last dose of NTZ and followed for 12 months. Relapse assessment, Expanded Disability Status Scale (EDSS), and MRI were performed prior to starting OCR and at months 3, 6, 9 (no MRI), and 12.

Results

Thirty-seven patients, 75.7% female with mean age of 43.8 (± 10.97) and a median of 33.5 [IQR = 63.2] NTZ infusions prior to starting OCR have been enrolled between August 9th, 2017 and February 3rd, 2020. 23 patients have completed the study duration of 12 months. Thirty-one subjects switched to OCR due to potential PML risk. One patient had a clinical relapse reported at month 12 although no MRI correlate. However, EDSS at baseline was 4.0 and at month 12 the score was 5.5. At month 3, one patient had one enhancing lesion, and one patient had 3 enhancing lesions. At months 6 and 12, there were no enhancing or new/enlarging T2 lesions. There were no significant changes in the EDSS, physical MSIS-29, and psychological MSIS-29 from baseline to months 6 and 12, though there was an increasing trend for EDSS. Median EDSS [IQR] was 3.00 [2.0] at baseline and median EDSS [IQR] was 4.00 [2.50] at month 12. Infusion reactions were seen in 40.5% of patients with the first dose (includes both 300mg infusions) and 13.5 % with the second dose (600mg infusion). Eight serious adverse events (SAEs) have been reported with three possibly related to OCR, breast cancer, urinary tract infection, and acute cystitis. No cases of PML have been reported.

Conclusions

The transition from NTZ to OCR resulted in limited disease activity. In 2 patients, MRI activity was present at 3 months, but no MRI changes were seen at months 6 and 12. One patient was reported to have a clinical relapse at month 12; however, there were no MRI changes. The trend in increasing EDSS is concerning.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0334 - Evobrutinib, a highly selective BTK inhibitor, prevents antigen-activation of B cells and ameliorates experimental autoimmune encephalomyelitis (ID 1125)

Speakers
Presentation Number
P0334
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

Background: B cells are key mediators of inflammatory processes in multiple sclerosis, a notion substantiated by the success of B-cell depletion therapies; however, overall depletion does not only target pathogenic B cells but can also affect regulatory B-cell properties. An alternative strategy may be the specific inhibition of Bruton’s tyrosine kinase (BTK), which is centrally involved in B-cell receptor (BCR) signaling and subsequently mediates B-cell activation and differentiation. BTK inhibitors therefore hold the promise to control pathogenic functions such as antigen presentation and cytokine release.

Objectives

Objectives: To evaluate the BTK inhibitor evobrutinib in a mouse model of experimental autoimmune encephalomyelitis (EAE).

Methods

Methods: C57Bl/6 mice received oral evobrutinib or vehicle starting 7 days before immunization with conformational MOG1-117 protein (a B cell–mediated model of EAE). EAE severity was assessed for 60 days using a standard scale. B-cell maturation and activation markers on B and T cells were analyzed by flow cytometry on day 12 post immunization. T cell proliferation and differentiation were assessed after a 3-day co-culture with BTKi-treated B cells. Intracellular calcium flux was analyzed using calcium-sensitive dyes and BCR or T cell receptor (TCR) stimulation. BTK expression and phosphorylation as well as cytokine production were assessed on healthy human B cells via PhosFlow protocols or ELISA, respectively.

Results

Results: Evobrutinib showed a dose-dependent amelioration of EAE severity throughout the 60-day observation period. Evobrutinib led to an accumulation of follicular type (FO) II B cells and a corresponding reduction in FO I B cells, a BTK-dependent transition. Expression of CD86, CD69, and major histocompatibility complex class II on B cells, and CD25 and CD69 on T cells, was reduced. Evobrutinib inhibited the B cell-mediated proliferation and proinflammatory differentiation of T cells. BCR-mediated mobilization of excitatory calcium was reduced by evobrutinib, while TCR signaling remained unaffected. In human B cells, BTK expression and phosphorylation were depending on the maturation of B cells, while the overall cytokine release was inhibited by evobrutinib.

Conclusions

Conclusion: Evobrutinib efficiently reduces BTK-dependent signaling after BCR stimulation, preventing B-cell activation, proinflammatory differentiation, and function. This translates into reduced CNS inflammation and clinical amelioration in a B cell–mediated EAE model.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0335 - Exploring the rate, persistence and associations of lymphopaenia in people with multiple sclerosis treated with dimethyl fumarate. (ID 712)

Speakers
Presentation Number
P0335
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Dimethyl Fumarate (DMF) has emerged as an effective therapy for relapsing-remitting multiple sclerosis (RR-MS). Common side effects include gastrointestinal disturbance and flushing, almost one third of patients withdrew from the pivotal phase III study. Reduction in absolute white cell and lymphocyte counts have been associated with therapy. A much rarer, life-threatening consequence of DMF-associated lymphopenia is progressive multifocal leukoencephalopathy (PML). Older patients and those who experience severe (<0.5 x 109 cells/litre) and prolonged lymphopenia (6 months or longer) are deemed to be at greatest risk.The evidence for prolonged lymphopenia as the sole factor for PML in DMF therapy is, however, not yet unequivocal, leading to a degree of historical variation in practice. Although the licensing summary suggests halting DMF at the threshold of prolonged lymphopenia, evidence on rate of recovery from lymphopenia is lacking.

Objectives

To enable clinicians to accurately counsel patients commencing DMF therapy using evidence-based recommendations. Specifically, the generation of an estimated treatment failure rate and reasons for this. Beyond this, the rate of recovery from severe lymphopenia (<0.5x109 cells/litre) following termination of therapy will also be observed.

Methods

Retrospective analysis of patient data in two NHS foundation trusts (Hull University Hospitals and York Teaching Hospital). The following data was collected from patient databases and anonymised: Sex, Date of commencement of therapy, Date of RRMS diagnosis, Change to DMF therapy, Lymphocyte count at baseline and during therapy, Reason for halting or altering DMF regime (i.e. lymphopenia, adverse events or patient/clinician concerns). SPSS was used for data analysis.

Results

N=275. 36.7% of patients terminated DMF treatment, with 52.9% doing so due to side effects (predominantly gastrointestinal and flushing) and 11.5% due to lymphopenia. No PML cases were reported. 12% of patients experienced at least one episode of lymphopenia. Mean months to 2 or more episodes of lymphopenia was 21.39 (SD 11.42) with 29% experiencing lymphopenia for over 6 months. Of those with lymphopenia, mean days to return to normal lymphocyte count was 131 (SD 95.6). Baseline lymphocyte counts were 0.5 x 109 cells/litre lower in those who went on to experience lymphopenia (P= 0.000081).

Conclusions

Prolonged lymphopenia remains a relatively uncommon adverse effect in most patients taking DMF. The most common cause of treatment failure is side effects. Stopping therapy is likely to be the most effective manner of correcting a prolonged lymphopenia, however this study was unable to accurately estimate rate of correction due to variation in sampling frequency. In line with others, this study suggests that lower baseline lymphocyte counts are associated with lymphopenia during DMF treatment and rigorous monitoring is especially important in this cohort.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0336 - Exposure to Natalizumab during pregnancy: A French national retrospective study (ID 890)

Abstract

Background

Pregnancy management in patients with relapsing-remitting multiple sclerosis (MS) treated by Natalizumab (NTZ) is challenging because of the risk of disease reactivation after treatment discontinuation.

Objectives

To compare clinical disease activity (annual relapse rate) during and after pregnancy among three therapeutic approaches: continuation of NTZ all along the pregnancy and the postpartum, discontinuation of NTZ in the second trimester and discontinuation of NTZ before pregnancy.

Methods

Data were collected from the French MS registry OFSEP (Observatoire Français de la Sclérose en Plaques). We included patients with relapsing-remitting MS who started a pregnancy between 6/2013 and 9/2018 while taking NTZ, or within six months after its suspension. 3 groups were compared : continuation of NTZ throughout pregnancy and postpartum (Group 1), 3 to 6 months of exposure to NTZ during pregnancy (Group 2) and suspension prior to pregnancy (Group 3). Annual relapse rate (ARR) during 2 years (9 months before and 15 months after preganncy onset) was the primaty outcome and effect on EDSS and MRI were secondary end-points.

The main analysis was performed using a negative binomial regression with the follow-up duration as the offset term. Univariate and multivariate anlyses after adjustment for baseline variables (age, EDSS, ARR in the year before starting NTZ, first-line patient on NTZ vs. second-line patient).

Results

117 patients from 27 centers* were included. Baseline mean age was 31,5 y, median EDSS was 2.0 and mean duration of disease was 7,89 y. The mean ARR were respectively 0.078 +/- 0.24 in Group 1, 0.308 +/- 0.43 in Group 2 and 0.456 +/- 0.63 in Group 3 during the observation period and was significantly higher in Groups 2 and 3 as compared with ARR in Group 1 (p=0,007). The risk of relapses was 4 times higher in Group 2 versus Group 1 (p=0,014) and 6 times higher in Group 3 versus Group 1 (p=0,001).

Multivariate analyses did not show any effect of the adjustment variables.

Evaluation of safety outcomes on the mother and the fetus is in progress.

* Investigators: AR, JCO, CD, PB (Bordeaux), SD, BA, AR, AM, CB, JP (Marseille), MD, S Pitton (Nancy), JD (Strasbourg), TM (Dijon), JC, D Biotti (Toulouse), OC, M Vaillant (Grenoble),E Berger (Besançon), D Laplaud (Nantes), G Defer (Caen), I Patry (Corbeil-Essonnes), P Vermersch (Lille), P Labauge (Montpellier), O Bourre (Rouen), B Stankoff (Paris-Saint-Antoine), A Créange (Créteil), P Cabre (Fort-de-France), E Thouvenot (Nîmes), T De Broucker (Saint-Denis), C Papeix (Paris-Salpêtrière), P Clavelou (Clermont-Ferrand), O Gout (Paris-F.Rothschild), A Montcuquet (Limoges), C Lebrun (Nice), O Heinzlef (Poissy) N Maubeuge (Poitiers).

Conclusions

Continuation of Natalizumab during all three trimesters of pregnancy is associated with a lower risk of relapses as compared with discontinuation before the pregnancy or even during the second trimester.

Safety data is being collected.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0337 - Extensive healthy donor age/gender adjustments and propensity score matching reveal physiology of multiple sclerosis through immunophenotyping (ID 466)

Speakers
Presentation Number
P0337
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

Quantifying cell subpopulations in biological fluids aids in diagnosis and understanding of the mechanisms of injury. Although much has been learned from cerebrospinal fluid (CSF) flow cytometry in multiple sclerosis (MS), previous studies did not contain enough healthy donors (HD) to derive age- and gender-related normative data and sufficient heterogeneity of other inflammatory neurological diseases (OIND) controls to identify MS-specific changes.

Objectives

1. To define physiological age/gender-related changes in blood and CSF cells. 2) To define/validate cellular abnormalities in blood and CSF of untreated MS. 3. To compare the effects of low-efficacy and high-efficacy drugs on MS-related cellular abnormalities.

Methods

1240 prospectively acquired paired CSF/blood samples were collected from 588 subjects, representing HDs, MS patients, and various controls. Samples were blinded during processing, stained with a 12-color antibody panel, and run by flow cytometry. All p-values were adjusted for multiple comparisons. HDs and untreated MS patients were compared in independent training and validation cohorts. Propensity score matching was completed between untreated and treated MS patients to account for differences in age, gender, and disability.

Results

Both CSF and blood of HDs have changes in immune cell populations with age, although the changes are more pronounced in blood than CSF. Different MS subtypes have similar immunological changes, where immune cell populations are constantly recruited to the CSF from the periphery. All MS drugs decrease CSF inflammation; low efficacy drugs tend to normalize it, meanwhile, high efficacy drugs overshoot CSF HD range.

Conclusions

Age-related changes suggest decreased immunosurveillance of CNS by activated, HLA-DR+ T cells associated with natural aging. MS is an immunologically single disease evolving in time. At early stage of the disease, peripherally activated innate and adaptive immune cells migrate into CSF to form MS lesions. T cells and NK cells are depleted from blood as they accumulate, together with B cells, in the CSF. Eventually, these immune cells remain in CNS tissue as compartmentalized inflammation. High efficacy treatments exert a stronger inhibitory effect on recently activated HLA-DR+ T cells, which may underlie their greater efficacy. High efficacy treatments also overshoot CSF immune cell depletion beyond physiological levels, likely disrupting natural immune surveillance of CNS tissue.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0338 - Fenebrutinib, a noncovalent, highly selective, long residence time investigational Btk inhibitor for the treatment of MS (ID 1864)

Speakers
Presentation Number
P0338
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

Bruton tyrosine kinase (Btk) has the potential to play a role in the acute and chronic inflammation that leads to disease progression in multiple sclerosis (MS) by B-cell and myeloid cell activation. Optimized molecular properties of targeted therapies in chronic conditions like MS are important to limit off-target adverse effects and maximize efficacy. Fenebrutinib (FEN) is a noncovalent investigational Btk inhibitor for the treatment of MS.

Objectives

To assess the potency, selectivity and kinetics of inhibition of Btk by FEN.

Methods

Btk inhibitory potency (IC50) and kinase selectivity of FEN, evobrutinib (EVO) and tolebrutinib (TOL) were assessed in a panel of 219 human kinases. FEN, TOL and EVO were screened at 1 µM; EVO was also tested at 10 µM due to its weaker Btk IC50. IC50 values were determined for all kinases inhibited by ≥50%. FEN was also tested in human whole blood for its ability to block activation of B cells (CD69) and myeloid cells (CD63). The rate of FEN release from the Btk•FEN complex was quantified in a preincubation-dilution experiment, where Btk activity was recovered with a rate constant koff and residence time 1/koff.

Results

FEN potently inhibits Btk (IC50=2.3 nM); TOL has an IC50 of 1.4 nM, whereas EVO has an IC50 of 32 nM. In whole blood, FEN potently blocks activation of B cells (CD69 IC50=8 nM) and basophils (CD63 IC50=31 nM). In the kinase panel, FEN (1 µM) inhibits only 3 of 218 off-target kinases by >50%, whereas TOL (1 µM) inhibits 19 of 218 off-target kinases. EVO inhibits 3 of 218 off-target kinases at 1 µM and 18 of 218 off-target kinases at 10 µM. On the basis of kinase IC50 values, FEN is >130-fold more selective against all 218 kinases tested, whereas EVO and TOL were found to be less selective. Finally, in a preincubation-dilution assay, the Btk•FEN complex is very stable; FEN dissociates very slowly from Btk and shows a residence time of 18.3 hours bound to Btk.

Conclusions

The high selectivity and potency of FEN has the potential to be associated with fewer off-target adverse events and an improved MS therapeutic index compared with less selective Btk inhibitors. FEN’s long residence time bound to Btk may also improve the MS therapeutic index by mimicking the durable pharmacological inhibition of a covalent inhibitor but without the safety risks of covalent Btk inhibitors.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0339 - Fingolimod immune suppression does not inhibit long-term efficacy of AAV gene immunotherapy   (ID 1914)

Speakers
Presentation Number
P0339
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

While there is no cure for MS, current disease modifying therapies (DMTs) focus on some form of immune suppression to slow disease progression. To circumvent the need for long-term DMTs and their adverse side effects, our lab has developed a novel adeno associated virus (AAV) gene immunotherapy that not only selectively induces neuroantigen specific regulatory T cells (Tregs), but can also prevent and/or stop preexisting demyelinating disease in an animal model of MS. Thus, when considering the development of a clinical trial, it will be important to know if the patient’s current immune modulating DMT will interfere with the ability of AAV to induce Tregs or their function.

Objectives

To determine if the DMT drug fingolimod, which sequesters lymphocytes in lymph nodes, will interfere with or inhibit the efficacy of AAV gene-immunotherapy to induce antigen specific Tregs that are responsible for disease suppression/reversal and maintain tolerance.

Methods

Experimental Autoimmune Encephalomyelitis (EAE) was induce in C57BL/6 (B6) mice using MOG35-55 or in SJL mice using PLP139-151. In the B6 cohort, mice received an AAV immunotherapy vector expressing MOG and began receiving oral gavage of fingolimod at the first sign of tail paralysis (~10 days post EAE) and daily for 25 days. In the relapsing-remitting SJL model, mice began receiving daily oral fingolimod during the first remission ~15 days after EAE induction. Ten days later, mice received an AAV vector expressing PLP. At ~35 days post EAE, fingolimod treatment was suspended. Disease severity was recorded daily on a standard 5-point scale of neurological disability.

Results

In the B6 experiment, mice that received both immunotherapy and fingolimod quickly reducing disease symptoms and remained essential disease free after fingolimod was discontinued, until end of experiment @45 days. In contrast, control mice receiving only fingolimod, relapsed shortly after fingolimod was discontinued and by day 35 disease severity was equal to EAE only controls.

In the SJL experiment, mice receiving AAV immunotherapy and fingolimod or fingolimod only failed to relapse during treatment. However, once fingolimod was withdrawn, control mice quickly relapsed into severe disease. Whereas, mice that also received the immunotherapy remained disease free, until end of experiment @65 days post EAE.

Conclusions

The data clearly suggests that simultaneously or overlapping treatment using the DMT, fingolimod, shows no apparent inhibition on the long-term effectiveness of the gene immunotherapy vector. In fact, the combinatorial effect may increase the effectiveness. In sum, our AAV gene-immunotherapy has significant clinical relevance as it restores a persistent and continuous immune tolerance such that long-term continuous DMT may be unnecessary for MS patients. Furthermore, when considering patient selection for clinical trials, patients currently taking fingolimod may not have to excluded.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0340 - High-dimensional immune profiling of dimethyl fumarate and ocrelizumab in multiple sclerosis (ID 1007)

Speakers
Presentation Number
P0340
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

Dimethyl fumarate (DMF) and ocrelizumab are two effective immunomodulators for multiple sclerosis (MS). Identifying overlapping mechanisms of action between the drugs may elucidate common pathways in preventing disease activity.

Objectives

In this study we analyzed cytokine and immune-profiling data to evaluate the similarities and differences between these two disease-modifying therapies in MS.

Methods

Plasma and PBMCs from MS patients were collected at baseline, 3 months and 6 months after treatment with DMF (n=16) and ocrelizumab (n=13). Immunophenotyping was performed with mass cytometry (CyTOF) and analyzed with gating based on cell surface markers. Cytokine analysis from plasma was performed with Olink assays and analyzed with linear mixed effects models.

Results

DMF reduced both effector T and memory B cell populations while increasing CD56bright natural killer (NK) cells. Ocrelizumab exerted its main immunomodulatory effect by reducing the frequency of all B cells and increasing frequency of NK cells. At 6 months, naïve B-cells began to reconstitute; however, memory B cells remain depleted. DMF treatment was associated with a significant reduction of plasma cytokines involved in inflammatory pathways, such as IL-6 and IL-12 signaling in MS and Dectin-1 signaling. In addition, DMF lowered plasma cytokines that are dysregulated in psoriasis and involved in allograft rejection pathways. Ocrelizumab treatment led to the upregulation of neurotropic proteins in the plasma of MS patients, including proteins involved in NAD biosynthesis and tryptophan metabolism.

Conclusions

Our high-dimensional immunophenotyping results suggest that DMF and ocrelizumab both increase NK cells in addition to affecting different immune cell populations and cytokine pathways to exert their effects in MS patients. Detecting similarities between the mechanisms of the two drugs may contribute to identifying more specific therapeutic targets.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0342 - Immune reconstitution inflammatory syndrome in a patient treated with alemtuzumab a few years earlier (ID 1627)

Presentation Number
P0342
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Alemtuzumab is a monoclonal antibody directed against antigen CD52 on cells of the immune system. It is used in the treatment of highly active multiple sclerosis. Immune reconstitution inflammatory syndrome (IRIS) develops due to reconstruction of cellular immunity and inflammation in the central nervous system, in most cases after progressive multifocal leukoencephalopathy (PML). Sometimes IRIS can also occur in the absence of PML.

Objectives

IRIS in a patient treated with alemtuzumab eight years earlier is described. A series of images of MR of the brain will be presented.

Methods

A 38-year-old male patient was admitted because of dysphasia, bulbar syndrome and severe agitation. In 2011 and 2012 he was treated with alemtuzumab because of highly active MS. After 7 years of remission, in 2019 he had a relapse, and in February 2020 he developed severe neurological exacerbation.

Results

MRI of the brain showed multiple big confluencing lesions hyperintensive in T2 weighted images, in the white matter, both supra- and infratentorially, associated with mass effect and contrast enhancement. The patient was treated with prolonged steroids therapy and plasma exchange. JCV-DNA was negative in the CSF. On series of control MRI there was gradual regression of lesions. Neurological state of the patient improved.

Conclusions

IRIS can be a complication of alemtuzumab treatment and arise from the restoration of the previously suppressed immune response, in the absence of active infection i.e. PML.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0343 - Inhibition of drug transporter breast cancer resistance protein has no effect on the pharmacokinetics of major active metabolites of ozanimod (ID 1170)

Speakers
Presentation Number
P0343
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Ozanimod, an oral sphingosine 1-phosphate receptor 1 and 5 modulator, was recently approved in the US and EU for the treatment of relapsing forms of multiple sclerosis. A previous study showed that co-administration of ozanimod with cyclosporine had no effect on ozanimod exposure but doubled the exposure of the minor active metabolites, RP101988 and RP101075 (the direct precursor of the major active metabolite CC112273). CC112273 and its interconverting active metabolite CC1084037 were not monitored in that study. A new study (NCT04149678) was conducted to further investigate this potential drug-drug interaction, particularly on the major active metabolites.

Objectives

This study’s primary objective was to evaluate the effect of cyclosporine, the index inhibitor of breast cancer resistance protein (BCRP), on the pharmacokinetics (PK) of ozanimod, CC112273, CC1084037, and RP101988.

Methods

In this phase 1, randomized, parallel-group, open-label study (NCT04149678), 40 healthy adult subjects were enrolled and randomly assigned to 1 of 2 treatment groups (20 per group). Group A received a single oral dose of ozanimod 0.46 mg, and group B received a single oral dose of ozanimod 0.46 mg plus a single oral dose of cyclosporine 600 mg. PK blood samples were collected up to 336 hours postdose, and PK parameters for ozanimod, CC112273, CC1084037, and RP101988 were calculated. Point estimates and 90% confidence intervals (CIs) for the geometric mean ratio between treatment groups (B vs A) for maximum concentration (Cmax) and overall exposure (AUC0-last) were determined with an analysis of variance.

Results

Cyclosporine increased exposure of the minor active metabolite RP101988 approximately 2-fold. Point estimates and 90% CIs for RP101988 Cmax and AUC0-last were 1.96 (1.70, 2.25) and 1.75 (1.47, 2.09), respectively. However, cyclosporine had no effect on ozanimod and its major active metabolites. Point estimates and 90% CIs between treatments for ozanimod, CC112273, and CC1084037 Cmax were 1.01 (0.88, 1.15), 0.87 (0.75, 1.003), and 0.99 (0.87, 1.14), respectively. Point estimates and 90% CIs between treatments for ozanimod, CC112273, and CC1084037 AUC0-last were 1.07 (0.92, 1.26), 1.02 (0.85, 1.22), and 1.11 (0.71, 1.72), respectively.

Conclusions

Results from this new study indicate that coadministration of ozanimod with inhibitors of BCRP had no effect on the exposure of ozanimod and its major active metabolites.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0344 - Injectable versus oral first-line disease-modifying therapies: results from Italian MS register (ID 1384)

Abstract

Background

The advent of oral first-line disease-modifying therapies (DMTs) for relapsing-remitting multiple sclerosis (RRMS) has expanded considerably the therapeutic landscape. However, here is an important need to gather real-world evidence data regarding long-term treatment effectiveness and safety in comparison to the old first-line injectables DMTs.

Objectives

To compare old injectable and oral first line DMTs for time to first relapse, time to confirmed disability progression (CDP), and time to discontinuation in a cohort of RRMS patients extracted from the Italian MS Registry.

Methods

Multicentre, observational, retrospectively acquired and propensity-adjusted cohort study of RRMS-naïve patients in the Italian MS Register starting injective or oral first line DMTs between 1 January 2010 and 31 December 2017 to evaluate their impact on disability outcomes in patients. Enrolled patients were divided into two groups: injectable group (IG) and oral group (OG).

Results

From a cohort of 11,416 patients, 4,602 were enrolled (3,919 on IG and 683 on OG). IG had higher rate of women (67.3% vs 63.4%, p<.05) and a lower mean age (36.1±10.9 vs 38.9±11.8, p<.001). For the event time to first relapse, Cox models after PS adjustment revealed a lower risk for OG patients (HR 0.58 CI95% 0.47-0.70, p<0.001). About the risk of CDP, no differences were found in the two groups (HR 1.14 CI95% 0.88-1.48, p=0.306). About the risk of DMT discontinuation, OG patients showed lower risk (HR 0.70 CI95% 0.57-0.86 p=0.001) than IG patients.

Conclusions

Real-world data from the Italian MS registry suggest that first line oral DMTs are associated to lower risks of experiencing a new relapse and of therapy discontinuation in comparison to injectable DMTs.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0345 - Interim Analysis of Pregnancy Outcomes Following Exposure to Dimethyl Fumarate in a Prospective International Registry (ID 412)

Speakers
Presentation Number
P0345
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Recent US estimates suggest that the prevalence of multiple sclerosis (MS) is nearly 3 times higher in women, many of childbearing age. Oral delayed-release dimethyl fumarate (DMF) has demonstrated a favorable benefit-risk profile in trials and post-marketing surveillance. DMF should be used in pregnant women with MS only if the potential benefit justifies the potential risk to the fetus.

Objectives

To provide pregnancy outcomes and DMF exposure data as of 08 April 2020 in women with MS treated with DMF in an ongoing prospective international registry (NCT01911767, TecGistry).

Methods

Women exposed to DMF from the first day of their last menstrual period before conception or during pregnancy were evaluated. Data were obtained at enrolment, 6−7 months of gestation, 4 weeks after estimated due date, and 4, 12 and 52 weeks after birth. As reported previously, outcomes included live births, pregnancy loss, ectopic/molar pregnancies, birth defects and anomalies, and infant or maternal death after delivery. Gestational weight was classified by percentile (<10th, 10th−90th, >90th) based on standardized growth charts.

Results

As of 08 April 2020, 345 patients were enrolled, with a median age of 32 years. Median gestational week at first exposure to DMF was 1 (range: 0, 13) and at enrollment was 9 (0, 39.3). Median (range) duration of fetal DMF exposure duration was 5 (0, 40) weeks. Among discontinuations, one was due to a serious AE. Of the known outcomes, 277 were live births (122 with 52 weeks of follow-up), 19 fetal losses including 1 molar and 1 ectopic pregnancy resulting in spontaneous abortions. One neonatal death and no maternal deaths were reported. Of 274 infants of known gestational age, 249 (91%) were full term, and 25 (9%) premature (<37 weeks). Gestational weight data were available for 232 infants, of whom 26 (11%) were small, 190 (82%) appropriate, and 16 (7%) large. Overall, 8 infants had adjudicator-confirmed birth defects, including ventricular septal defect, congenital hydronephrosis, ureteral duplication, pyloric stenosis, transposition of the great vessels, unilateral developmental dysplasia of the hip, and 1 premature infant with multiple birth defects.

Conclusions

The pregnancy outcome frequencies observed in this updated analysis were consistent with previous reports and did not exceed those seen in the MS and general populations. No additional safety signals were identified.

Supported by: Biogen

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Disease Modifying Therapies – Risk Management Poster Presentation

P0346 - Is the gut a relevant reservoir for persistent JCPyV infection? (ID 1327)

Speakers
Presentation Number
P0346
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Natalizumab is an effective therapy for treatment of relapsing multiple sclerosis (MS). A serious side effect of natalizumab treatment is the occurrence of progressive multifocal leukoencephalopathy (PML) associated with JC polyomavirus (JCPyV) infection. A large fraction (20-30%) of individuals shed JCPyV DNA of wildtype variants in urine, yet around 50% of patients with the detection of anti-JCPyV antibodies in blood do not. PML-type JCPyV DNA variants have not been found in urine. Thus, the relevant reservoir of JCPyV remains unknown. We hypothesize that the gut may be this relevant reservoir and that natalizumab might alter the adaptive immunity in the gut. This could result in an increase in viral replication which would, in turn, facilitate viral genome alterations potentially inducing the formation of JCVPyV PML-type variants.

Objectives

Assessment of the gut as a potential reservoir for JC polyomavirus, associated with the development of progressive multifocal leukoencephalopathy.

Methods

The presence of JCPyV DNA in stool, urine and EDTA blood of natalizumab-treated MS patients (n=27; 22 female, 5 male) with known anti-JCPyV antibody index values in blood was assessed: antibody index above 1.5 (n=13), antibody index 1.5-0.9 (n=4), antibody index below 0.9 (n=4) and 6 with no detection of anti-JCPyV antibodies. Different DNA extraction methods and PCR techniques were applied and assay sensitivities assured performing spiking experiments.

Results

JCPyV DNA could not be detected in any of the EDTA blood or stool samples. Four urine samples had detectable JCPyV viral load, ranging from 4,500-427,000 copies/mL. All of these samples derived from patients with high antibody index values (>1.5).

Conclusions

The gut is either not the relevant reservoir for PML-associated JCPyV, or stool samples taken at a single occasion are not appropriate to test the hypothesis of JCPyV infection of the gut. As in our cohort the proportion of patients with detectable JCPyV DNA in urine was comparably low, further studies are ongoing validating our results, and improving sensitivity of the JCPyV PCR protocol from stool specimens.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0347 - Late-onset neutropenia in a multiple sclerosis patient after first dose ocrelizumab switched from rituximab (ID 127)

Speakers
Presentation Number
P0347
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Ocrelizumab is a humanized monoclonal anti-CD20 antibody approved for treatment of relapsing-remitting and primary progressive multiple sclerosis (MS). Before approval of this drug, the chimeric anti-CD20 antibody rituximab was used off-label for treatment of MS. On treatment with rituximab late-onset neutropenia (LON) was reported as a rare adverse event primarily in rheumatologic patients.

Objectives

So far, only two patients developing LON on treatment with ocrelizumab were reported leaving open the question about potential underlying mechanisms. By reporting a case of LON in a patient treated first with rituximab followed by ocrelizumab, we aim to raise awareness to this rare, but potentially threatening adverse event.

Methods

Here we report the case of a 21 years old female caucasian patient with highly active relapsing-remitting multiple sclerosis, who experienced LON after first dose ocrelizumab switched from rituximab.

Results

Our patient was first treated with two cycles rituximab in a dosage of 375 mg/m² body surface due to highly active multiple sclerosis. On treatment with rituximab she did not show any hematologic abnormalities. After interruption of treatment due to pregnancy she was switched to ocrelizumab and developed grade IV LON with neutrophil counts as low as 0.1x109/L.

Conclusions

This first case of LON in a patient treated with different anti-CD20 antibodies highlights the necessity of regular hemogram examinations on treatment with ocrelizumab. Patients may develop LON during ocrelizumab even if rituximab was previously well tolerated.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0348 - Lipoic acid modulates inflammatory responses of monocytes and monocyte-derived macrophages via cyclic-AMP and Nrf2-dependent mechanisms. (ID 1800)

Speakers
Presentation Number
P0348
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

Supplementation with oral lipoic acid (LA) significantly reduces brain atrophy in progressive multiple sclerosis (MS) subjects. However, its mechanisms of action are unclear. We hypothesize that LA provides protection by acting on peripheral immune cells; alterations in the peripheral immune system in MS are well established. Peripheral monocytes (Mo) migrate into the CNS and differentiate into macrophages, which are the predominant cell type in acute inflammatory lesions in MS. LA treatment results in generally less inflammatory phenotypes of human Mo and monocyte-derived macrophages (MDM), including alterations in inflammatory cytokines, inhibition of phagocytosis, and stimulation of the immunomodulator cyclic AMP (cAMP). LA is also an antioxidant that activates Nuclear factor erythroid-2-related factor 2 (Nrf2) in other cell types.

Objectives

Identify the mechanisms by which LA attenuates inflammatory responses of Mo and MDM. For cAMP-dependent immunomodulatory functions, determine the involvement of direct effectors (protein kinase A, PKA and exchange-protein activated by cAMP, EPAC). For Nrf2-dependent antioxidant functions, determine whether target gene NQO1 [NAD(P)H dehydrogenase quinone 1] expression is induced. Finally, examine expression of heme-oxygenase-1 (HO-1), a downstream effector of both cAMP and Nrf2 signaling, and determine the relative contribution of each signaling pathway to its activation.

Methods

Treat human Mo and MDM with LA in the presence of inhibitors of cAMP and Nrf2 signaling and perform qPCR, ELISAs, and phagocytosis assays to examine expression of NQO1 and HO-1, inflammatory cytokine secretion, and phagocytic activity.

Results

LA treatment increases mRNA expression of NQO1; this increase is blocked by Nrf2 inhibition. LA stimulates mRNA and protein expression of HO-1; this increase is blocked by inhibition of either Nrf2 or PKA, but not EPAC. Additionally, PKA appears to (partially) mediate the effects of LA on cytokine secretion in Mo, while Nrf2 and EPAC mediate these effects in MDM. Finally, inhibition of Nrf2 in Mo and inhibition of either Nrf2 or EPAC in MDM (partially) blocks LA inhibition of phagocytosis.

Conclusions

Both cAMP and Nrf2 signaling mediate LA’s modulation of inflammation, with differential contributions in Mo vs. MDMs. This information will facilitate the use of LA in MS therapy to achieve optimal efficacy, either on its own or as a targeted co-therapy with current disease-modifying drugs.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0349 - Long term effectiveness and safety of teriflunomide in Relapsing Remitting Multiple Sclerosis, and improvement in quality of life: Tericare study (ID 1654)

Presentation Number
P0349
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Teriflunomide is a once-daily oral immunomodulator approved for the treatment of relapsing forms of multiple sclerosis (MS) or relapsing remitting MS (RRMS) depending on the local label. Teri-CARE is a real-world study investigating quality of life and clinical outcomes in patients with RRMS treated with teriflunomide 14 mg in Spain.

Objectives

To evaluate effectiveness of teriflunomide in Relapsing Remitting Multiple Sclerosis (RRMS) and its impact on quality of life, fatigue and depression.

Methods

Prospective multicenter study in RRMS patients treated with teriflunomide for ≤4 weeks. Clinical data and questionnaires were completed during the inclusion visit and every 6 months for 2 years: MSIS-29 (MS-Impact Scale), MFIS (Modified Fatigue-Impact Scale), BDI (Beck Depression Inventory).

Results

325 patients with RRMS (36% naive, 71% female) were included. Median±SD age was 43,2±10,4, MS duration was 7,2±7,3 years, EDSS was 1,75±1,52, annualized relapse rate (ARR) was 0,4. 30% of patients presented T1Gd+ lesions (2,1±1,8). 49% reduction on ARR was observed on year 1 (0,22) and 60% on year 2 (0,17). EDSS was maintained stable after 2 years (1,83±1,66; p=0,081) and 80% of the patients did not show disability progression. T1Gd+ median lesion decreased at year 1 (1,5±0,7) and at year 2 (1,2±0,6). Nineteen patients reported 20 serious adverse events and no death was reported. After 2 years of treatment, a significant reduction in the psychological impact of MS was observed in the MSIS-29 (32,4±25,4 vs 28,8±24,5; p=0,001), but not in the physical component. At baseline, patients presented a mild grade of fatigue (MFIS: 26,4±21,1) and depression (BDI: 12,3±10,0), which were maintained at year 2 without significant changes.

Conclusions

Long term treatment with teriflunomide significantly reduces relapses and maintains disability progression stable. Teriflunomide improves aspects of quality of life and seems to delay the MS impact on fatigue and emotional well-being.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0350 - Long-term drug persistence in natalizumab JCV negative patients in the Swedish post-market surveillance study IMSE-1 (ID 464)

Speakers
Presentation Number
P0350
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Natalizumab (NTZ) is approved for treatment of relapsing-remitting multiple sclerosis. Progressive multifocal leukoencephalopathy (PML) caused by the reactivation of the John Cunningham virus (JCV) is a safety concern with NTZ treatment.

Objectives

To describe the long-term drug persistence in natalizumab JCV negative patients in a Swedish population-based setting.

Methods

The IMSE-1 study obtains demographic, clinical and safety data from the Swedish population-based Neuro Registry. Key inclusion criteria for this study were NTZ patients with a negative JCV values. Drug persistence was defined as the duration of time from initiation to discontinuation of therapy, estimated by the Kaplan-Meier approach, and Cox regression was used to identify possible independent factors related to drug discontinuation.

Results

A total of 1177 NTZ patients were included,76% were female and the mean age at treatment start was 34.3 (SD 10.0) years. The mean treatment duration was 5.5 (SD 3.0) years. 57% of the patients switched to NTZ from interferons and Copaxone, 27% were treatment naïve, and 14% from other disease-modifying treatments. At 10 years following treatment initiation of NTZ 6.5% had discontinued due to lack of efficacy, 6.7%, 24.4% and 28.9% due to adverse events, pregnancy and other reasons, respectively. An increased EDSS score at baseline increased the risk of discontinuation due to the lack of effect (HR 1.30; 95% CI 1.04-1.62), but the opposite was true for SMDT at baseline (HR 0.97; 95% CI 0.95-0.99). Also, relapses during treatment initiation had a significant effect on the risk of discontinuation due to lack of efficacy (HR 1.67; 95% CI 1.31-2.11). Only calendar year of symptoms and calendar year of treatment initiation had a significant effect on drug discontinuation due to adverse events (HR 1.11; 95% CI 1.04-1.18, HR 1.25; 95% CI 1.10-1.41).

Conclusions

Data from the Swedish IMSE-1 study suggest that long-term drug discontinuation due to a lack of efficacy or adverse events are minimal, and that the most common reason for treatment discontinuation was due to pregnancy.

Funding: The IMSE-1 study is funded in a scientific collaboration agreement with Biogen.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0351 - Lymphocyte reconstitution following discontinuation of Dimethyl fumarate (DMF) due to lymphopenia in the Swedish post-market surveillance study IMSE-5 (ID 463)

Speakers
Presentation Number
P0351
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Dimethyl fumarate (DMF) is an oral therapy approved for patients with relapsing-remitting multiple sclerosis (RRMS), and in which lymphocyte decline is a known pharmacodynamic effect of DMF. Currently, research has suggested meaningful lymphocyte reconstitution may occur within 2-4 months after discontinuation of DMF. To date, the only factor shown to be associated with a slower rate of recovery is the duration of lymphopenia.

Objectives

To describe lymphocyte count profiles following discontinuation of Dimethyl fumarate (DMF) due to lymphopenia in a nationwide Swedish population-based setting.

Methods

The IMSE-5 study obtains demographics, clinical and safety data, including absolute lymphocyte count (ALC), from the Swedish population-based Neuro Registry. Key inclusion criteria were RRMS patients, treatment with DMF for at least 3 months, age >18 years at initiation, had ALC values at start of DMF treatment, during treatment, and following discontinuation of DMF treatment. All patients had discontinued DMF due to lymphopenia. The least square mean estimation of ALC values at different time points was calculated using Linear Mixed Models

Results

A total of 18 DMF patients were included, 72% were female and the mean age at treatment start was 51.3 years. The mean treatment duration was 3.1 (SD 0.8) years, and 22% were treatment naïve, 50% had switched from interferons or glatiramer acetate (GA). and three patients switched from natalizumab and fingolimod. The estimated ALC values following discontinuation of DMF due to lymphopenia compared to the time for discontinuation significantly increased during follow up (p<0.001). E.g. at date of drug discontinuation mean ALC was 0.35x109/L (95% CI 0.33-0.37), in 6 weeks following discontinuation ALC was 0.50 x109/L (95% CI 0.26-0.74) and in 12 weeks ALC increased to 0.91 x109/L (95% CI 0.74-1.07). The mean time from discontinuation to a new treatment initiation following DMF was 99.8 (SD 88.5) days; and 50% switched to rituximab and two patients to teriflunomide, and one to GA.

Conclusions

Data from the Swedish IMSE-5 study suggest that a lymphocyte reconstitution occurs within 12 weeks following the discontinuation of DMF. However, larger datasets will be needed to verify this finding

Funding: The IMSE-5 study is funded in a scientific collaboration agreement with Biogen.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0352 - Lymphocyte Subtypes Repopulation Pattern and Secondary Autoimmunity in patients with RRMS treated with Alemtuzumab in a Real World setting (ID 1112)

Speakers
Presentation Number
P0352
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Alemtuzumab is a humanized monoclonal antibody targeting CD52 expressing T and B lymphocytes used as a second line treatment for patients with highly active Relapsing Remitting Multiple Sclerosis (RRMS). Treatment with alemtuzumab has been associated with increased incidence of secondary auto-immune adverse events. Although the exact underlying mechanisms remain unclear, it has been hypothesized that secondary auto-immunity is a result of the fast / excessive repopulation of autoreactive CD19 lymphocytes following their initial depletion.

Objectives

To investigate the potential association of peripheral lymphocyte subtypes kinetics following treatment with Αlemtuzumab with auto-immune adverse events as well as with disease activity and disease progression in patients with RRMS, in a real-world setting.

Methods

Α retrospective analysis of data from a series of 33 patients that received two courses of treatment and completed at least 24 months of follow up was performed. Primary endpoints included incidence of new or exacerbation of preexisting auto-immunities, disease activity and disease progression in association with lymphocyte depletion and repopulation patterns. Lymphocyte subpopulations (CD4+/CD8+ T cells, CD19+ B cells total and memory, CD56 NK cells) were measured using flow cytometry at baseline and at months one, three, six and twelve after each treatment course. Patients were assessed clinically and with MRI every six months throughout the 2-year follow-up period. Statistical analysis included generalized linear models for repeated measures.

Results

Overall, 17 adverse events of autoimmune origin and 2 cases of exacerbation of previously existing auto-immunities were observed. Lymphocyte repopulation patterns did not show significant differences in association with incidence of auto-immune reactions. Repopulation kinetics were also unrelated to any other primary outcome investigated in this study.

Conclusions

Our findings suggest that lymphocytes repopulation patterns do not have a predictive value of the incidence of secondary auto-immunity, as well as the activity and the progression of the disease, following treatment with Alemtuzumab. The mechanisms behind the differentiation among patients in regards to autoimmune reactions may lie in more specific lymphocyte subpopulations that have not been included in this study or in deeper molecular paths mediated by specific cytokines. Further study is required in this field.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0353 - Lymphopenia in patients treated with dimethyl fumarate. Risk factors and clinical significance. Experience in daily clinical practice (ID 1420)

Speakers
Presentation Number
P0353
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Dimethyl fumarate (DMF) treatment can cause sustained severe lymphopenia, which may be associated with an increased risk of developing infections, leading to discontinuation of treatment.

Objectives

The objective of the study is to identify the frequency and severity of lymphopenia and analyze risk factors for its development in our sample of patients with remitting recurrent multiple sclerosis (RRMS) treated with DMF. Another objective is to analyze whether the appearance of lymphopenia influences the evolution of the disease.

Methods

We carried out a retrospective, descriptive and analytical study of 50 RRMS patients treated with DMF between October 2014 and June 2020, followed for an average of 36.94 months.

Results

A total of 22 patients (44%) developed lymphopenia. Eleven patients developed grade 2 and 7 patients grade 3 lymphopenia. Eighty-two percent of patients developed lymphopenia in the first year. Only in 4 patients did lymphopenia resolve, 3 cases of grade II and 1 case of grade I lymphopenia.

Those patients who developed lymphopenia had a lower absolute lymphocyte count (ALC) before the start of DMF (p 0.013). Although with a trend towards statistical significance (OR 3.88, CI 0.87-17.3. p 0.068) an age at the start of DMF greater than 55 years was not correlated with an increased risk of lymphopenia. Seventy-six percent of the patients had received previous treatments for RRMS, including glatiramer acetate(22.5%), interferon (32.5%), teriflunomide (15.5%) and fingolimod (2.5%), without posing a risk of developing grade II-III lymphopenia.

In our population, the development of lymphopenia was not correlated with a greater probability of reaching NEDA3 at 2 years. Neither was it found to be associated with an increased risk of clinical or radiological activity or discontinuation due to ineffectiveness.

In our sample, lymphopenia was associated with a four times greater risk of developing infections (OR 4.1, CI 1.07-16.1. P 0.033), although all cases were mild. Six patients (12%) discontinued DMF due to sustained grade III lymphopenia. Three of them maintained an ALC of less than 800 at least 6 months after the end of DMF.

Conclusions

In our series, lymphopenia is a frequent adverse effect, it appears especially in the first year and in most cases it remains, even months after stopping DMF. Therefore, surveillance should be increased and control of ALC should be maintained given the increased risk of infection if lymphopenia develops, especially in those patients with lower ACL at baseline.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0354 - Management of infectious risk in multiple sclerosis: implication for screening, prophylaxis and therapies (ID 1839)

Speakers
Presentation Number
P0354
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

The DMTs largely used in MS may result in higher risk of infectious complications. Screening for and treatment of latent tuberculosis infection (LTBI) should be considered for patients receiving alemtuzumab, teriflunomide, fingolimod and natalizumab. Hepatitis B virus (HBV) reactivation may be harmful mainly for ocrelizumab and alemtuzumab treated patients.

Objectives

Aim of the study was to define the infectious risk in DMTs-treated MS patients with approaches tailored to individual patients.

Methods

At the Neuroinfectious Unit of Policlinico Umberto I (Rome), before starting or switching to DMTs, MS patients were evaluated for infectious risk. HBV and Mycobacterium tuberculosis (MTB) were investigated by serological test as hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (HBsAb), hepatitis B core antibody (HBcAb), and by quantiFERON®-TB Gold In-Tube (QFT) assay, respectively. HBV-DNA detection was performed in chronic hepatitis B MS patients and monthly monitored during DMTs. In QFT positive patients, active tuberculosis (TB) was excluded by medical history and chest X-ray and when necessary, sputum smear microscopy, sputum culture and MTB PCR were also performed. All LTBI patients were undergone to TB prophylaxis (isoniazid+rifampicin) for 3 months. DMTs were started after one-month prophylaxis.

Results

One hundred thirty-eight MS patients (79 females, 59 males) with a median age [interquartile range (IQR)] of 47.5 (37-56), median years of disease (IQR) of 8 (2-18) and median EDSS (IQR) of 3.5 (2-6), were enrolled. Before starting DMTs, 10.1% (14/138) of patients had chronic B hepatitis and 10.1% (14/138) showed QFT positivity. During DMTs follow-up, one patient revealed HBV reactivation. The patient remained asymptomatic with liver enzymes unchanged. HBV-DNA became undetectable after 2 weeks of specific antiviral treatment without discontinuing ocrelizumab. Among QFT positive patients, no TB reactivation was observed. Interestingly, one of the QFT negative patients became positive during fingolimod treatment.

Conclusions

HBV and TB screening should be recommended in MS patients candidate for DMTs. HBV monitoring may avoid a fatal event and the choice of a preemptive strategy spares HBV prophylaxis when unnecessary. Beside preventing TB reactivation, TB prophylaxis based on two active molecules, allows an earlier starting of DMTs. Moreover, TB screening may contribute to reduce the transmission, morbidity, and mortality of active disease in global population.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0355 - Management of lymphopenia associated with dimethylfumarate and fingolimod (ID 1472)

Speakers
Presentation Number
P0355
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Dimethylfumarate (DMF) and fingolimod (FTY) are licensed for the treatment of relapsing remitting multiple sclerosis (RRMS). Patients taking these medications may develop severe prolonged lymphopenia. The UK SPC recommends for DMF ‘interruption should be considered in patients with lymphocyte counts <0.5x109/L persisting for more than 6 months’ and for FTY ‘absolute lymphocyte count <0.2x109/l, if confirmed, should lead to treatment interruption until recovery’. There are currently no agreed guidelines for the long term management of patients who develop lymphopenia on DMF and FTY, which can lead to variance in treatment decisions when lymphopenia occurs.

Objectives

To review the number of patients who developed lymphopenia on DMF and FTY and to review the treatment decision for each episode of lymphopenia and determine the outcome, including when switching treatment to another disease modifying treatment (DMT) at The National Hospital for Neurology and Neurosurgery.

Methods

Retrospective audit of patients referred to the pharmacist led off-protocol blood monitoring clinic due to lymphopenia over a one year period (December 2018 to January 2019). Patients were followed up at varied time intervals until a sustained lymphocyte count recovery was achieved. In addition, the outcome of 20 patients on DMF and FTY who were referred to the off-protocol blood monitoring clinic for LC monitoring when switching to another DMT were assessed.

Results

27/478 patients on DMF were referred due to low LC. 12/27 patients experienced grade 3 lymphopenia for more than 6 months. 7/12 patients continued treatment with DMF, of which 3 patients had their dose reduced but still experienced chronic lymphopenia.16/179 patients on FTY were referred due to low LC. 12/16 patients experienced grade 4 lymphopenia for more than 1 month. 4/12 patients stopped FTY and 7/12 patients continued treatment with reduced dose. Mean washout period for 4 patients on DMF referred due to low LC prior to switching DMT was 115 days, however 1 patient had to commence bridging therapy with an injectable as LC remained <1.0 x 109/L for over a year. Mean washout period for 16 patients on FTY referred due to low LC prior to switching DMT was 90.4 days. 4 patients had to commence bridging therapy with an injectable as LC remained <1.0 x 109/L for over 6 months.

Conclusions

Few patients who experience chronic lymphopenia on DMF and FTY stop or switch treatment, and dose reduction of DMTs may not improve LC at the expense of reduced efficacy. The small case series of patients with low lymphocytes switching from DMF or FTY to other DMTs show the washout periods to allow for LC recovery are varied, and there are no clear markers to predict the time it takes for LC to recover. Follow up of this cohort is ongoing to establish if patients who have had treatment with DMF or FTY continue to experience recurrent lymphopenia when switched to another DMT.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0356 - MOG-derived Imotopes, a new class of MHC-II epitope modification, inducing cytolytic CD4 T-cells as novel immunotherapy in multiple sclerosis          (ID 1280)

Speakers
Presentation Number
P0356
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

ImotopesTM are synthetic peptides comprising an MHC-II T cell epitope sequence of an autoantigen associated in its flanking region with an amino acid motif having a thiol-disulfide oxidoreductase activity. Specific stimulation of CD4+ T cells with their cognate ImotopeTM can elicit cytolytic CD4+ T cells (cCD4) which are able to induce apoptosis of antigen presenting cells (APCs) presenting said T cell epitopes and also to eliminate pathogenic T cells activated by other epitopes on the same APC (bystander effect). Hence, ImotopesTM treatment has the potential to specifically eliminate pathogenic auto-immune responses and to possibly cure auto-immune diseases like multiple sclerosis.

Objectives

This study aimed to develop an ImotopeTM comprising an MHC-II T cell epitope contained within the MOG autoantigen, and to demonstrate its potency to generate in vitro specific and cytolytic CD4+ T cells from MS patients PBMCs.

Methods

MS patients PBMCs were used as a source of naïve CD4+ T cells. These were co-cultured with autologous APCs loaded with the ImotopeTM and periodically re-stimulated. ImotopeTM ability to generate antigen specific CD4+ T cells was evaluated by flow cytometry analysis and quantification of cytokines secretion in cells culture supernatants. Moreover, the lytic activity of the induced CD4+ T cells was evaluated by APC apoptosis quantification upon cognate interaction.

Results

ImotopeTM-induced CD4+ T cell lines were generated from several MS patients (n=6). Upon ImotopeTM re-stimulation, their specificity was detected by upregulation of the activation marker CD154 and by cytokines release, like for example IL-5. Furthermore, ImotopeTM-specific CD4+ T cell lines were reactive to the wild type T cell epitope, confirming their capacity to respond to the natural autoantigen. Importantly, ImotopeTM-induced CD4+ T cell lines were able to drive ImotopeTM-loaded APCs into apoptosis demonstrating their cytolytic phenotype.

Conclusions

The MOG-derived ImotopeTM designed to treat MS patients is able to induce autoantigen specific CD4+ T cells with a cytolytic phenotype (cCD4). This opens new avenues for therapeutic intervention with curative potential in MS.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0357 - Mouse astrocytes exhibit agonist-induced functional S1P1 receptor antagonism (ID 1250)

Speakers
Presentation Number
P0357
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

Sphingosine-1-phosphate (S1P) receptor subtype 1 (S1P1) plays a key role in regulation of lymphocyte trafficking. In multiple sclerosis patients, S1P1 agonists, such as fingolimod or siponimod, inhibit the egress of pathogenic lymphocytes from lymph nodes and their infiltration into the central nervous system (CNS) via lymphocyte-expressed S1P1 receptor down-modulation, also known as S1P1-functional antagonism. However, there is no evidence of this phenomenon in cells of the CNS.

Objectives

To assess the presence of agonist-induced S1P1 down-modulation in astrocytes using a calcium (Ca2+) signaling assay.

Methods

Murine astrocytes (C8-D1A) were incubated overnight and then loaded with a probe (Fluo-4AM, a dye that becomes fluorescent upon Ca2+ binding) for 1 hour, followed by adenosine triphosphate (ATP; 10 µM) over 30 min to activate the Ca2+ pumps. The cells were then treated with various S1P1 agonists (S1P [natural ligand for S1P receptors], AUY954 [selective S1P1 agonist], fingolimod [S1P1,3,4,5 agonist] or siponimod [S1P1,5 agonist]) at different concentrations (0.0001 µM up to 30 µM) to construct dose-response curves using agonist-induced Ca2+ signaling, measured as an increase in the intracellular fluorescence (via a FLuorescent Imaging Plate Reader [FLIPR]). To investigate the S1P down-modulation, the astrocytes were pretreated overnight with S1P1 agonists (1 µM) prior to probe loading, ATP priming, and agonist stimulation.

Results

All of the tested S1P1 agonists increased intracellular Ca2+ influx in the astrocytes in a dose-dependent manner, with concentration inducing half-maximal effect (EC50) within the range of 2–5 nM. Similar results were obtained after overnight pretreatment with the natural ligand, S1P (S1P1,2,3,4,5 agonist), confirming that S1P does not induce down-modulation of its own receptors.However, cells pretreated overnight with AUY954 did not exhibit agonist-induced intracellular Ca2+ signaling, suggesting the down-modulation of the S1P1 receptors. Similar outcomes were observed upon pretreatment with either fingolimod or siponimod, indicating their role as functional S1P1 antagonists on the murine astrocytes.

Conclusions

To our knowledge, this is the first report of agonist-induced S1P1 down-modulation in the astrocytes. Additional investigations on other neuronal and glial cells are warranted to establish whether this is a generalized phenomenon in the CNS.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0358 - Multiple Sclerosis with anti-N-methyl-D-aspartate receptor immunoglobulin G antibodies. An unusual relationship. (ID 1790)

Abstract

Background

The association between demyelinating diseases and the presence of anti-N-methyl-D-Aspartate receptor antibodies (anti-NMDAR-ab) has been analyzed in recent years. This infrequent coexistence has been seen above all with neuromyelitis optica spectrum disorders (NMOSD) and myelin oligodendrocyte glycoprotein associated disorders (MOGAD). The overlap with multiple sclerosis (MS) has been poorly described. In most of the published cases, patients presented symptoms consistent with NMDAR encephalitis, before, after, or concomitantly with demyelinating disease.

Objectives

We present the case of a patient with newly diagnosed Relapsing Remitting Multiple Sclerosis (RRMS) and with detection of anti-NMDAR-ab, without symptoms suggestive of encephalitis.

Methods

27-year-old woman, with gender identity disorder who was admitted for distal paresthesias in her lower limbs and in her hands which had developed in the last week. The examination revealed hypoesthesia and moderate hypopalestesia in these areas, with hyperreflexia in her lower limbs, suspecting myelitis as a diagnostic possibility.

Results

We performed a lumbar puncture that showed mild pleocytosis with normal proteins, increased Ig G and the presence of oligoclonal bands Ig G in cerebrospinal fluid (CSF).

Brain and spinal cord magnetic resonance showed twelve brain lesions, as well as several lesions in the cervical and dorsal spinal cord with a typical demyelinating appearance of MS and some of them with gadolinium enhancing.

In an autoimmunity study, anti-NMDAR-ab were detected at high titers in CSF and serum, with negative anti-aquoporin 4 (AQP4) and anti-MOG Ig G antibodies (performed in two centers using cell-based assay).

Given the presence of anti-NMDAR-ab, it was decided to extend the study by conducting a screening test for occult neoplasia that was negative, as well as an electroencephalogram and a neuropsychological study that did not show data suggestive of anti-NMDAR-ab clinical expression.

In the presence of a typical clinical syndrome together with characteristic findings in the complementary tests of RRMS, we treated the sensitive spinal cord outbreak with megadoses of corticosteroids with full resolution. The review of the little published evidence shows cases similar to ours that months or years later can develop NMDAR encephalitis. Given this risk, we believed that the use of anti-CD20 therapy of proven efficacy in RRMS was justified, which in turn presents a mechanism of action similar to Rituximab, widely used in pathology secondary to anti-NMDAr-ab. Finally, after a few weeks of stability, Ocrelizumab treatment was started, with a good response.

Conclusions

The coexistence of MS and NMDAR encephalitis is an entity under study. In our case, the anti-NMDAR-ab is asymptomatic so far, but it forces us to dismiss neoplasia, to monitor symptoms in the following years, and it has also been decisive in the choice of the disease-modifying drug.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0359 - Natalizumab and eosinophilia: epidemiological characteristics and clinical associations (ID 1442)

Speakers
Presentation Number
P0359
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Natalizumab is used as an immunomodulatory treatment in relapsing-remitting multiple sclerosis (RRMS). Blood eosinophilia as an adverse effect has been described.

Objectives

We aim to describe the frequency of blood eosinophilia and associated clinical symptoms in our monocentric cohort of natalizumab treated patients with relapsing remitting Multiple Sclerosis.

Methods

In our tertiary neurological care centre in Switzerland, we retrospectively longitudinally identified 115 natalizumab-treated and 116 untreated RRMS patients with eosinophil counts since July 2016 with our pharmacovigilance system and compared eosinophil counts, clinical symptoms and patient demographics.

Results

In total, 44/115 natalizumab-treated patients (38%) developed eosinophilia (>0.4 G/l), which occurred significantly more frequently compared to 116 untreated MS patients (n=3; 3%). Of 44 natalizumab-treated patients with eosinophilia, 43 remained asymptomatic; one patient one patient developed an eosinophilic pneumonia after 2 infusions of natalizumab, which resolved without sequelae after cessation. All untreated MS patients with eosinophilia remained asymptomatic.

Conclusions

Our cohort confirmed that eosinophilia is a potential side effect of natalizumab in RRMS patients and most commonly remains asymptomatic. However, in one of our natalizumab-treated patients (0.9% of all patients), an eosinophilic pneumonia occurred as a rare but severe side effect. Physicians should be vigilant for symptoms of an eosinophilic disease in natalizumab-treated patients. Further studies on drug safety in real-life settings using automated big data approaches are warranted to better describe drug-associated adverse effects.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0360 - No difference in radiologic outcomes for natalizumab patients on extended interval dosing compared with standard interval dosing in MS PATHS (ID 557)

Presentation Number
P0360
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Natalizumab extended interval dosing (EID) is associated with lower risk of progressive multifocal leukoencephalopathy than every-4-week standard interval dosing (SID). Independent real-world (RW) studies suggest that natalizumab effectiveness is maintained in patients who switch from SID to EID. MS PATHS (Multiple Sclerosis Partners Advancing Technology and Health Solutions) is a learning health system comprised of a collaborative network of healthcare institutions that provides access to RW clinical and MRI data collected using standardized acquisition protocols.

Objectives

Compare the effectiveness of natalizumab EID and SID using quantitative MRI metrics from highly standardized RW images in MS PATHS.

Methods

An MRI segment was defined as 2 MRI acquisitions and associated interval duration. MS PATHS patients with ≥1 MRI segment, ≥2 infusion cycles (infusion interval >21 days and ≤84 days), and complete covariate information were eligible. MRI segments with average infusion cycle (AIC) ≤35 days and >35 days were defined as SID and EID, respectively. For each MRI segment, new T2 lesions and changes in T2 lesion volume (T2LV) and brain parenchymal fraction (BPF) were compared for SID and EID using inverse probability weighting (IPW) with logistic regression and robust linear regression.

Results

IPW analysis included 327 SID patients (596 MRI segments) and 67 EID patients (85 MRI segments). The mean AIC for SID was 29.5 (standard deviation [SD] 1.8) days and 40.8 (4.9) days for EID. Mean MRI segment duration for SID and EID was 9.7 (SD 5.5) and 9.6 (5.3) months, respectively. Proportions of patients with no new T2 lesions were similar for the SID and EID groups (75.6% vs 75.3%; adjusted odds ratio for 0 vs ≥1 lesion=0.967 [95% CI 0.500, 1.871]; P=0.921). SID and EID patients did not differ significantly in adjusted T2LV change (−0.070 [95% CI −0.129, 0.111] mL vs 0.022 [−0.132, 0.180] mL; P=0.233) or BPF change (−0.1222% [95% CI −0.1524%, −0.0921%] vs −0.1442% [−0.2234%, −0.0649%]; P=0.617).

Conclusions

MRI activity was low in SID and EID MS PATHS patients, and there were no significant differences in MRI outcomes between the 2 groups. These results confirm and extend previous RW studies of natalizumab EID effectiveness. Study limitations include modest EID sample size and potential channeling bias. The ongoing phase 3b randomized trial NOVA (clinicaltrials.gov NCT03689972) will further evaluate the effectiveness of natalizumab EID versus SID.

MS PATHS is supported by Biogen.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0361 - Non-thyroid secondary autoimmune diseases after alemtuzumab treatment: real-world data from a nationwide prospective observational cohort in Sweden. (ID 664)

Speakers
Presentation Number
P0361
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Alemtuzumab (ALZ) belongs to the immune reconstitution therapies for relapsing-remitting multiple sclerosis (RRMS). ALZ therapy is associated with an increased risk for secondary autoimmune diseases (SAD), in particular autoimmune thyroid disorders (AITD), but there are also an association to increased risk of immune mediated thrombocytopenic purpura (ITP) and other rare autoimmune disorders.

Objectives

To investigate the occurrence of SAD, other than AITD, and if auto-antibodies (Ab) could predict the development of non-thyroid SAD (NTSAD).

Methods

All RRMS patients in Sweden initiating ALZ (n=124, 74 females) 2014-2019, were consecutively included in this prospective observational study. Plasma samples were obtained prior to ALZ and at 6, 12 and 24 months of follow-up for analyses of glutamic acid decarboxylase Ab (GADAb), antinuclear Ab (ANA), smooth muscle Ab (SMA), antimitochondrial Ab (AMA) and anti-glomerular basement membrane Ab (GBMAb). Monthly blood and urine tests, as well as clinical symptoms, were followed to detect NTSAD.

Results

At mean follow-up of 4.5 (SD 1.6) years 8 patients (6.5%) had developed NTSAD; 5 ITP (4%), 2 neutropenia (2%), and 1 warm antibody haemolytic anaemia (1%). Mean time from baseline to respective NTSAD was 2.1 (SD 1.7) years, 0.6 (SD 0.7) years, and 5.5 years. At their diagnoses positive auto-Ab against platelets, neutrophils and erythrocytes, were present in 1, 0 and 1 ALZ treated patient respectively. No treatment was given for ITP in 3, 1 had intravenous immunoglobulin, romiplostim, corticosteroids, 1 had platelet transfusion, corticosteroids. 1 with neutropenia had granulocyte-colony stimulating factor. No treatment was given for the case with haemolytic anaemia. At baseline 1% (n=1/115) had positive GADAb, 12% (n=13/112) positive ANA, 4% (n=5/112) positive SMA, 0% (n=0/112) positive AMA and 3% (n=3/115) positive GBMAb. Besides these, the number of patients who at least once during the follow-up were positive for the auto-Ab that we regulatory checked for was as follows; 1% (n=1/124) GADAb, 10% (n=13/124) ANA, 3% (n=4/124) SMA, 0% (n=0/124) AMA and 0% (n=0/124) GBMAb, none of these developed any associated NTSAD.

Conclusions

In this real-world cohort study the occurrence of NTSAD, after ALZ treatment, was mainly hematologic, most frequent ITP (4%) and the majority required no treatment. Although the occurrence of auto-Ab was slightly more common after ALZ, compared to the general population, no corresponding NTSAD was found. This was in contrast to thyroid auto-Ab which often precede thyroid disease.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0362 - Novel treatment approach for fingolimod-associated progressive multifocal leukoencephalopathy in a patient with relapsing remitting multiple sclerosis (ID 967)

Speakers
Presentation Number
P0362
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Progressive multifocal leukencephalopathy (PML) due to the polyoma JC virus (JCV), remains an untreatable viral infection. Aside from addressing the underlying cause of immunodeficiency, there remains no evidenced-based treatment for PML. PML is rarely seen in fingolimod-treated relapsing remitting multiple sclerosis (RRMS) patients.

Objectives

We present a 62 year-old man with RRMS of 20-years duration treated with fingolimod for 6 years who developed PML and discuss the response to a PD-1 inhibitor, pembrolizumab.

Methods

Onset of illness was insidious with progressive left leg weakness, gait unsteadiness, slurred speech, double vision, asymmetric cerebellar ataxia, bilateral internuclear ophthalmoplegia and spastic paraparesis. Expanded disability status scale (EDSS) increased from 6.0 to 6.5. Fingolimod was immediately withheld.

Results

Magnetic resonance imaging (MRI) scan demonstrated new, patchy, non-enhancing hyperintense lesions within the white matter of frontal lobes, right thalamus and brainstem. 160 copies/ml of JCV-DNA were detected in the cerebrospinal fluid (CSF). Mirtazepine dose was increased to 45mg daily. Despite a few weeks’ clinical stability, MRI appearances and JCV-DNA copies worsened over the next 3 weeks followed by gait deterioration. Maraviroc 300mg twice daily was then introduced. Subtle punctate contrast enhancement, suggestive of a mild immune reconstitution inflammatory syndrome (IRIS), was transiently seen within the midbrain and right frontal areas of signal change 6 weeks after fingolimod cessation, followed by a single focal-to-generalised tonic clonic seizure. EDSS increased to 8.0. Mefloquine 250mg weekly and 3 monthly doses of 200mg pembrolizumab, were administered. Serial CSF examinations and several imaging modalities including spectroscopy and fused FDG-PET-MRI were used to distinguish between PML, PML-IRIS and MS activity. The patient’s symptoms and “PML lesions” on brain MRI scans remained stable, although a handful of small, enhancing ovoid lesions developed between the first two doses of pembrolizumab. Following the second dose of pembrolizumab, a sustained but gradual improvement in imaging and examination parameters was observed with JCV-DNA becoming undetectable 16 weeks following fingolimod withdrawal. EDSS improved from 8.0 to 6.5.

Conclusions

This case highlights several challenges of managing PML, a highly life threatening condition. To our knowledge this is the first case of combined therapy and use of pembrolizumab in a fingolimod-associated PML.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0363 - Ocrelizumab as exit strategy from natalizumab: results from a clinical series (ID 854)

Speakers
Presentation Number
P0363
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Natalizumab (NTZ) is a highly effective treatment for relapsing-remitting (RR) multiple sclerosis (MS), but its prolonged use can be associated with an increased risk of progressive multifocal leukoencefalopathy (PML). Therefore, NTZ is mainly interrupted in the context of PML risk management strategy, but its discontinuation can be followed by a marked increase of disease activity. Currently, there is no consensus on either the duration of the washout period, or the best subsequent treatment approach. Few data are available on the use of anti-CD20 monoclonal antibodies (mostly rituximab) after NTZ withdrawal, whereas only a small case series of patients switching to ocrelizumab (OCR) has been published in literature.

Objectives

To evaluate the effectiveness, tolerability and safety of OCR in a real-world cohort of MS patients switching from NTZ.

Methods

Demographic, laboratory, clinical and MRI data were collected in this retrospective, observational study, performed on MS patients attending Parma MS centre (Northern Italy).

Results

23 patients (14 females, mean age 40.4 ± 8.57 years) were analysed during a mean follow-up of 15 months (range 5-34), since NTZ discontinuation. Patients had the following characteristics at OCR start: RR course in 74% and progressive active disease in 26%, mean EDSS 3.1 (1.5-6.5), mean disease duration 11 ± 5.67 years and median number of NTZ infusions 28 (13-122). The reasons for switch included PML concern in 78% of cases and suboptimal response to NTZ in 22%. The majority (83%) of patients was JCV+ and only 6 were treated with NTZ extended interval dosing for ≥18 months. The median washout period was 50 days (41-251); all patients underwent a brain MRI immediately before OCR start. Only 4/23 (17%) and 1/19 (5%) patients experienced clinical relapses (all within the first 6 months of therapy) and MRI activity, respectively. ARR decreased from 0.41 (during NTZ) to 0.18 with OCR. Mild adverse events (mostly infusion reactions, hypogammaglobulinemia and leukopenia) occurred in 74% of cases. No patients discontinued OCR and no PML cases emerged.

Conclusions

OCR is effective and well tolerated in highly active MS patients switching from NTZ. A median 6-week transition period appears reasonably safe to balance the risk of disease reactivation with that of opportunistic infections. Larger datasets are needed to confirm the risk of carryover PML in relationship with the length of washout period.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0364 - Ocrelizumab real-world safety and effectiveness in the two years of treatment in multiple sclerosis. (ID 1855)

Speakers
Presentation Number
P0364
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Ocrelizumab (OCR), used in the treatment of multiple sclerosis (MS), is a monoclonal antibody targeting CD20, resulting in B-cell depletion.

Objectives

To describe the patient two-year experience of MS patients treated with OCR at the Rocky Mountain MS Center at the University of Colorado.

Methods

94 randomly selected MS patients prescribed OCR prior to May 2018 at the Rocky Mountain MS Center at the University of Colorado were retrospectively followed for up to two years from OCR start date. Lab data, relapse history, adverse events, MRI outcomes, disease history and patient characteristics were collected. Descriptive statistics were used to describe the sample group.

Results

Patients had a mean age of 44.2 years at date of first infusion; were predominantly female (75.5%); and had a mean MS disease duration of 10.4 years. Of the sample group, 76 (80.9%), 16 (17.0%), and 2 (2.1%) were relapsing-remitting, secondary progressive, and primary progressive MS, respectively. Two (2.1%), 1 (1.2%), and 6 (7.4%) patients experienced a clinical relapse, enhancing lesion and new T2 lesion, respectively. Of 48 patients with available MRI data for re-baselining after initiation of OCR, 1 (2.1%) patient had a new T2 lesion. Twenty (21.3%) patients discontinued OCR at our center at <24 months. Nine patients were lost to follow-up or relocated care, 7 patients discontinued due to issues with insurance, 1 patient discontinued due to adverse events, specifically hypogammaglobulinemia, and 3 patients discontinued due to other reasons, such as family planning and concern for cancer. During the first and second infusion course, 19 (20.2%) and 7 (7.4%) experienced an infusion reaction that interrupted the OCR infusion, respectively, and none experienced a life-threatening reaction or were hospitalized. After initiating OCR, 3 patients were diagnosed with basal cell carcinoma. Infections resulting in an emergency department visit or hospitalization occurred in 11 (11.7%) and 1 (1.1%) patients, respectively. Eleven (11.7%) patients experienced lymphopenia ≤500/mm3, and 2 (2.1%) experienced neutropenia ≤1000/mm3. Seven (7.4%) patients experienced IgG levels ≤500, 25 (26.6%) experienced IgM levels ≤40.

Conclusions

Our data suggests OCR is safe and effective in the treatment of MS. Additional data on an increased sample size will be presented.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0365 - Ocrelizumab treatment in patients with progressive multiple sclerosis: a single-center real-world experience (ID 1628)

Speakers
Presentation Number
P0365
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Ocrelizumab (OCR) treatment in pivotal trials of patients (pts) with progressive multiple sclerosis (PMS) has demonstrated to slow disability worsening, with a good safety profile. However, real-word data on efficacy and adverse events (AE) are still scarce.

Objectives

To provide first experience data regarding efficacy and safety of OCR use in PMS pts treated within a real-world setting.

Methods

We collected safety and efficacy data from all PMS pts treated with OCR at the MS Center of the University of Genoa. The probability of disability-, relapse- and MRI activity-free survival and NEDA-3 status was calculated with Kaplan-Meier estimator and Cox proportional hazards regression analysis. AE were recorded throughout the follow-up (FU).

Results

We recorded data from 59 PMS pts [42 (71%) with primary-progressive (PP) MS and 17 (29%) with secondary progressive (SP) MS, 24 females (41), mean (SD) age 49.8 (8.2) years] with a mean disease duration (DD) of 12.1 (10.1) years, a median (IQR) baseline EDSS of 5.5 (3.5-6.0) and median number of previous DMTs 1 (0-2). SPMS patients had longer DD (20.8vs8.6; p=0.004) and had mean ARR of 0.24 (0.4). 21 (36%) pts had not received any DMT prior to OCR. Mean FU was 2.0 (1.1) years. 14 (24%) patients had an active MRI brain scan at baseline. At 1-year FU, MRI-inflammatory-activity-free survival was 87.3% (CI95%: 76.9-97.7%), relapse-free survival was 100% and progression-free survival was 82.7% (72.3-93.1%). NEDA-3 status was achieved in 72.3% (59.0-85.5%) of pts. No differences were noted between patients with PP and SPMS. At multivariate analyses, no baseline characteristic was found be predictive of a higher probability of progression-free survival, MRI-activity-free survival and NEDA-3 status. We recorded 69 AE in 36 pts (32 upper respiratory tract infections; 6 herpes simplex-1 reactivation; 7 lower urinary tract infections; 1 acute myeloid leukemia following myelodysplastic syndrome; 1 appendicitis treated with surgical procedure). No serious infusion-associated reactions were reported.

Conclusions

We report short-medium term efficacy data in a real-world population of progressive patients treated with OCR, including a relatively high proportion of patients without MRI activity at baseline assessment. Our data suggest that OCR should be considered as treatment option in both patients with PPMS and SPMS.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0366 - Ocrelizumab-Therapy associated Lymphopenia is linked to age in patients with Multiple Sclerosis in a Single-Centre Retrospective Cohort Study. (ID 1413)

Speakers
Presentation Number
P0366
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Ocrelizumab is a humanised monoclonal anti-CD20 antibody approved for intravenous treatment of both relapsing-remitting Multiple Sclerosis (RRMS) and primary progressive Multiple Sclerosis (PPMS) since 2018. The OPERA I, II and ORATORIO trials have shown evidence of efficacy and safety of B-cell depletion with Ocrelizumab but also detected newly occurring lymphopenia in 20% to 26% of patients. Although Ocrelizumab is increasingly clinically established, treatment associated lymphopenia in patients with Multiple Sclerosis (pwMS) has barely been studied.

Objectives

Our aim was to objectify and analyse incidence, course, and severity of lymphopenia in pwMS and to investigate risk factors in a real-life setting.

Methods

We performed a single centre retrospective cohort study in n=72 Ocrelizumab-treated patients with RRMS and PPMS. Patients were followed-up from 2016 to 2020. Age, sex, and Expanded Disability Status Scale (EDSS) at initiation of Ocrelizumab treatment (baseline) were investigated as well as number, drugs, and duration of prior treatments. Absolute numbers of lymphocytes (cells/microliters) at baseline and during treatment were collected. Lymphopenia was defined by <1000 cells/microliters. Odds ratios (OR) were calculated for lymphopenia and age, duration, and previous treatments.

Results

Patients were medium aged 41 years (range 21 to 60 years) with a median EDSS of 4.0. The cohort was 75% female. Of all patients 82% had received prior treatments with Dimethyl Fumarate (40.28%), Fingolimod (23.61%) and Natalizumab (23.61%) being the most relevant drugs. Mean lymphocyte counts were 1745 ±702 at baseline, 1318 ±523 after three months and 1488 ±478 after fifteen months follow-up. We observed lymphopenia in n=15 (20.83%) patients after three months of Ocrelizumab but only in 10.55% after 15 months follow-up (OR 1.46 versus 1.0 for lymphopenia and therapy duration at three and fifteen months). While 73.33% of patients with lymphopenia were aged >40, only 54.39% with normal lymphocyte count were over 40 (OR 2.31 for lymphopenia and age >40). Number and type of prior treatments did not differ significantly between patients with and without lymphopenia (OR 0.95 for lymphopenia and prior treatment).

Conclusions

We observed Lymphopenia in 20.83% of patients after three months of treatment with Ocrelizumab. Analyses of possible risk factors indicate patients’ age to be the major risk factor for development of lymphopenia during ocrelizumab therapy.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0367 - Online Medical Simulation Identifies Rationales for the Use and Avoidance of DMTs for Highly Active MS Among Neurologists (ID 1141)

Speakers
Presentation Number
P0367
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Despite the availability of over a dozen different disease-modifying therapies (DMTs) for the long-term management of multiple sclerosis (MS), evidence shows that clinicians have difficulty personalizing the selection of these therapies. To help address this issue it is important to assess the clinical decision-making process of clinicians who manage MS. .

Objectives

A study utilizing a proprietary online medical simulation platform assessed the specific reasons why neurologists chose or avoided DMTs in patients with highly active MS.

Methods

A cohort of US-based neurologists who participated in a simulation-based CME intervention were evaluated. The simulation consisted of two cases presented in a platform that allowed physician learners to choose from lab tests and assessment scales as well as the free form identification of a specific diagnosis and appropriate therapeutic treatment. Both of the cases involved a patient with highly active MS and who is a candidate for higher efficacy DMTs. Clinical decisions made by the participants regarding assessment, diagnosis, and treatment are captured. After a physician learner identifies a specific DMT, he or she is then prompted to select an appropriate rationale for why a DMT was chosen. A rationale was also asked if a DMT was chosen which was not an immune reconstitution therapy. The data being reported focus only on the rationale portion of the simulation. Data were collected between June 6, 2019 and September 25, 2019.

Results

112 neurologists completed the first case simulation and 80 neurologists completed the second case simulation. The first case was a patient diagnosed with MS 8 months ago and initially prescribed dimethyl fumarate, but is experiencing a debilitating relapse with new lesions on MRI. Among the monoclonal antibodies chosen by the learners, perceived efficacy was the most frequently chosen rationale. Fingolimod and siponimod were chosen due to the oral route of administration. In learners who did not choose alemtuzumab or cladribine, insurance coverage and adverse events were the reasons given for avoiding these therapies. In the second case, the patient was diagnosed with MS 22 months ago, was on several prior DMTs, and most recently experienced a relapse with new MRI lesions while receiving fingolimod. Learners who chose to treat this patient with cladribine and natalizumab did so because of its perceived efficacy. The most frequent reason for choosing alemtuzumab was because it results in immune reconstitution and those who chose ocrelizumab did so because of positive clinical trial data. In learners who did not choose alemtuzumab or cladribine, insurance coverage and adverse events were the most common reasons.

Conclusions

This study demonstrated that neurologists choose DMTs for different reasons depending on the case. Additional programming should continue to identify rationales for the selection of DMTs in clinically representative cases of MS.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0368 - Persistent severe lymphopenia of at least one-year duration after dimethyl fumarate discontinuation: three case reports (ID 1901)

Presentation Number
P0368
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Dimethyl fumarate (DMF) is an oral disease-modifying therapy (DMT) that was approved by the FDA to treat relapsing-remitting multiple sclerosis in 2013. Since then, several studies evaluating the safety of this medication have revealed a favorable risk-benefit ratio. The most common adverse events (AEs) are flushing and gastrointestinal symptoms such as nausea or diarrhea. However, there are other less common AE that can potentially be harmful, including persistent lymphopenia. On average, 2.4-7% of the patients on DMF develop grade III lymphopenia (defined as absolute lymphocyte count (ALC) <0.5 × 109 cells/L). In most cases, ALCs reconstitute within weeks to months after discontinuation of DMF.

Objectives

Understanding the AE profile of a medication is important in order to ensure patient safety and provide the most appropriate care.

Methods

Here we report three cases of RRMS presenting with severe persistent lymphopenia of at least one-year duration after DMF discontinuation.

Results

One of the patients continues to have severe lymphopenia 4 years after cessation of DMF. No other anti-proliferative agents were administered to these individuals.

Conclusions

The most important risk factors for developing lymphopenia are increased age, lower baseline ALC, and previous treatment with natalizumab. There are has been a report of 38 cases of severe, prolonged lymphopenia after DMF discontinuation. However, the majority of these patients had grade III lymphopenia persisting for ≥6 months by 3 years on DMF treatment, yet treatment continued for a median of 2.9 years. The unique characteristic of our three patients is that DMF treatment duration was <2 years before grade III lymphopenia onset and despite discontinuation of DMF within 1-year of severe lymphopenia onset, their ALCs didn’t recover. To date, they continue to have severe lymphopenia. This clinical experience highlights the importance of considering lymphopenia as a possible AE prior to starting DMF. Furthermore, it also emphasizes the need to establish protocols to manage DMF induced lymphopenia, especially in situations that require immune-competence for.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0369 - Posibble Risk Factors in Fingolimod Rebound Syndrome (ID 1874)

Speakers
Presentation Number
P0369
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Fingolimod Rebound Syndrome (FRS) is defined as flare-up of the disease activity upon withdrawal of treatment in patients with MS. FRS is usually seen between the 4th and 16th week following fingolimod discontinuation. In different studies , FRS development rates change between 5% and 52%. It has been reported that, during cessation of fingolimod besides having low lymphocyte count and low EDSS score; response to the treatment (no clinical/radiological activity during the treatment period) and wash out period left after fingolimod could affect FRS development.

Objectives

The objective of this study was to identify our potential risk factors and the modifable determinants on the development of FRS.

Methods

MS patients presenting between 2012 – 2019 and treated with fingolimod were all included in the study. Fingolimod was discontinued after at least 6 months and those experience FRS after cessation were evaluated in terms of all demografic and treatment features.

Results

In totally 661 patients 8.9% (n=59) discontinued fingolimod depending on various reasons. Among the discontinued group 10 (16.9%) patients experienced FRS.

72.9% of the patients were female in the total discontinued group, 60% was female in the FRS group. The median (min-max) MS duration was 10 (2–25) years in the whole group, while it was 9 (4–23) in the FRS group. The median time under fingolimod was 42.5 (16–78) and 43.5 (13–72) months respectively in the discontinued and FRS groups. The washout period after fingolimod was statistically similar between groups (64.5 (7–1270) and 106.5 (7–1110) days respectively (p=0.117)). The mean±SD duration between drug discontinuation and development of FRS was found as 56.98±1.79 days. The median (min-max) of EDSS score of the FRS patients was 4 (1–7) and of the total group it was 4.5 (1–8.5).

Conclusions

Patients should be closely monitored during first two months of cessation of fingolimod therapy and appropriate immunomodulatory treatment should be initiated without delay.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0370 - Post-approval safety of subcutaneous interferon β-1a in the treatment of multiple sclerosis, with particular reference to respiratory viral infections (ID 812)

Speakers
Presentation Number
P0370
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Subcutaneous interferon β-1a (sc IFN β-1a) is a well-established disease-modifying therapy for relapsing multiple sclerosis (RMS). Since its introduction to the market, the estimated cumulative exposure to sc IFN β-1a amounts to 1,766,525 patient-years (to 03 May 2020). In recent months the COVID-19 pandemic has become a concern for MS patients and their healthcare providers in terms of the associated safety of their disease-modifying therapy.

Objectives

To report on the post-approval safety profile of sc IFN β-1a in patients with RMS, including COVID-19 and other respiratory viral infections.

Methods

Serious and non-serious adverse events (AEs) from post-approval spontaneous individual case safety reports are presented from February 1998 to May 2020. AE rates are shown as total number of patients. Up-to-date COVID-19 findings are summarized.

Results

A total of 525,268 AEs have been reported, with 6.6% of events classified as serious. No new safety concern has been identified, and there was no trend towards increased respiratory viral infections occurring during sc IFN β-1a treatment. An analysis of the top five most common respiratory viral infection AEs reported spontaneously (influenza, viral infection, H1N1 influenza, viral bronchitis, and viral upper respiratory tract infection) did not reveal any abnormal trend outside the known safety profile of sc IFN β-1a, and cases were typically non-serious. The most commonly reported respiratory viral infection was influenza with 2369 cases (constituting 0.45% of all AEs), followed by viral infection (319), H1N1 influenza (15), viral bronchitis (6), and viral upper respiratory tract infection (5). There was also no suggestion of an increased risk of more severe respiratory viral infection or other adverse drug reactions in patients with RMS and experiencing a respiratory viral infection while being treated with sc IFN β-1a. As of 9 June 2020, the Merck safety database included 23 cases of confirmed COVID-19 in sc IFN β-1a treated MS patients. An update on latest findings on COVID-19 infections will be presented.

Conclusions

Cumulative to May 2020, no new safety concern has been identified from the post-approval data of sc IFN β-1a, including no increased risk for respiratory viral infections.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0371 - Practice improvement by retrospective analysis of changes in lymphocyte levels in patients with multiple sclerosis on dimethyl fumarate. (ID 394)

Speakers
Presentation Number
P0371
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

There are currently no recommendations on lymphocyte subset monitoring as best practice for patients on disease-modifying therapies, including dimethyl fumarate (DMF). Instead, patients are monitored for general lymphocyte count, which may mask changes in subsets of clinically relevant cell populations. There have been several cases of patients on DMF without severe lymphopenia but did have a high CD4+:CD8+ T cell ratio who went on to develop progressive multifocal leukoencephalopathy (PML), caused by the reactivation of John Cunningham virus (JCV). These incidents suggest that monitoring changes in subpopulations is clinically relevant and important. Since CD3+CD8+ (CD8+) T cells and CD3-CD56+ Natural Killer (NK) cells are primarily responsible for eliminating cells with actively replicating viruses., changes in circulating levels of these specific populations of cells may put patients at risk of developing recurring infections, including JCV.

Objectives

Our objective was to characterize the changes in immune profile associated with use of DMF. We hypothesized that CD4+ T cells counts would remain relatively stable while CD8+T cells and NK cell levels would decrease. Demonstrating changes in the relevant lymphocyte populations in our cohort will promote monitoring and assessment of lymphocyte subpopulations of patients on DMF.

Methods

A retrospective analysis of longitudinal data from 299 patients who have been treated with dimethyl fumarate at the Fraser Health Multiple Sclerosis clinic in British Columbia, Canada. The blood test results date range from January 1 2013- April 1 2020. The following cell populations were analysed: white blood cells, neutrophils, lymphocytes, CD3+CD4+ T cells, CD3+CD8+ T cells, CD3+ cells, CD19+ B cells and CD3-CD56+ NK cells. We created a linear regression model to estimate average changes in lymphocyte subpopulation counts.

Results

On average, our patients remain on DMF for 31 months, after which time CD8+ T cell count decreases by -67% and reaching lower range after 21 months. CD4:CD8 T cell ratio increases 41.6% and reaches upper range only 2 months after treatment start. White blood cells, lymphocytes, CD4+ T cells and NK cells also decrease (-29%, -49%, -48% and -52%, respectively) but at a much slower rate. During recovery, while CD8+ T cells, CD4+ T cells, NK cells and lymphocytes were able to recover in 3-4 months, CD4:CD8 T cell ratio would not recover until 9 months after treatment end.

Conclusions

Our results suggest that lymphocyte count may not be sensitive enough to detect early and critical changes to lymphocyte subsets that may be important for preventing viral infection.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0372 - Predictors of  Therapeutic Adherence in Multiple Sclerosis  in Argentina   (ID 1425)

Speakers
Presentation Number
P0372
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Adherence to prescribed treatment in chronic disease is a critical factor for a successful therapeutic response. However, in conditions like multiple sclerosis (MS), where the treatment is mainly preventive, it might be inadequate. The reasons for poor adherence may be related to multiple factors.

Objectives

The objective is to evaluate adherence to Multiple Sclerosis treatment and identify predictors that could affect it.

Methods

This is a cross-sectional study consisting of a cohort of MS patients conducted at a National Medical Care Program: PAMI (Programa Atención Médica Integral) in Argentina, during January 1st and October 1st 2017 available in the database of drug dispensing. Variables related to disease, patient, health system and treatment were evaluated from a brief telephone survey. The medication possession ratio (MPR) was used to estimate adherence, MPR<80% defined nonadherence. The association between predictor variables and adherence were assessed with a logistic regression model.

Results

Out of the 648 patients included in the database, a total of 360 (55.5%) surveys were conducted. 311/360 (86.4%) stated that they were receiving treatment for MS at the moment of the survey. Mean age was 55.3 (SD 12), 216 (60%) female. The optimal adherence to treatment was 45.3%.

Median disease duration was 14.5 years (IQR 13). During last year, 117 (32.5%) had relapses. Fatigue was moderate to severe in 297 (82.5%) of patients, 201 (56%) patients required assistance to walk. 107 (33.6%) of patients forgot to take the medication and 103 (29%) presented symptoms suggestive of depression.The mean of neurological controls were 3.8 (SD 2.6) per year. The median delay to authorization of medication was 2.3 (IQR 10) weeks.

198 (63.7%) received injectables therapies, most commonly used were interferons. In the multivariate model, we only found an association between adherence and the oral route of administration (OR 1.96 CI95% 1.20-3.20, p= 0.006). In a secondary post hoc analysis we found that the predictors of receiving oral drugs were higher educational level (OR 2.86 CI95% 1.06-7.66) and the presence of associated comorbidities (OR 1.59, CI95% 0.98-2.57).

Conclusions

Treatment adherence has been suboptimal. The use of injectable drugs was associated with nonadherence to treatment. No adherence predictors associated with the patient, disease and health system were found.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0373 - Profile of multiple sclerosis patients on treatment with ocrelizumab and socio-economic impact of the disease (ID 1735)

Speakers
Presentation Number
P0373
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

BACKGROUND: Multiple sclerosis (MS) is a progressive disease from the onset, independently of disease phenotype. Early treatment with highly effective disease modifying therapies (DMTs) contributes towards prevention of disease progression, hence improved quality of life of MS patients and a diminished socio-economic burden.

Objectives

OBJECTIVE: The primary objective was to assess the MS patients’ profile and treatment satisfaction from treatment with ocrelizumab; the secondary objective was to investigate the socio-economic impact of the disease.

Methods

METHODS: A retrospective analyze, under the routine clinical practice, of patients receiving ocrelizumab was conducted at University Clinic of Neurology in Skopje, excluding any personal data.

Results

RESULTS: Data was collected for 87 patients receiving ocrelizumab at our Clinic, whereby 93% were diagnosed with RMS (relapsing multiple sclerosis) and 7% with PPMS (primary progressive multiple sclerosis). 78% of the cohort were females; mean age was 38.9 years (range 19-58) and mean EDSS score was 3.9 (range 1-6). 7.4 % of RMS patients were treatment naïve, the rest were eligible for ocrelizumab as second line treatment. 49% of the patients are unemployed, whereby 28% cannot work because of MS and 37% have premature pension. 76% and 15% of the treated patients are satisfied and very satisfied from their treatment with ocrelizumab, respectively. 100% of the patients prefer to receive their treatment every six months, which results with less frequent hospital visits and increased convenience for the patient.

Conclusions

CONCLUSIONS: The use of ocrelizumab in treatment of MS patients enables an innovative approach in MS management, resulting with a high treatment satisfaction level among treated patients and diminished socio-economic burden in terms of convenience and indirect costs. Prevention of disease progression contributes towards preserving the working capacity of MS patients, which has a long-term positive impact on the society as a whole. Ocrelizumab as a highly efficient and well-tolerated DMT is becoming the standard of care for a wide spectrum of MS patients offering unprecedented benefits for quality of life improvement.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0374 - Progressive MS patients of older age on ocrelizumab: real-world experience at Columbia University Irving Medical Center (ID 1059)

Speakers
Presentation Number
P0374
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Seminal trials evaluating ocrelizumab in multiple sclerosis (MS) have primarily shown benefit in patients with younger age, lower baseline EDSS, shorter disease duration, and evidence of higher inflammatory disease activity. The risk/benefit profile in patients who do not fit this description, accounting for a significant proportion of patients with progressive MS on this therapy, is unknown.

Objectives

To describe our experience with older primary progressive MS (PPMS) and secondary progressive MS (SPMS) patients on ocrelizumab.

Methods

The Genentech My Patient Solutions® online database was queried for patients at our center at least 55 years old at the time of ocrelizumab enrollment. Patients with PPMS or SPMS were entered into a database for retrospective chart review. Descriptive statistics were performed.

Results

A total of 56 patients with progressive forms of MS (33% PPMS, 66% SPMS) ages 55 years and older (median 64, range 56-77) at the time of ocrelizumab initiation were identified. At baseline, 46% of patients had more than three documented comorbidities, median EDSS was 6.0 (range 2 - 7.5) and disease duration was 17.7 years. 87% of patients had exposure to at least one prior DMT (most commonly rituximab n=27; glatiramer acetate n=18; interferon beta-1a n=17). At two years, 44% of patients with a baseline EDSS < 5.5 had >1-point increase (n=4, delta-EDSS 1.5) and 39% with a baseline EDSS >5.5 had >0.5-point increase (n=11; delta-EDSS 0.5) confirmed on sequential visits >12 weeks apart. EDSS remained stable in 57% (n=21) and improved in 3.0% (n=1). T25FW increased by >20% in 21% of patients (n=8; delta-T25FW 33%); though data was limited by ambulatory status and variable testing. Subjectively, 46% of patients reported feeling worse, 17% stable, 13% equivocal, and 5% improved at two years. Infections were reported in 27% (n=15) of patients, 2 of which were severe. No neoplasms were diagnosed during treatment. 13 patients discontinued therapy due to progression of disease (n=4), infection (n=4), clinical trial enrollment (n=2), hypogammaglobulinemia (n=1), infusion-related reaction (n=1), and poor venous access (n=1).

Conclusions

In this small, retrospective study of older progressive patients on ocrelizumab, 40% (n=15) had clinically meaningful disability progression at two years. This is a higher rate than reported in younger, less disabled patients with PPMS in clinical trials. More research is still needed to clarify the risk/benefit profile in this understudied MS subpopulation with a high rate of comorbidities and unique disease trajectory contributing to functional decline.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0375 - Quantifying the risk of disease reactivation after DMT discontinuation – the VIAADISC score (ID 765)

Abstract

Background

There is a lack of evidence guiding treatment decisions regarding discontinuation of disease-modifying therapy (DMT) in multiple sclerosis (MS)

Objectives

To generate and validate a composite (clinical and MRI-based) score able to identify individual patients with relapsing MS (RMS) with a high risk of experiencing disease reactivation after discontinuation of DMT.

Methods

The study was conducted using a generation and a validation dataset drawn from two separate prospectively collected observational databases. We included RMS patients who received interferon-beta or glatirameracetate for ≥12 months, then discontinued DMT for ≥6 months and had ≥2 years of follow-up available. In the generation sample (n=168), regression analysis was performed to identify clinical or MRI variables independently predicting disease reactivation after DMT discontinuation. A predictive score was calculated using the variables included in the multivariable model. This score was then applied to the validation sample (n=98).

Results

The variables included in the final model as independent predictors of disease reactivation were age at discontinuation (p<0.001), MRI activity at discontinuation (p<0.001), and duration of clinical stability (p<0.001). The resulting score (Vienna Innsbruck DMT discontinuation score based on age, activity on MRI and duration in stable course; VIAADISC) was able to identify patients at high (83-84%), moderate (35-38%) and low risk (7%) of disease reactivation within 5 years after DMT discontinuation both in the generation and in the validation cohorts.

Conclusions

The composite VIAADISC score may be a valuable tool informing patients and neurologists in the face of deciding if and when to discontinue injectable DMTs.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0376 - RAM-589.555 favors neuroprotective/anti-inflammatory profile of CNS-resident glial cells in acute relapse EAE affected mice (ID 1276)

Speakers
Presentation Number
P0376
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

Targeting RNA Polymerase-1 (POL1) machinery is a new strategy for suppression of multiple sclerosis (MS) relapse activity. Oral administration of POL1 inhibitor RAM-589.555, which is characterized by high permeability and bioavailability in naïve mice, ameliorates proteolipid protein (PLP)-induced experimental autoimmune encephalomyelitis (EAE) by suppressing activated autoreactive lymphocytes.

Objectives

To assess the accessibility of RAM-589.555 to the central nervous system (CNS) of EAE-mice and further investigate its immunomodulatory effects on CNS-resident astro- and micro-glial cells in-vitro and in-vivo.

Methods

Effects of RAM-589.555 on activated microglia and astrocyte viability, proliferation, and secretion of neurotrophic factors were assessed in-vitro. The pharmacokinetic of RAM-589.555 was evaluated in the blood and central nervous system (CNS) of EAE affected mice. High-dimensional single-cell mass cytometry was applied to characterize the effect of RAM-589.555 on EAE-affected mice’s CNS-resident micro- and astro-glial cells and CNS-infiltrating immune cells, which were obtained seven days after RAM-589.555 administration at EAE onset. Simultaneously, the expression level of pre-rRNA, the POL1 end product, was assessed in blood cells, microglia, and astrocytes to monitor RAM-589.555 effects.

Results

RAM-589.555 demonstrated blood and CNS permeability in EAE mice. In-vitro, incubation with 400 nM of RAM-589.555 significantly reduced viability and proliferation of lipopolysaccharide (LPS)-activated microglia by 70% and 45% (p<0.05), respectively, while tumor necrosis factor a (TNFα)-activated astrocytes were not affected. The secretion of neurotrophic factors was preserved. Furthermore, seven days after administration of RAM-589.555 at EAE onset, the level of pre-rRNA transcript in peripheral blood mononuclear cells (PBMC) was decreased by 38.6% (p=0.02), while levels of pre-rRNA transcript in microglia and astrocytes remained unchanged. The high-dimensional single-cell mass cytometry analysis showed decreased percentages of CNS-resident microglia and astrocytes, diminished proinflammatory cytokines (IL-1β, IL-6, IL-12, IL-17, TNFα and IFNγ) and an increase of their anti-inflammatory cytokines (IL-4, IL-10 and TGFβ) in RAM-589.555-treated compared to vehicle-treated mice (p<0.05).

Conclusions

These data correlate RAM-589.555-induced clinical amelioration and its CNS permeability to decreased CNS-inflammation, and decreased micro- and astro-gliosis, while restoring micro- and astro-glial anti-inflammatory and neuroprotective capacity.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0377 - Real world experience with cladribine: patient profile, efficacy and safety. (ID 1430)

Presentation Number
P0377
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

Cladribine is a nucleoside analog of deoxyadenosine, recently approved for treatment of active multiple sclerosis (RMS) defined by neuroimaging or clinical features.

Objectives

We analyze our treated patients profile, efficacy and safety in real clinical practice after two years of experience.

Methods

Two-year retrospective observational study of our RMS patients treated with oral cladribine, analyzing demographic, clinical, efficacy and safety data.

Results

n=81 (78% women), mean age 37.7 years (21-65) and a previous mean EDSS of 2.67(1-6). The mean time of evolution of RMS prior to treatment was 6.7 years and the mean annualized relapse rate 1,2. 50% of patients had at least 10 lesions in T2 with a mean of ehanced lesions of 0.9 (0-4). The mean of previous treatments was 1.25 and the mean time with last treatment was 2.44. Drug tolerance was good, with less than 15% adverse effects (Aes), all mild and self-limiting. Lymphocyte counts reached a mínimum mean value of 1.03x103/mm3 in month 3, with subsequent recovery and only 3 patients reaching asymptomatic grade 3 (0.04%). Currently 24 patients have received second year according to protocol, haveing detected previos radiological activity in four of them (0.05%) and clinical activity in two (0.02%), being reason for discontinuation in one patient without completing complete course of treatment.

Conclusions

In our experience, and after its first two years in clinical practice, oral cladribine is emerging as a treatment with a good efficacy and safety profile in active MS, in parallel with the available evidence.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0378 - Real World Experience with Ocrelizumab in patiens with Relapsing-Remitting Multiple Sclerosis (ID 380)

Speakers
Presentation Number
P0378
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Ocrelizumab is an anti-CD20 humanized monoclonal antibody approved for the treatment of relapsing-remitting multiple sclerosis

Objectives

To describe baseline characteristics of patients with RRMS treated with OCR. Analyze previous disease modifying treatments(DMT), reasons to change, safety and laboratory parameters

Methods

Retrospective observational study in patients with RRMS treated with OCR from November 2016 to May 2020 at Virgen Macarena Hospital, Seville, Spain.

Demographic/disease characteristics, ARR, previous DMTs, reasons to change DMT, adverse events changes in disability, and cerebral MRI findings were collected at enrolment.

Results

38 RRMS patients were treated with OCR (65,8%females) Mean follow-up after OCR initiation:11,4 months (1-40) 47,4% have received two or more cycles of treatment.

Average age was 39.8 years (21-58) Mean time since RRMS diagnosis was 9,9 years (0,3-26,2) The patients had been treated with a mean of 1,5DMT prior to OCR. 3 of them were treatment naïve. DMT previous OCR was IFN-b 2pax, glatiramer acetate 2pax, teriflunomide 4pax, dimethyl fumarate 3pax, rituximab 1pax, fingolimod 16pax, natalizumab 3pax, alemtuzumab 3pax. The reason to DMT change were: lack of efficacy:32 pax; security:6 pax (vJC seroconversion or alemtuzumab contraindications)

After 11,4 months of OCR initiation, annualized relapse rate (ARR) decreased from 1,2 to 0, and the EDSS score remained unchanged: mean 3,8 (1,5-6,5). None of the patients had relapses after OCR initiation.

Regarding cerebral MRI parameters, Gd+ lesions diminished from 1,3 previous to 0 after OCR. T2 lesion burden showed no changes on cerebral MRI.

The more frequent adverse events were infusion reactions (26,32% of patients: 4 fatigue; 3 headache; 3 redness skin; 2 allergic reaction) All of them were mild but in two patients lead to treatment discontinuation (allergic reaction). Infections occurred in 3 patients (2 urinary tract infection, 1 zoster reactivation)

Five patients (13,2%) showed decrease in total lymphocyte count (3 grade 1; 2 grade 2) 18,9% patients showed IgM index under lower limit of the normal range. All patients showed normal levels IgG index before and after OCR. Percentage of CD19+Cells diminished in all patients: median of 14%(previous) to 1%(after OCR) No clear associations between lymphopenia/immunoglobulines and infections was detected.

Conclusions

This data shows that RRMS patients treated with OCR in a real world clinical setting show significant decreases in ARR and the majority maintain EDSS score unchanged. The most common adverse event were mild infusion reactions and mild infectious diseases. Some patients showed lymphopenia and IgM below lower limit of normal. No clear associations between lymphopenia/immunoglobulines and infections was detected.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0379 - Real World Experience with Ocrelizumab in patients with Primary Progressive Multiple Sclerosis (ID 381)

Speakers
Presentation Number
P0379
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Ocrelizumab is an anti-CD20 humanized monoclonal antibody. Is the first disease modifying treatment(DMT) approved for the treatment of primary-progressive multiple sclerosis(PPMS). It has shown to reduce Confirmed Disability Progression at 12 and 24 weeks over placebo

Objectives

To describe the baseline characteristics of patients with PPMS. Analyze effectiveness, safety and laboratory parameters in PPMS patients treated with OCR

Methods

Retrospective observational study in patients with PPMS treated with OCR from January 2011 to May 2020 at Virgen Macarena Hospital, Seville, Spain.

Demographic/disease characteristics, ARR, previous DMTs, adverse events, changes in disability, and cerebral MRI findings were collected at enrolment.

Results

18 PPMS patients were treated with OCR(50%females) Mean follow-up since OCR initiation:13,8 months(1-38) 16 patients(88,89%) have received ⥸2 courses.

Average age: 47 years(37-57) Mean time since PPMS diagnosis: 5,38 years(0,5-12,3)

6 patients(33,3%) received a previous DMT(3Laquinimod, 1Rituximab, 1Fingolimod, 1Teriflunomide)

Mean EDSS changed from 5,7 to 5,8 after a mean of 13,8 months receiving OCR(1 patient worsened) None of the patients have had relapses or GD+ lesions prior or after OCR. T2 lesion burden showed no changes on cerebral MRI.

The main adverse events were infusion reactions, that appeared in 38,89% of patients (6fatigue, 1skin redness) None lead to treatment discontinuation. Infections appeared in 22,2% of patients (3urinary tract infection, 1herpes simplex reactivation) All solved with treatment.

None of the patient showed decrease in total lymphocyte count. 2 patients (11,1%) showed IgM index under lower limit of the normal range. All patients showed normal levels IgG index before and after OCR. Percentage of CD19+Cells diminished in all patients: median of 13%(previous) to 1%(after OCR) No clear assotiations between lymphopenia or low serum IgM was detected.

Conclusions

In our sample, 94,4% of PPMS patients treated with OCR show EDSS stabilization after 18 months of treatment. ARR and MRI parameters showed no changes. The main adverse events were mild infusion reactions(38,9%) and mild infections(22,2%)

The principal analytical finding was decrease of CD19+Cells and/or IgM decrease. No clear assotiations between lymphopenia or low serum IgM was detected.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0380 - Real-world data of peginterferon beta-1a from a Swedish national post-marketing surveillance study (IMSE 6) – effectiveness and safety profile (ID 677)

Speakers
Presentation Number
P0380
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Subcutaneous peginterferon beta-1a (PegIFN) was approved for relapsing-remitting multiple sclerosis (RRMS) in Europe 2014. The clinical trial program showed that PegIFN reduced the relapse rate and proportion with disability progression compared to placebo. At its launch in Sweden, PegIFN was included in the Swedish “Immunomodulation and Multiple Sclerosis Epidemiology Study” (IMSE 6), providing possibilities to track long-term effectiveness and safety in a population-based setting.

Objectives

To follow-up the long-term effectiveness and safety of PegIFN treatment in Swedish patients in a real-world context.

Methods

Data was obtained from the nationwide Swedish Neuro Registry (NeuroReg) between June 2015 and May 2020. Effectiveness measures were assessed using the Wilcoxon Signed Rank Test and drug survival using the Kaplan-Meier curve.

Results

A total of 364 patients (78% female; 87% RRMS; mean age at treatments start 43 years) were followed up to 57 months (mean 20 months), of which 200 (55%) patients had been treated for at least 12 months. The majority of the patients had switched from other injectables (164 patients, 45%) or were treatment naïve (90 patients, 25%) prior to treatment with PegIFN. Over the duration of the follow-up, 68% (247/364) patients discontinued their PegIFN treatment for various reasons (60% adverse events, 24% lack of effect) and switched mainly to rituximab (105 patients, 43%). The overall drug survival was 32%, 40% for men and 30% for women. The one- and two-year drug survival rate was 57% and 40%, respectively. The mean number of relapses were reduced from 0.35 one year before treatment start to 0.11 one year after (35% missing data). All clinical effectiveness measures (Extended Disability Status Scale (EDSS), Multiple Sclerosis Severity Scale (MSSS), Multiple Sclerosis Impact Scale (MSIS-29), European Quality of Life – 5-Dimension test (EQ-5D), Visual Analogue Score (VAS) and Symbol Digit Modalities Test (SDMT)) remained stable. Statistically significant changes were observed in SDMT (p=0.027). A total number of 18 adverse events (6 serious) were reported to Swedish Medical Product Agency.

Conclusions

These findings are consistent with PegIFN being a safe disease modifying treatment, however, a relatively high proportion of patients switched due to adverse events. All clinical effectiveness measures remained stable in patients treated with PegIFN for at least 12 months in this nationwide population-based real-world study. Longer follow up is needed to address the long-term effectiveness.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0381 - Reduced sphingosine kinase gene expression in SPMS vs. RRMS astrocytes revealed by single-nucleus RNA-seq (ID 1784)

Speakers
Presentation Number
P0381
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

The sphingosine 1-phosphate (S1P) receptor modulators, siponimod and fingolimod, have overlapping yet also distinct mechanisms underlying their efficacy for treating multiple sclerosis (MS). Siponimod directly binds to S1P receptors (S1P1,5), whereas fingolimod is a prodrug that requires sphingosine kinases (SPHK1/2) to generate active fingolimod-phosphate (engaging S1P1,3,4,5). Both drugs functionally antagonize S1P1 on immune and central nervous system (CNS) cells. Siponimod showed activity in clinical trials of progressive MS (SPMS), whereas fingolimod (trialed in PPMS) did not. However, the mechanistic explanation for the clinical differences between these two S1P receptor modulators is unclear.

Objectives

Single-cell transcriptome profiles of SPMS and RRMS brains might identify differential gene pathways in relevant cell types that may explain the clinical differences between siponimod vs. fingolimod.

Methods

We applied single-nucleus RNA sequencing (snRNA-seq) using 10x Genomics on nuclei derived from region-matched prefrontal cortices of SPMS vs. RRMS-affected brains.

Results

The snRNA-seq yielded 33,197 high quality nuclei that were clustered into major CNS cell types. SPMS brains, as compared to RRMS brains, showed perturbation in sphingolipid pathway genes, and most notably, a downregulation of SPHK1 in astrocytes. Functional proof-of-concept was obtained in an animal model of MS, experimental autoimmune encephalomyelitis (EAE), which resulted in diminished fingolimod efficacy in astrocyte-specific Sphk1/2 double knockout mice.

Conclusions

SPMS brains show reduced SPHK1/2 expression, particularly SPHK1 in astrocytes of SPMS brains. Although it is not clear whether or not this results in reduced local exposure to active fingolimod-P in the MS brain, animal EAE studies are consistent with its functional reduction. These data further support changes in the metabolism of sphingolipids during MS progression that highlight a major metabolic difference for fingolimod vs. siponimod, which could have significant clinical relevance particularly since siponimod does not require SPHK1/2 for receptor activation.

We thank Dr. Shaun R. Coughlin (UCSF) for providing the Sphk1/2flox/flox mice. This work was supported by a grant from Novartis Pharma AG (JC) and the NIH R01NS103940 (YK).

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0382 - Reduction in CUA MRI lesions in the first 6 months of cladribine tablets treatment for highly active relapsing multiple sclerosis: MAGNIFY-MS study (ID 982)

Speakers
Presentation Number
P0382
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

The MAGNIFY-MS study (NCT03364036) aims to determine the onset of action of cladribine tablets 3.5 mg/kg over 2 years (CT3.5) in patients with relapsing multiple sclerosis (RMS). Efficacy data from the pivotal trial CLARITY showed that outcomes in CT3.5-treated patients were superior to placebo with regard to number and relative reduction of standardized combined unique active (CUA) lesions over the 96-week trial. Carrying out early and frequent magnetic resonance imaging (MRI) will provide valuable insights into the onset of action of CT3.5.

Objectives

To report on the onset of action of CT3.5 by observing changes in counts of CUA MRI lesions during the first 6 months of the MAGNIFY-MS study.

Methods

MRI scans were performed at screening, baseline, and at months 1, 2, 3 and 6 following CT3.5 treatment on patients with highly active RMS. Differences in CUA lesions between post-baseline periods (period 1, months 1–6, period 2, months 2–6, and period 3, months 3–6) were compared to the baseline period. CUA lesion count was standardized to period length and number of MRIs in a period. A mixed effects linear model was used to account for within pooled centre correlation and adjusted for CUA lesion count during the baseline period, age, and baseline expanded disability status scale (EDSS; >3, ≤3). Type-I-error inflation due to multiple testing was controlled by a gatekeeping procedure.

Results

The full analysis set considered for primary analysis included 270 patients. Reductions in mean CUA count were observed from month 1 onwards compared to baseline; by -1.193 in period 1, -1.500 in period 2 and -1.692 in period 3 (all p<0.0001). In particular, the mean T1 Gd+ lesion counts were decreased from month 2 onwards compared to baseline; by -0.857 at month 2, -1.355 at month 3 and -1.449 at month 6 (all p<0.0001). Sensitivity analysis using negative binomial distribution showed that the treatment effect increased with time measured as lack of CUA in subsequent periods; by 61% in period 1, 77% in period 2, and 87% in period 3 (all p<0.0001). The proportion of patients without any CUA lesions increased in the first 6 months; by 52% in period 1 (p=0.0241), 66% in period 2 (p<0.001), and 81% in period 3 (p<0.001).

Conclusions

MRI was used to assess disease activity in a group of highly active RMS on CT3.5 treatment from one month onwards. Data show an early onset of action on CUA lesions that was significant from month 1 versus baseline, with a treatment effect that increased over the first 6 months.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0383 - Resistance of CD11c+ B cells to anti-CD20 depletion with treatment initiation and early preferential repopulation of anti-inflammatory B cells in MS (ID 1210)

Speakers
Presentation Number
P0383
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

Anti-CD20 therapy is highly efficacious in limiting new disease activity in multiple sclerosis (MS), which depletes most circulating B cells and a small subset of T cells. However, relatively little is known about how anti-CD20 therapy affects T cells.

Objectives

We aimed to define phenotypic and functional profiles of B cells during depletion and early reconstitution following anti-CD20 antibody initiation.

Methods

Peripheral blood mononuclear cells (PBMC) were serially isolated and cryopreserved using strict standard operating procedures prior to treatment, early (3-4 months) and/or later (approx. 6 months). Following anti-CD20 (ocrelizumab) treatment initiation, in 18 previously treatment-naive MS patients. Functional immune phenotyping was performed in batch using multi-parametric flow cytometry panels developed and validated for use with cryopreserved PBMC.

Results

In addition to plasmablasts which, as expected, were not fully depleted, CD11c+ B cells appeared less efficiently depleted after treatment initiation. By 6 months post-treatment, B cells were partially repopulated, though to differing extents across individuals. In general, CD10+ transitional B cells (implicated as anti-inflammatory), and a subset of memory B cells, were preferentially repopulated. The repopulating B cells exhibited increased proliferation, though they expressed lower levels of activation markers and higher levels of regulatory markers. Ratios of IL-6/IL-10-producing B cells were significantly diminished in the reconstituting population, as compared to the treatment-naïve baseline.

Conclusions

The abnormal pro-inflammatory/anti-inflammatory imbalance of B cells seen in untreated MS patients appears improved in reconstituting B cells even after an initial cycle of ocrelizumab, though with a considerable degree of heterogeneity across patients. Unexpectedly, CD11c+ B cells, that have been implicated as pro-inflammatory in other systemic autoimmune diseases, appeared less susceptible to depletion. Of interest is whether a particular imbalance between CD11c+ B and other B cell subsets may underlie the infrequent episodes of disease activity observed early after treatment initiation.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0384 - Risk Factors for Developing Lymphopenia and Hypogammaglobulinemia in anti-CD20 Treated Patients with Multiple Sclerosis (ID 1482)

Speakers
Presentation Number
P0384
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Anti-CD20 treatment has been associated with both lymphopenia and hypogammaglobulinemia, which can increase the risk of infection. Who develops lymphopenia and hypogammaglobulinemia and the time course is not well understood.

Objectives

To evaluate risk factors in developing lymphopenia and hypogammaglobulinemia in anti-CD20 treated patients with multiple sclerosis (MS).

Methods

A random sample of patients with neuroimmune conditions treated with rituximab at the Rocky Mountain MS Center at the University of Colorado were identified and followed retrospectively. Patients who switched to ocrelizumab remained in the study. Patient characteristics, IgG, IgM, and absolute lymphocyte counts on rituximab/ocrelizumab were analyzed.

Results

Laboratory data on 546 patients were studied including 527 MS and 17 neuromyelitis optica spectrum disorder patients with mean disease duration of 9.2 years, mean age of 44.1, 68.7% women and 76.5% Caucasians. Patients were followed for a mean of 30.2 months with a mean cumulative rituximab dose of 3,312mg. Of the 527 MS patients, 96 (17.6%) switched to ocrelizumab (mean cumulative ocrelizumab dose of 1,175mg). Fifty-seven (10.4%) patients had lymphopenia (≤500cells/mm3), 38 (7.4%) low IgG (≤500 mg/dL), and 143 (37.9%) low IgM (≤40 mg/dL). A decrease of 31.5mg/dl per year in IgG from 920mg/dL in year 1 to 857mg/dL in year 3 was observed. Respectively, median time to lymphopenia, low IgG, and low IgM were 11.3, 36.2 and 23.6 months. Of patients who developed low IgG (≤500 mg/dL), 73.9% had a preceding (34.8%) or concurrent initial low IgM (39.1%). Higher doses (per gram) of anti-CD20 increased the odds of low IgG (OR: 1.28, 95% CI: 1.12-1.47; p<0.001) and low IgM (OR: 1.31, 95% CI: 1.18-1.45; p<0.001), but not of lymphopenia (p=0.246). Similarly, follow-up time (months) on anti-CD20 therapy increased the odds of low IgG (OR: 1.49, 95% CI: 1.23-1.80; p<0.001) and low IgM (OR: 1.45, 95% CI: 1.28-1.65; p<0.001), but not of lymphopenia (p=0.237). Increasing age was associated with an increased odds of lymphopenia (OR: 1.03, 95% CI: 1.00-1.05; p=0.030), but not low IgG (p=0.27) or IgM (p=0.18). Males had greater odds of low IgM values compared to females (OR: 2.87, 95% CI: 1.84-4.48; p<0.001).

Conclusions

MS patients treated with anti-CD20 therapies frequently develop low IgM. Lymphopenia and low IgG are less common but should be monitored given their association with an increased risk of infections.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0385 - Risk factors for ocrelizumab infusion reaction in a rural Appalachian population (ID 1190)

Speakers
Presentation Number
P0385
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Ocrelizumab is an anti-CD20 monoclonal therapy for multiple sclerosis. The most common adverse reaction seen with ocrelizumab is infusion-related reaction (IRR). While the majority of these infusion reactions are mild in severity, some patients have a serious reaction or discontinue therapy. Additionally, the major randomized controlled trials, OPERA 1 and 2, and ORATIO, demonstrated IRRs at 34% and 40%, respectively. Risk factors for IRRs are not clearly established.

Objectives

Determine current rates of ocrelizumab infusion-related reactions, length of infusions, and risk factors for infusion-related reactions amongst multiple sclerosis patients in a rural Appalachian clinic.

Methods

226 patients were analyzed for IRR and associated risk factors. Statistical analysis was performed using IBM Statistics (Version 26), and P values ≤ 0.05 were considered statistically significant. Frequency of IRR was compared between groups using Fisher’s exact test, and binary logistic regression models were used to identify predictors of IRR. Means of normally distributed linear variables were compared between groups using independent samples T test.

Results

79 of 226 patients had at least one IRR (35%). IRRs occurred 128 times per 900 individual infusion sessions, (14%). Of all the demographic and medical history variables evaluated, female sex was the only significant factor associated with having an IRR: females were 2 times more likely than males to have an IRR (P=.021). Additionally, patients who had an IRR during the initial induction therapy were 12 times more likely to have a subsequent IRR than patients without an induction IRR (p<.0001). The mean length of infusion was significantly longer in patients who had an IRR compared to those who did not, 241 minutes and 217 minutes, respectively (p<.0001).

Conclusions

Our study showed at least one IRR occurring in 35% of patients receiving ocrelizumab which is nearly identical to the rates reported in clinical trials. Similar to the 2019 study by W Conte et al, male sex was protective against IRR. Patients with IRR during initial induction dose carried a high risk of further IRR; therefore, this subgroup could benefit from more aggressive pre-medications. Not surprisingly, IRRs extended the length of infusions but only by an average of 24 minutes. This does make the full length of an ocrelizumab infusion about 6 hours when pre-infusion and post-infusion waits are included. Due to sparse treatment centers, lengthy infusions create a travel challenge for rural Appalachian patients. Studies are ongoing to test the safety of faster infusion rates with ocrelizumab which would benefit our patient population substantially.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0386 - Safety and Effectiveness of Dimethyl Fumarate Maintained Over 5 Years in Multiple Sclerosis Patients Treated in Routine Medical Practice (ID 430)

Speakers
Presentation Number
P0386
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

In clinical studies, delayed-release dimethyl fumarate (DMF) demonstrated a favorable benefit–risk profile in patients with relapsing-remitting multiple sclerosis (MS). Real-world studies enable characterization of risks that may only emerge with long-term exposure in clinical practice. ESTEEM (NCT02047097) is an ongoing 5-year study characterizing long-term safety and effectiveness of routinely prescribed DMF in MS patients.

Objectives

To report 5-year safety and effectiveness in patients with multiple sclerosis (MS) treated with DMF under routine care.

Methods

Patients treated with DMF were recruited from ~380 sites. The primary objective was to determine incidence, type, and pattern of serious adverse events (SAEs), and AEs leading to discontinuation. Secondary objectives included assessment of DMF effectiveness on annualized relapse rate (ARR) and patient-reported outcomes (PROs).

Results

On April 3, 2019, 5084 patients had ≥1 dose of DMF and qualified for analysis. Mean (SD) age was 40.0 (11.2) years at enrollment, and 74% were female. In total, 1506 patients were treated for >24–48 months, and 441 were treated for >48 months. Two hundred and forty-five patients (4.8%) experienced SAEs; infections (n=64; 1.3%) and nervous system disorders (n=35; <1%) were most common. There were 1676 (33.0%) permanent treatment discontinuations: 965 (19.0%) due to AEs (most commonly: gastrointestinal AEs [395, 7.8%] and occurrence of lymphopenia [125, 2.5%]) and 260 (5.1%) due to insufficient efficacy. Overall ARR over the period of up to 5 years (0.09; 95% CI: 0.09–0.10) was significantly lower than in the year prior to baseline (0.82, 95% CI: 0.80–0.84), representing an 88.6% risk reduction [95% CI: 87.7–89.4 P<0.0001]). At 54 months, the Kaplan-Meier estimated probability of patients without relapse was 71.1% (n=4286). PROs were generally stable from baseline to Year 5.

Conclusions

Results from the ongoing study with up to 5 years follow-up reveal no new safety concerns emerging from real-world use of DMF. DMF demonstrated beneficial therapeutic effects for those patients that remained on treatment up to 5 years.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0387 - Safety and tolerability of cladribine in multiple sclerosis – clinical experience of two tertiary centers (ID 1491)

Speakers
Presentation Number
P0387
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Cladribine is a selective and oral immunological reconstitution treatment, approved in Europe in 2017 and in Portugal in 2018 for very active multiple sclerosis (MS) with relapses. Its safety and efficacy profile were assessed in phase III CLARITY (2005-2009) trial. Post-commercialization studies in real life conditions, are essential to confirm this profile.

Objectives

To assess the safety and tolerability of cladribine in MS patients a real-world clinical setting, during treatment follow-up.

Methods

Observational, multicentric, prospective study. Consecutive MS patients treated with cladribine were included in two tertiary hospitals in Lisbon and followed during treatment. Demographic and clinical aspects, EDSS, previous disease-modifying drugs (DMD) and annual relapse rate (ARR) were recorded, as well as laboratory, imaging monitoring and adverse reactions during treatment.

Results

Eighty-five included patients, 54 (63.5%) female, mean age 42±12 years old, mean disease duration 9±7 years. Seventy-seven (90.6%) had relapsing-remitting MS, and the remaining had secondary progressive MS. Median pre-treatment EDSS was 2,0 (1,5-4,0). Most (65.9%) patients had been submitted to more than one DMD before, 43 (51.2%) with first-line therapies and 9 (10.7%) were naïve. Cladribine was started in 57 (68.7%) patients due to inefficacy of previous drug. Mean follow-up time was 13±6 months, and 54 (63.5%) completed first year of treatment. Second year of treatment was delayed in some patients due to global COVID-19 pandemic. Most frequent adverse reactions were lymphocytopenia (43,5%), infections (20,8%) and fatigue (18,1%). After two months of first dose, CD19+ lymphocyte count showed greater reduction compared with CD4+ and CD8+. There were no grade 4 lymphocytopenia cases registered. Four (5.5%) serious adverse reactions were recorded. There were no cases of cladribine withdrawal because of adverse reactions.

Conclusions

This cohort has similar characteristics to the CLARITY trial study population. Registered adverse reactions were comparable to previously described, showing higher incidence of fatigue and lower incidence of infections. This study confirms the short-term tolerability and safety profile of cladribine in real life scenarios.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0388 - Safety of dimethyl fumarate for multiple sclerosis: A systematic review and meta-analysis (ID 255)

Speakers
Presentation Number
P0388
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

The safety profile of dimethyl fumarate (DMF) used in the treatment of multiple sclerosis (MS) is not fully understood.

Objectives

The objective of this study was to systematically review the literature for adverse events (AE) associated with DMF for MS.

Methods

We searched MEDLINE, EMBASE, CINAHL, Web of Science, CENTRAL, and clinicaltrials.gov for articles published from database inception to May/2019. Studies (observational and randomized controlled trials (RCTs)) reporting AEs, serious AEs (SAE), or discontinuation due to AEs were included. We summarized the proportion of DMF-exposed patients affected and calculated the risk ratios (RR) and number needed to treat for an additional harmful outcome (NNTH) and 95% confidence intervals (CI) for the DMF relative to placebo-exposed participants. RCT findings were pooled via meta-analyses.

Results

Twenty-one observational studies, 4 RCTs, 1 RCT extension study, and 2 open-label studies were included, totalling 12,380 MS patients on DMF followed for an average of 19.8 months. Compared to placebo, DMF-exposed patients had a higher risk of grade III/IV lymphopenia (NNTH=28.8;95%CI:20.2-50.5), pruritus (NNTH=22.1;95%CI:14.0-52.3), flushing (NNTH=3.7;95%CI:3.3-4.1), gastrointestinal related events (NNTH=5.7;95%CI:3.5-15.7), nausea (NNTH=23.4;95%CI:14.9-54.7), diarrhea (NNTH=21.2;95%CI:13.6-47.6), and abdominal pain (NNTH=19.2;95%CI:12.9-37.9). Patients discontinued DMF because of GI symptoms (498/5619;8.9%), lymphopenia (163/4003;4.1%), and flushing (173/4779;3.6%). From pooled analyses of 4 RCTs, AE risks were higher in the DMF versus placebo groups (RR=1.37;95%CI:1.27-1.48), but SAEs were similar (RR=1.01;95%CI:0.77-1.33).

Conclusions

Over the short-term, DMF was associated with a higher risk of AEs. The NNTH included 4 for flushing, 6 for gastrointestinal complaints, and 29 for severe or life-threatening (grade III/IV) lymphopenia. The longer-term safety of DMF, including consequences of lymphopenia remain unknown.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0389 - Safety of ocrelizumab in multiple sclerosis: updated analysis in patients with relapsing and primary progressive multiple sclerosis (ID 952)

Speakers
Presentation Number
P0389
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Ongoing safety reporting is crucial to understanding the long-term benefit–risk profile of ocrelizumab in patients with multiple sclerosis (MS). Safety/efficacy of ocrelizumab have been characterized in Phase II (NCT00676715) and Phase III (NCT01247324; NCT01412333; NCT01194570) trials in patients with relapsing-remitting MS, relapsing MS (RMS) and primary progressive MS (PPMS).

Objectives

To report longer-term safety evaluations from ocrelizumab clinical trials and open-label extension (OLE) periods up to January 2020 and selected post-marketing data.

Methods

Safety outcomes are reported for the ocrelizumab all-exposure population in Phase II/III trials and associated OLEs plus ongoing Phase IIIb trials in MS (VELOCE, CHORDS, CASTING, OBOE, ENSEMBLE, LIBERTO and CONSONANCE). The number of post-marketing ocrelizumab-treated patients is based on estimated number of vials sold and US claims data. To account for different exposure lengths, rates per 100 patient years (PY) are presented.

Results

In clinical trials, 5,680 patients with MS received ocrelizumab (18,218 PY of exposure) as of January 2020. Reported rates per 100 PY (95% confidence interval) were: adverse events (AEs), 248 (246–251); infections, 76.2 (74.9–77.4); serious AEs, 7.34 (6.96–7.75); serious infections, 2.01 (1.81–2.23); malignancies, 0.46 (0.37–0.57); and AEs leading to discontinuation, 1.06 (0.92–1.22). As of April 2020, over 158,000 patients with MS have initiated ocrelizumab globally in the post-marketing setting. Data remain generally consistent with those observed in clinical trials.

Conclusions

Reported rates of AEs in the ocrelizumab all-exposure clinical trial population and post-marketing settings remain generally consistent with the controlled treatment period in RMS/PPMS populations. Rates of serious infections and malignancies remain within the range reported for patients with MS in real-world registries. In patients with RMS and PPMS, ocrelizumab demonstrates a consistent and favorable safety profile, and these longer-term data are in accordance with the safety outcomes initially observed during the controlled treatment periods. Regular reporting of longer-term safety data will continue.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0390 - Seroconversion rate following HBV vaccination in clinical practice: the role of immunosenescence and concomitant DMT treatment (ID 1702)

Speakers
Presentation Number
P0390
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

The use of progressively more powerful disease-modifying therapies (DMTs) in multiple sclerosis (MS) has increased the risk of severe infection of vaccine-preventable diseases, as hepatitis B (HBV). Considering the low risk of vaccination and the potential complication of acute infection by HBV in patients undergoing immunomodulating therapies, vaccination is considered in seronegative patients.

Objectives

We aimed to evaluate if immunosenescence and DMT-treatment influenced the seroconversion rate following HBV vaccination.

Methods

We selected all seronegative MS patients submitted to HBV vaccination in our institution between January 2016 - May 2020. In our center, an accelerated HBV vaccination regimen is administrated with a 3 dose protocol (Day 0, 7, and 21). The antibody anti-HBs is reevaluated 4 weeks after the last dose and a fourth dose might be administrated if necessary.

Seroconversion status was defined as the outcome variable. To evaluate if immunosenescence influenced seroconversion, we compared the seroconversion rate of patients 50-years-old or younger and older than 50; to evaluate if DMTs were determinant in seroconversion rates we compared the following groups of patients: treatment-naïve, under BRACE and non-BRACE DMTs.

Results

We included 101 patients, 58 (57.4%) female, mean age 45.7 ± 13.5 years. At the time of vaccination 33 (32.7%) patients were treatment-naïve, while the remaining 68 (67.3%) were under the following DMTs: 27.7% BRACE, 8.9% teriflunomide, 12.9% dimethyl fumarate, 7.9% fingolimod and 9.9% natalizumab.

Seroconversion was observed in 69.3% of patients following vaccination. The seroconversion rate was similar between different age groups: 74.1% vs 69.2% in patients 50-years-old or younger and older than 50, respectively (p=0.65). The seroconversion rates were similar between BRACE-treated and treatment-naïve patients (85.2% vs 81.8%, p=1) but lower in the group of patients under non-BRACE DMTs comparing to BRACE- treated patients (54.1% vs 85.2%, p=0.014) and treatment-naïve patients (54.1% vs 81.8%, p=0.021).

Conclusions

Seroconversion following HBV vaccination was not influenced by age in our sample; however, treatment with DMTs other than BRACE was associated with a lower seroconversion rate following vaccination. Vaccination should then be considered at an early stage of MS treatment, preferably in naïve-RRMS or patients under BRACE DMTs.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0391 - Severe neutropenia after cladribine first cycle in a patient with Multiple Sclerosis (ID 1807)

Speakers
Presentation Number
P0391
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Cladribine in a desoxiadenosine analogue approved for Multiple Sclerosis (MS) treatment. It produces rapid B and T cells depletion, associating lymphopenia in some cases the first months after treatment. Neutropenia is extremely rare.

Objectives

We present one patient with MS that develops severe neutropenia after the second dose of the first cycle of cladribine.

Methods

We reviewed patient's clinical history, complementary tests and outcome, as well as available bibliography about this topic.

Results

53 year-old female with past medical history of psoriasis. She suffered from an optic neuritis in 2008. Brain MRI done then showed typical MS lesions. Because of clinical and radiological stability, she did not receive any disease modifying therapy until 2018. Then, she was started on dimethyl fumarate that was discontinued a few months later due to lymphopenia and joints pain. Once the lymphocyte count was normal, she was started on cladribine in December 2019. One week after the second dose of the first cycle, she presented with asthenia. Gabapentine had also been added due to neuropathic pain. Blood test revealed severe leucopenia (0.51 x 109/l), grade IV lymphopenia (0.19 x 109/l) and grade IV neutropenia (0.20 x 109/l). Rest of the bool count and smear were normal. Bone marrow aspirate showed slight hypocellularity with good representation of the three series, suggestive of post-chemotherapy aplasia recovery, indicative of cladribine induced neutropenia. Granulocyte colony stimulating factor was administered during 2 days, with progressive recovery until normal neutrophil count was achieved within 10 days. Grade II lymphopenia persists (0.74 x 109/l) after 3 months. The patient has remained afebrile and without any incidence. Evaluation of the second cycle of cladribine according to clinical, radiological and blood test evolution is still pending.

Conclusions

Neutropenia is a very rare adverse effect of cladribine in MS treatment, but it may be life-threatening. Thus, clinical and blood test monitoring is essential. In the case presented, we postulated that gabapentine may have an additive effect in cladribine hematologic toxicity.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0392 - Shorter infusion time of ocrelizumab: results from the ENSEMBLE PLUS study in patients with relapsing-remitting multiple sclerosis (ID 900)

Speakers
Presentation Number
P0392
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Ocrelizumab (OCR) is an intravenously administered anti-CD20 antibody approved for relapsing and primary progressive multiple sclerosis (MS). Shortening the infusion duration to 2hrs reduces the total site stay (including mandatory pre-medication/infusion/observation) from 5.5–6hrs, to 4hrs, which may reduce patient and site staff burden.

Objectives

ENSEMBLE PLUS aims to investigate the safety and tolerability of OCR when administered over a shorter infusion time.

Methods

ENSEMBLE PLUS is a randomized, double-blind substudy to the ENSEMBLE study (NCT03085810). In ENSEMBLE, treatment-naïve patients with active, early-stage relapsing-remitting MS (18–55 years; disease duration ≤3 years; EDSS score 0–3.5) receive OCR 600mg infusions every 24 weeks for 192 weeks. In ENSEMBLE PLUS, OCR (600mg) administered over the approved infusion time (3.5hrs; conventional duration), was compared with a 2hr infusion (shorter duration); the infusion duration of the initial 2×300mg dose was unaffected. The frequency and severity of infusion-related reactions (IRRs) were assessed during and 24hrs post-infusion. The ENSEMBLE PLUS primary endpoint was the proportion of patients with IRRs at the first Randomized Dose.

Results

In total, 373 and 372 patients were randomized to the conventional and shorter infusion groups, respectively. At the first Randomized Dose, 99 patients (26.5%) in the conventional and 107 (28.8%) in the shorter infusion group had IRRs (difference in proportions, stratified estimates [95% CI]: 2.4% [-3.8, 8.7]); most common symptoms during the infusion were throat irritation, dysphagia and ear pruritus, whilst 24hrs post-infusion were fatigue, headache and nausea. IRRs led to infusion slowing/temporary interruption in 22 patients (5.9%) in the conventional and 39 (10.5%) in the shorter infusion group. The majority of IRRs were mild or moderate. Across all Randomized Doses, four severe (Grade 3) IRRs occurred in total, one in the conventional and three in the shorter infusion group. Overall, >99% of IRRs resolved without sequelae in both groups. No IRRs were serious, life-threatening or fatal; no IRR-related discontinuations occurred. Adverse events (AEs) and serious AEs were consistent with the known OCR safety profile.

Conclusions

Frequency and severity of IRRs were similar between conventional and shorter infusions. No new safety signals were detected. Shorter ocrelizumab infusions reduce the infusion site stay, thus may reduce patient and staff burden.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0393 - Similar clinical outcomes for natalizumab patients switching to every-6-week dosing versus remaining on every-4-week dosing in real-world practice (ID 679)

Speakers
Presentation Number
P0393
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Natalizumab 300 mg every 4 weeks (Q4W) is an effective therapy for relapsing-remitting multiple sclerosis (MS) but is also associated with increased risk of progressive multifocal leukoencephalopathy (PML) in anti–JC virus seropositive patients. Analysis of the TOUCH Prescribing Program safety database showed that natalizumab extended interval dosing (EID; average dosing interval approximately 6 weeks) is associated with lower risk of PML than Q4W dosing. Previous analysis of TYSABRI Observational Program (TOP) data showed no difference in relapse outcomes for patients on Q4W and every-6-week (Q6W) dosing. Comparative disability outcome data in well-matched real-world populations are lacking.

Objectives

Compare relapse and disability outcomes in propensity-score (PS)–matched TOP patients who switched to Q6W dosing with outcomes in patients who remained on Q4W dosing.

Methods

Intentional dosing data collected in TOP as of November 2019 were used to identify patients with ≥1 year of Q4W dosing who remained on Q4W or switched to Q6W dosing. Patients with dosing intervals ≥12 weeks or <3 weeks were excluded. Patients with similar exposures were PS-matched 1:1 with age, sex, Expanded Disability Status Scale score, time from MS onset, exposure duration, and relapse activity as covariates. Between-group comparisons were made for the post-switch follow-up period for Q6W patients and the matching time period for Q4W patients. Adjusted relapse rates (ARRs) were calculated using negative binomial regression with robust standard error estimation. Hazard ratios (HRs) for time to first relapse and 24-week confirmed disability worsening (CDW) were estimated with Kaplan-Meier and Cox methods.

Results

The analysis included 236 matched pairs of Q6W and Q4W patients. Mean (SD) follow-up times for Q6W and Q4W patients were 2.00 (1.30) and 1.89 (1.15) years, respectively. ARRs (0.146 vs 0.139; P=0.796), time to first relapse (HR [95% CI] 1.078 [0.723–1.608]; P=0.711), and time to CDW (HR [95% CI] 0.749 [0.270–2.074]; P=0.578) did not differ significantly for Q6W and Q4W patients.

Conclusions

Relapse and disability outcomes in TOP were similar for PS-matched patients who switched to Q6W or remained on Q4W dosing. These results are consistent with prior matched and unmatched analyses in real-world settings and underscore the need for the ongoing, prospective, randomized efficacy trial of natalizumab Q6W vs Q4W dosing (NOVA, clinicaltrials.gov NCT03689972).

The TOP study was supported by Biogen.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0394 - Siponimod treatment leads to a dose-dependent reduction of EAE severity associated with downregulation of microglial activity. (ID 1898)

Speakers
Presentation Number
P0394
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

The sphingosine-1-phosphate (S1P) modulator siponimod has been approved for the treatment of active secondary progressive multiple sclerosis. While the reduction of relapse frequency represents a well established effect of S1P modulators in the treatment of multiple sclerosis, their impact on progressive disease is still controversial.

Objectives

The objective of this study was to elucidate effects of siponimod treatment on resident CNS cells in the context of glial cell-mediated neurodegenerative pathomechanisms in progressive multiple sclerosis. We focussed on the impact of siponimod treatment on functional microglial phenotypes.

Methods

Experimental autoimmune encephalomyelitis (EAE) was induced in wild type C57BL/6 mice aged 8-12 weeks with MOG35-55 peptide emulsified in CFA and the additional injection of pertussis toxin. Siponimod treatment was started 20 days post immunization, after mice had reached peak disease and was performed at least for 60 days. Siponimod was administered orally via food pellets containing 3 mg, 10 mg or 30 mg siponimod/kg, respectively. The clinical outcome of mice was measured by the EAE score and their performance in the elevated beam test. After 60 days of treatment, mice were sacrificed for FACS analysis of microglia isolated from brain and spinal cord using the Multi Tissue Dissociation Kit 1.

Results

Siponimod treatment induced a robust reduction of mean clinical scores of mice in all siponimod treatment groups compared to the vehicle group. Dose-dependent clinical differences in disease severity of siponimod-treated mice were observed in the elevated beam test, with mice treated with the highest siponimod dose performing better than mice treated with the low or intermediate siponimod dose. In siponimod-treated animals MHC class II expression of microglial cells was downregulated in a dose-dependent manner.

Conclusions

Therapeutic siponimod treatment started 20 days post immunization and continued over two months leads to a reduction of EAE severity in a dose-dependent manner that is associated with a downregulation of microglial MHC class II expression as a marker of microglial activity. It remains unclear whether the effect of siponimod on microglial activity is directly mediated by modulation of microglial S1P receptors.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0395 - Species variation in sphingosine 1-phosphate receptor subtype 5 affects response to ozanimod in preclinical models of multiple sclerosis (ID 91)

Speakers
Presentation Number
P0395
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

Ozanimod is a sphingosine 1-phosphate (S1P) receptor modulator that binds with high affinity selectively to human S1P receptor subtypes 1 (S1P1) and 5 (S1P5). Ozanimod was recently approved in the US and EU for the treatment of relapsing forms of multiple sclerosis. While assessing the potency of ozanimod for mouse and rat S1P5, we observed reduced activity compared with the human homologue.

Objectives

To utilize and characterize observed species variation in the S1P5 response to ozanimod in order to understand the role of S1P receptors in the mouse experimental autoimmune encephalomyelitis (EAE) and cuprizone models of multiple sclerosis.

Methods

Using site-directed mutagenesis coupled with radioligand binding and GTPγS binding assays, we identified a single amino acid responsible for reduced potency of ozanimod at rodent S1P5. Together with pharmacokinetic exposure measurements, this allowed us to define the roles of S1P1 and S1P5 in key preclinical efficacy models.

Results

The mouse and rat amino acid sequence of S1P5 has an alanine at position 120, whereas in the human homologue there is a threonine at position 120. This amino acid change is key to the binding affinity of ozanimod to the rodent S1P5 receptor homologues. The potency of functional downstream signaling is also affected as this change mediates an approximate 100-fold rightward shift in the potency of ozanimod relative to that of human S1P5. Due to this observed reduced activity of ozanimod at mouse S1P5, central nervous system exposures achieved in preclinical EAE and cuprizone models demonstrated adequate target engagement of S1P1 but not of S1P5. Observed ozanimod efficacy readouts included a reduction in circulating absolute lymphocyte counts and clinical scoring in the EAE model, and neuroprotection but not remyelination in the cuprizone model.

Conclusions

Ozanimod has high affinity and potency for human S1P5; the observed reduced affinity and potency for rodent S1P5 has been identified to be due to a single amino acid substitution at position 120 in the rodent sequence. Findings using rodent models should be interpreted with caution as, depending on exposures achieved, they may reflect the effect of ozanimod on S1P1 receptor modulation only and possibly not S1P5 effects.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0396 - Sustained and rapid B-cell depletion with ofatumumab: Population pharmacokinetic B-cell modeling in relapsing MS patients (ID 1259)

Speakers
Presentation Number
P0396
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

In the Phase 3 ASCLEPIOS trials, ofatumumab 20 mg subcutaneous (s.c.; initial doses: Days 1, 7, 14; subsequent doses: every 4 weeks from Week 4 onwards) showed superior efficacy versus teriflunomide in relapsing MS patients.

Objectives

To characterize the pharmacokinetic (PK) relationship of ofatumumab for B-cell counts in RMS patients, assess the PK and B-cell dynamics given the Phase 3 dose regimen through PK-B cell simulations and explore the effect of covariates on PK and B cells.

Methods

The PK-B cell model was developed using data from Phase 2 (OMS115102, MIRROR, APLIOS) and Phase 3 (ASCLEPIOS I and II) trials. Nonlinear mixed effects modeling was performed using Monolix (v.2019R2) and R (v.3.6.1) programs. Simultaneous fitting was performed to assess the interaction between PK and B cells. A priori selected covariates were included in the covariate analysis and only those with significant effects based on a Wald test were included in the final model. The effect of body weight, age, administration route, s.c. injection device, and baseline B-cell count on PK and B-cell parameters were evaluated.

Results

In total, 9,168 plasma concentrations from 1,440 patients were included in the PK analysis and 17,158 B-cell counts from 1,486 patients in the B-cell analysis. A quasi-steady state binding model with two compartments and a first order absorption for s.c. administration with a time effect on the target synthesis rate adequately described ofatumumab PK. An indirect response model was used to describe the stimulation of B-cell lysis by free ofatumumab concentrations. Simulations demonstrated a rapid, median B-cell depletion to <10 cells/µL in 8.75 days; no signs of B-cell repletion occurred between doses, and that over 94% of patients had <10 cells/µL at B-cell steady state and pre-dose. Effect of weight on the steady state area under the curve was 71.8% higher and 52.0% lower for a 50 kg (5th percentile) and 110 kg (95th percentile) patient relative to a 70 kg patient (median), respectively. Steady state maximum concentrations were similar. Regardless of weight, all patients achieved low B-cell counts, similar to results observed in the Phase 3 ASCLEPIOS trials. Baseline age, B-cell counts and injection device had negligible effect on PK parameters.

Conclusions

The PK-B cell model showed early, rapid, and sustained B-cell depletion with ofatumumab, confirming the rationale for the chosen Phase 3 dosing regimen. No change in dosing schedule is warranted based on body weight effect on ofatumumab PK.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0397 - Switches to immune-reconstitution therapies in Europe and the United States: Analyses from annual retrospective patient chart audits (ID 980)

Speakers
Presentation Number
P0397
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

There are currently two immune-reconstitution therapies (IRTs) licensed for relapsing multiple sclerosis (MS) - alemtuzumab (ALZ), an anti-CD52 monoclonal infusion, and cladribine (CdA), a short-course oral, T- and B-cell depletor.

Objectives

To review real world data of characteristics and disease-modifying treatment (DMT) history among EU and US patients switched to IRTs.

Methods

In 2019, 276 EU neurologists contributed online chart reviews for a retrospective audit of 1,266 MS patients who switched to a new DMT (ALZ: 77; CdA: 47) within the prior 3 months. In 2020, 204 US neurologists contributed 1,009 chart reviews (ALZ: 35; CdA: 21). Conducted at the .05 alpha level, independent samples t-test was used to test differences in means, and z-test (with Bonferroni correction) in proportions, between DMTs.

Results

Overall, IRT use was low, with slightly more patients switched to ALZ (EU: 6.1%; US: 3.5% of switch charts) than CdA (EU: 3.7%; US: 2.1%), except in Germany. While age, gender, recent relapse, and lesion counts did not differ by therapy or region, US patients treated with ALZ trended towards being diagnosed more recently compared to CdA-treated patients (mean: 30 vs. 68 months; p=0.058).

In the US, CdA was more likely than ALZ to be prescribed to patients with relapsing-remitting MS (RRMS) (86% vs. 60%; p=0.043) and trended towards being used less in RRMS patients with perceived risk for transition to secondary progressive MS transition (CdA: 17% vs. ALZ: 43%; p=0.077).

In both regions, most IRT switches were first DMT switches. In the EU, patients switched to CdA were more likely to have switched from an interferon (CdA: 28% vs. ALZ: 23%). In the US, glatiramer acetate more frequently preceded CdA (CdA: 38% vs. ALZ: 23%), while an anti-CD20 monoclonal antibody was more likely to have preceded ALZ (ALZ: 29% vs. CdA: 5%; p=0.030).

Conclusions

IRT treatment patterns in the EU and US are similar, with the exception of known differences in preceding injectable DMT use. In the US, patients are more likely to have been treated with anti-CD20 therapy before switching to ALZ than CdA, perhaps due to perceived differences in IRT efficacy profiles. ALZ is also more likely than CdA to be used among US patients diagnosed with, or at risk of transitioning to, progressive MS. Conversely, in the EU, the two IRTs are prescribed to very similar patient types.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0398 - Switching from natalizumab to ocrelizumab in patients with relapsing-remitting multiple sclerosis. (ID 1725)

Speakers
Presentation Number
P0398
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Ocrelizumab (OCR) is an alternative therapy for relapsing-remitting multiple sclerosis (RRMS) patients with an increased risk of natalizumab (NTZ) associated progressive multifocal leukoencephalopathy (PML). We developed a switch protocol for PML surveillance and prevention of rebound disease activity.

Objectives

To evaluate clinical, radiological and biochemical markers in patients switching from NTZ to OCR using the locally developed switch protocol of the MS Center Amsterdam.

Methods

All patients with previous NTZ and current OCR treatment were selected from an ongoing observational cohort study with regular collection of blood samples in the Amsterdam University Medical Center (UMC) MS Biobank. Reasons for therapy switch were discriminated between patients with (indirect switchers) and without (direct switchers) use of other disease modifying treatment (DMT) during interval. Clinical, biochemical and radiological endpoints were prospectively collected from first NTZ to last OCR infusion. Serum neurofilament light (sNfL) was analyzed in direct switchers, using baseline and last follow-up samples during NTZ treatment and samples taken before every OCR infusion.

Results

Forty-one patients with current OCR and previous NTZ treatment were included with a median follow-up of 7.7 years. Twenty-eight patients switched directly, of which 21 due to PML risk. Three direct switchers suffered from a relapse, of which 1 patient showed evidence of disease activity on brain Magnetic Resonance Imaging (MRI). Two other male patients were diagnosed with carry-over PML with favorable outcomes. Before OCR became available, 13 patients switched from NTZ to other DMT due to PML risk but eventually escalated to OCR because of disease activity, progression or adverse events. Among these indirect switchers, 4 patients showed evidence of clinical or radiological disease activity. Excluding carry-over PML, OCR treatment maintained or established complete disease activity suppression in 84% of patients. Clinical measures of disability showed no significant changes. Mean sNfL significantly decreased during NTZ treatment and remained stable during OCR treatment.

Conclusions

A stringent protocol can contribute to an effective switch from NTZ to OCR in RRMS. In this observational cohort study of direct and indirect switchers, disease activity suppression was maintained or established in 84% with concurrent stability of clinical measures and sNfL.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0399 - Switching from ocrelizumab to cladribine: real world data (ID 1938)

Speakers
Presentation Number
P0399
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

As the number of available therapies in MS increases, knowledge about how to safely switch between therapies is increasingly important. Real world data can provide safety and efficacy data on switching that is not likely to be provided through randomised controlled trials.

Both ocrelizumab, an anti B cell therapy, and cladribine, a selective lymphocyte depleting agent, are highly effective therapies and have recently been licenced around the world for treatment of RRMS. There is no previously published data on the safety and tolerability of the switching between these two therapies.

Objectives

To characterise lymphocyte profile and immunoglobulin levels following initiation of cladribine oral tablets in patients switched from ocrelizumab and to evaluate short term safety profiles in this cohort.

Methods

A cohort of 20 patients with MS from a single centre in Australia were identified who had been switched from ocrelizumab to cladribine. Patients received a cumulative dose of 1.75 mg/kg over 2 treatment weeks. Absolute lymphocyte count (ALC) was recorded at a number of time points. Safety and tolerability data were reviewed.

Results

TThe average ALC at baseline, Month 2, 4, 7 and 12 were 1.6, 1.0, 0.75, 1.1 and 1.0 x106 respectively. No cases of grade 4 lymphopenia were recorded. All ALCs were greater or equal to 0.6 x106 at month 7. The average IgG level at the end of ocrelizumab was 8.56 g/L and 12 months after starting cladribine was 9.19 g/L which was statistically higher (p=0.007). No serious adverse effects were recorded.

Conclusions

Data from this cohort has not revealed any safety concerns switching from ocrelizumab to cladribine. Seven months after starting cladribine the average ALC had returned to the lower limit of normal. Twelve months after switching from ocrelizumab to cladribine the average IgG level had increased.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0400 - Switching to Ocrelizumab from other second line treatments in relapsing-remitting Multiple Sclerosis: a single Center cohort (ID 1150)

Speakers
Presentation Number
P0400
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

Ocrelizumab (OCR) is a new a humanized monoclonal antibody able to bind to a specific epitope of CD20, expressed in the majority of B-cell lines. OCR has been approved for treatment of aggressive relapsing-remitting Multiple Sclerosis (RR-MS) and for primary progressive MS.

Objectives

To evaluate the clinical and radiological outcomes in a cohort of RR-MS patients after switching from other second line treatments (Natalizumab – NTZ, Fingolimod - FTY or Alemtuzumab - ALEM) to OCR. We also evaluated safety of OCR treatment

Methods

All consecutive patients (pts), evaluated in the City of Health and Science University Hospital of Turin MS Center, switching to OCR from other second line treatment, were included in the study. Study outcomes were: clinical disease activity (EDSS progression, relapses), radiological disease activity (new/enlarging T2 lesions, T1 Gd+ lesions) evaluated by MRI scans at 3, 6 and 12 months after starting OCR compared with a reference MRI scan performed within one month before switching, and treatment safety (any infusion reaction and/or adverse event related to OCR therapy).

Results

We identified 42 patients (mean age 42±9 years, 27 (64%) female, mean Expanded Disability Status Scale 4) who switched from NTZ (23 pts), FTY (16 pts) and ALEM (3 pts) to OCR between January 2019 to June 2020. Mean disease duration from MS diagnosis to start of OCR was 11±6 years. Reasons for switch were: persistence of disease activity (23 patients), PML risk (17 pts) or tolerability (2 pts). Mean washout period was 60 days after NTZ and 45 days after FTY. During the follow-up period (mean 10±2 months) no significant adverse events were observed during OCR treatment: 6 pts (14%) had minor infusion reactions, no serious infections were reported. Switching to OCR appears to be effective in most patients: 4/42 (1pt switched from FTY, 3 pts from NTZ) had a relapse treated with corticosteroids, occurring within 4 months after starting OCR. One patient experienced an early rebound of disease activity within 6 weeks after stopping FTY, before switching to OCR. MRI follow-up showed new/enlarging T2 lesions in 4 patients (3 switching from FTY and 1 from NTZ), on average 7 months after starting OCR, and a T1 Gd+ lesion in one patient switching from FTY (3 months after starting OCR). All other patients did not show clinical or radiological disease activity.

Conclusions

In our single Center cohort, switching to OCR from other second line treatments appears to be safe and in most patient effective.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0401 - Switching disease modifying treatment in relapsing multiple sclerosis: Delphi consensus of the Demyelinating Group of the Spanish Society of Neurology (ID 234)

Speakers
Authors
Presentation Number
P0401
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

The increasingly number of available Disease Modifying Therapies (DMTs) have led to enhanced perspectives for treating relapsing multiple sclerosis (RMS). The different DMTs have greatly contributed for a more personalized treatment approach with improved clinical outcomes. Currently the DMT landscape makes the decision to switch between different options complex - considering both their different clinical profiles and patient characteristics, especially in absence of unified recommendations for switching.

Objectives

The Demyelinating Expert Group of the Spanish Society of Neurology (SEN) considered to carry out a consensus project with the objective of answering critical questions about DMT sequencing for an optimal patient management.

Methods

After an exhaustive literature review, the expert group identified 5 main topics to integrate the proposed questions: I) treatment objectives and risk-benefit balance; II) reasons for switching; III) suboptimal response definition; IV) strategies for treatment change; V) washout periods. Delphi´s methodology was used for assessing the level of agreement among the discussed statements.

Results

The expert group workshops leaded to formulate a total number of 106 final statements to cover the defined 5 main topics. From them, consensus (at least 80% of agreement between participants) was reached in 99 responses (93%), while 7 (7%) were finally discarded for lack of agreement.

Conclusions

These Spanish Neurologists´switching recommendations addressed DMT sequencing difficulties that clinicians face in MS clinical practice. Evidence from reviewed literature added to Spanish MS experts´clinical experience resulted in those basic guidelines that will optimize DMT use and patient management in Spain.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0402 - Targeting monocyte migration for treatment of MS: Human ex-vivo proof-of-concept for Anti-MOSPD2 mAbs in patients with RR and progressive MS (ID 1067)

Speakers
Presentation Number
P0402
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

In multiple sclerosis (MS), blood-borne monocytes constitute a part of the central nervous system (CNS)-infiltrating cells and are instrumental for disease pathogenesis. Therefore, inhibiting the migration of monocytes to the CNS could be a novel therapeutic approach for treatment of patients with MS and additional CNS inflammatory indications. MOSPD2 is a protein expressed on the surface of monocytes and is essential for their migration. We previously demonstrated that treatment with anti-MOSPD2 monoclonal antibodies (mAbs) prevented development and progression of experimental autoimmune encephalomyelitis (EAE) and restricted CNS-infiltration of monocytes.

Objectives

In this study, we tested the ability of anti-MOSPD2 mAbs to inhibit the migration of blood-borne monocytes isolated from relapsing-remitting (RRMS) primary progressive (PPMS) or secondary progressive MS (SPMS) patients.

Methods

Blood samples were drawn from RRMS, PPMS and SPMS patients. Isolated monocytes were tested for chemotaxis in the presence of two anti-MOSPD2 drug candidates, each binding a different epitope. Isotype control antibody was used as a reference.

Results

Twenty-five samples from RRMS, 4 from PPMS and 4 from SPMS patients were tested. At the time of sampling, patients were subscribed for treatment with various medications including dimethyl fumarate, natalizumab, cladribine, ocrelizumab, glatiramer acetate and interferon-beta. RRMS patients had an EDSS score at the range of 0-6. PPMS and SPMS patients had an EDSS score at the range of 5.5-6.5. Incubation with mAb1 and mAb2 profoundly inhibited migration of monocytes from all RRMS and progressive MS patients tested, by up to 97%. The ability to inhibit monocyte migration was not affected by patient subscribed medication for both RR and progressive MS.

Conclusions

Our data show that anti-MOSPD2 mAbs significantly inhibit the migration of monocytes isolated from MS patients in an ex-vivo setting, regardless of patient diagnosis, disease severity or treatment applied. Therefore, anti-MOSPD2 mAbs hold a therapeutic potential for RRMS and progressive MS, through a distinct mechanism of inhibiting monocyte accumulation in the CNS.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0403 - T-bet+ B-cell development in MS: Association with Bruton’s Tyrosine Kinase activity and targeting by evobrutinib (ID 1104)

Speakers
Presentation Number
P0403
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

B-cell depletion is an efficacious treatment in relapsing and progressive multiple sclerosis (MS). A phase II trial (NCT02975349) showed promising results for Bruton’s tyrosine kinase (BTK) inhibitor evobrutinib in the treatment of MS. Previously, we found that T-bet+ B cells preferentially infiltrate the central nervous system and are induced under IFN-γ- and TLR9-stimulating, germinal center-like conditions in MS.

Objectives

We aimed to elucidate how BTK is expressed and activated in distinct ex vivo B-cell subsets during the course of MS. Moreover, the relation between BTK activity and T-bet+ B-cell differentiation was assessed both ex vivo and in vitro.

Methods

We determined BTK and phosphorylated BTK (pBTK) levels in transitional, naive mature, class-switched and non class-switched B cells in blood from both treatment-naive patients with CIS, RRMS, SPMS and PPMS and healthy controls (HC; n=30 per group), as well as clinical MS responders and non-responders to natalizumab (pre- vs 1y post-treatment) using flow cytometry. Purified naive mature and memory B cells were cultured under several IL-21/CD40L-inducing conditions with and without evobrutinib.

Results

BTK was mainly expressed in non-class-switched memory B cells, while pBTK levels were high in both class-switched and unswitched memory B cells. In contrast to BTK, pBTK was significantly higher in ex vivo memory B cells of RRMS and SPMS compared to CIS, PPMS and HC groups. In both RRMS and SPMS, pBTK was also less induced after a-IgM stimulation. BTK and pBTK levels were elevated in blood B cells from clinical responders, but not in non-responders to natalizumab. These levels correlated positively with CXCR3 and VLA-4 expression. No correlation was seen for CXCR4, CXCR5, CD40 and HLA-DR. In vitro experiments revealed that pBTK in B cells was particularly triggered by IFN-γ and TLR9 induction. Evobrutinib attenuated class-switching during in vitro cultures of naive B cells, while it interfered with plasmablast formation in memory B-cell cultures. T-bet and T-bet-related markers (CD21, CD11c) were only affected by evobrutinib in IFN-γ- and TLR9-stimulating naive B-cell cultures.

Conclusions

These data demonstrate that BTK is more activated in memory B cells from RRMS and SPMS patients and functionally related to pathogenic T-bet+ B-cell development. This study provides new mechanistic insights into how evobrutinib intervenes in human B-cell differentiation and can modulate the clinical course of MS.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0404 - The Bruton’s tyrosine kinase inhibitor evobrutinib ameliorates meningeal inflammation in experimental autoimmune encephalomyelitis (ID 1354)

Speakers
Presentation Number
P0404
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

Leptomeningeal inflammation in multiple sclerosis (MS) is associated with worse clinical outcomes and greater cortical pathology. Both B cells and myeloid cells are found in areas of meningeal inflammation. We previously demonstrated that, in the relapsing–remitting encephalomyelitis (EAE) model in SJL mice, ultra-high field contrast-enhanced magnetic resonance imaging (MRI) could identify and track areas of meningeal inflammation. Bruton’s tyrosine kinase (BTK) mediates signaling through B cell receptor and Fc receptor pathways and leads to B cell and myeloid cell activation. We therefore hypothesized that a BTK inhibitor could target meningeal inflammation in EAE.

Objectives

To test the effect of evobrutinib, a highly selective BTK inhibitor, as a potential therapy targeting meningeal inflammation in a mouse model of MS.

Methods

We immunized 7- to 8-week-old female SJL/J mice with proteolipid protein 139–151 peptide and complete Freund’s adjuvant to induce EAE. Animals were weighed and disease severity was scored starting at 7 days post-immunization; at 6 weeks they underwent Gadolinium-enhanced MRI. Mice demonstrating the presence of meningeal contrast enhancement were randomized to receive daily oral doses by gavage of evobrutinib (10 mg/kg) or vehicle control between Weeks 6–10 post-immunization. MRI was repeated at Weeks 8 and 10 to assess meningeal inflammation, and brain tissues were collected for histopathological analysis.

Results

At baseline, both vehicle (n=16) and evobrutinib (n=19) groups had a similar number of areas of meningeal contrast enhancement (median: 10.5 vs 11; p=0.25). Following treatment, a greater reduction in the number of areas of meningeal contrast enhancement was identified in the evobrutinib group vs the vehicle group (median change: -3 vs 0.5; p=0.003). A significant decrease in B cells in areas of meningeal inflammation in the evobrutinib group compared to the vehicle group was noted. Also, astrocytosis in the adjacent cortex was reduced in the evobrutinib group compared with vehicle.

Conclusions

An amelioration of established meningeal inflammation, as assessed by imaging and pathological measures, in a relapsing–remitting EAE model was observed with evobrutinib treatment, suggesting the potential utility of this agent to target this phenomenon in MS patients.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0405 - The consequences of switching from Gilenya to generics for Fingolimod (ID 1129)

Speakers
Presentation Number
P0405
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

On May 2017, two generic drugs for fingolimod were introduced into the market in Israel, and many MS patients treated with Gilenya (Novartis) were switched to Fingolimod (Teva), or to Finolim (Rafa).

Objectives

To analyze the consequences of switching from original Gilenya to generic fingolimod preparations in a single MS center.

Methods

Inclusion criteria included relapsing MS patients who were treated with Gilenya (G) for at least one year before May 2017, switched to and remained on generic fingolimod (F) for at least one year thereafter. Retrospective data within one year before and after the switch were compared.

Results

Twenty seven patients fulfilled the inclusion criteria (F=20, RRMS=20, SPMS=7, average age 49±11.4, average disease duration=16.6±7.6 years). Ten patients had to be switched back to the original Gilenya by the request of their neurologist due to intolerable new or worsening adverse events (n=9), clinical relapse (n=1), or elevation of liver enzymes > X3 ULN (n=1). Liver enzyme abnormalities were detected in 2/27 patients during G treatment and in 4/27 during F treatment (p=NS). There was a trend towards reduced lymphocyte count after G-F switch (644±221 vs. 593±182, p=0.149). Median EDSS increased from 2.75 (1.0-6.0) to 3.0 (1.5-6.5) (p=NS). Age, disease duration and disease type (RRMS or SPMS) did not predict the need for switching back to G.

Conclusions

The tolerability of generics for fingolimod seems to be lower than the original Gilenya. Despite the small number of patients, short follow-up period and the minor or no differences between F and G treated patients detected in most parameters which do not allow for drawing definite conclusions regarding the comparative efficacy and safety of G and F, these results raise concerns about the use of generics, even for simple chemical drugs such as fingolimod, in a complex and heterogenous disease such as MS that spans over many domains. This may suggest that pharmacodynamic and clinical evaluations, not merely the demonstration of bioequivalence, are needed before approving generic drugs for MS.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0406 - The effect of cladribine upon naïve and activated CD4+ T regulatory cells in MS patients. (ID 1953)

Speakers
Presentation Number
P0406
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

The administration of oral cladribine has been shown to reduce relapses and slow accumulation of disability. The Clarity study demonstrated that up to 70% of patients had a prolonged period of no relapses for some years after the second year of therapy. The cause for the prolonged period of relative remission is not entirely understood.

Objectives

To observe changes in the T cells subsets at 3, 6 and 12 months after treatment with cladribine, in particular, the effector and T regulatory cell subsets of CD4+T cells. We compared changes in 10 healthy donors (HD) and 10 patients with MS receiving cladribine over 12 months.

Methods

Blood was collected from healthy donors and MS patients (n=10/group) before treatment with Cladribine and 1, 3, 6 and 12 months after the treatment. Peripheral blood mononuclear cells (PBMC) were isolated using Ficoll and subjected to flow FACS. CD4+CD25+CD127loFoxp3+T regulatory cells (Treg) were gated into populations based on CD45RA expression, naïve Treg that express CD45RA (Population I) and activated Treg where CD45RA is lost. Most activated Treg increase expression of Foxp3 and CD25 (Population II) whereas less activated Treg do not increase CD25 and Foxp3 expression (Population III). Activated Treg migrate to sites of inflammation by expression of chemokine receptors similar to effector T cell subtypes; Th1-like (CXCR3), Th17-like (CCR6).

Results

Lymphocyte and CD4+ cell counts fell but were recovering at 12 months in MS treated with cladribine but remained stable in HD. CD4+CD25+CD127loTreg numbers fell but their proportion of CD4+T cells increased in MS treated, but remained stable in HD. The proportion of CD4+CD25+CD127loFoxp3+Treg was preserved. There were no changes in the proportion of Treg in population I, II or III. CXCR3+ cells in Population II and IV declined over 12 months, whereas CCR6+ cells in population II and IV declined at 1 and 3 months but recovered by 6 and 12 months

Conclusions

There was a drop in the CD4+ cell numbers although the proportion within lymphocyte did not change. The number of Naïve Treg (population I) dropped but not to zero and then slowly recovered. The number of activated Treg (Population II) increased by 6 months. The relative preservation of Population I may be partially responsible for the absence of autoimmune diseases that is seen in some circumstances of immune reconstitution. Whether the persistence or presence of Population II is associated with prolonged clinical response will require further study.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0407 - The Impact of Ocrelizumab on Immunoglobulin Levels and the Risk of Infection. (ID 476)

Speakers
Presentation Number
P0407
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Ocrelizumab (OCR), an anti-CD20 antibody, was approved in the US in March 2017 for treating relapsing (RMS) and primary progressive MS (PPMS). Infections were more commonly seen in patients receiving OCR in earlier trials. Last year European Medicines Agency updated the OCR prescribing information to include the association between a reduction in immunoglobulins especially IgG and serious infections.

Objectives

To determine if there is a relationship in baseline and follow up immunoglobulins levels and the risk of having an infection

Methods

MS patients in our OCR registry with at least one IgM/IgG value and who received ≥2 doses of OCR were included. IgG/IgM levels were obtained within a month of each infusion. Wilcoxon rank-sum tests and linear models were used to examine the relationships between IgM/IgG and infections.

Results

337 patients were included. 72.4% were female; median age was 53.2 [IQR = 19.8] years with a median disease duration of 13.5 [IQR = 11.8] years. 78% had RMS, 13.4% had SPMS, and 8.6% had PPMS. 27% of patients were treatment naïve. Median time on OCR was 26 [IQR = 8.9] months. 88.7% of patients had more than one IgG and IgM value. Infections were seen in 226 (67.1%) patients. The median age of patients who did and did not have an infection was 53.5 [IQR =20.2] and 53 [IQR = 18.1] respectively. Prior natalizumab use was associated with a higher rate of infection, 46 of 62 (74%). No significant differences were found between IgM levels nor IgG levels for cases of infection (56 [IQR = 53], 792 [IQR = 294.5] mg/dL) and non-infection (52 [IQR = 51], 828.5 [IQR = 310.2]) mg/dL) (

Conclusions

Older patients with longer duration of disease and OCR therapy have been found to have more infections, but we did not observe age as a risk factor for infection in this cohort. Furthermore, neither baseline nor follow up IgM or IgG levels predicted infections in this study. However, the median time on OCR was a little over 2 years which may be too soon to see a difference in the rate of infection and immunoglobulin levels.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0408 - Therapeutic Plasma Exchange in MS relapses: long term outcome (ID 1415)

Speakers
Presentation Number
P0408
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

High-dose short-term intravenous methylprednisolone (IVMP) is the standard treatment for Multiple Sclerosis (MS) relapses. However, 25% of patients do not respond and remain with significant disability. In these patients, therapeutic plasma exchange (TPE) has proven effective, although evidence of long-term efficacy after use of this procedure is lacking.

Objectives

The aims of this study were to: 1) compare outcomes of patients treated with or without TPE at 12, 18 and 24 months, and 2) evaluate features associated with better response to TPE.

Methods

We performed a retrospective cohort study of all relapse remitting MS patients (RRMSp) treated with IVMP and TPE between January 2011 and January 2018 and compared them to a second group of RRMSp, matched for age, sex, disease duration and disability level at time of relapse, treated only with IVMPS. Number of relapses were recorded. Good response to treatment was defined as at least 50% reduction in EDSS score. Results were reported as median and interquartile range for numerical variables, and as percentage of the total number of patients, for categorical variables. P values below 0.05 were considered significant.

Results

Twenty-four patients (66% female, age: 39± 11 years) treated with TPE, and 43 patients treated with IVMP alone (70% female, age: 39± 6 years) were included. TPE-treated patients had experienced more relapses in the 2-years prior to the study (3±2 vs 2±1, p=0,03). Time from symptom onset to treatment with IVMP or duration of IVMP treatment was similar in both groups (5 ± 9 days vs 7± 11 days, p=0.1). After the relapse, TPE-treated patients were escalated to a high efficacy disease modifying therapy more frequently during follow up than the comparator group (25% vs 16%, p=0,02).

Although initial EDSS scores were similar in both groups, no differences were found in EDSS or Kurtzke functional systems scores at 12, 18 and 24-months follow-up (TPE 1 (0-2) vs IVMP 1 (0-2)).

65% of RRMSp treated with TPE had a good response to treatment. No significant association was found between positive response and initial relapse severity, distribution or number of gadolinium-enhancing lesions, or time to TPE.

Conclusions

No differences in functional outcomes were found in MS relapses treated with or without TPE after 24 months follow up; nor were any predictors of favorable response to treatment with TPE in this preliminary analysis.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0409 - Treatment Failure in patients with multiple sclerosis initiating frequently used first line therapies (ID 885)

Speakers
Presentation Number
P0409
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Despite an array of disease modifying therapies (DMTs), interferons/glatiramer acetate (IFN/GA) and dimethyl fumarate (DMF) are still the most frequently used to treat multiple sclerosis (MS) in United States.

Objectives

Our objective was to evaluate treatment patterns and disease breakthrough for patients initiating IFN/GA/DMF as first-line therapies to determine if there is an unmet need for more effective agents to be used first-line.

Methods

Adult MS patients (age ≥18) with ≥1 DMT claims of IFN/GA/DMF from January 2016-March 2018 were identified using a large US administrative claims database (IBM® MarketScan® Database). The date of the first MS DMT claim was defined as the index date and patients were followed for one year. Treatment switch was defined as changing from initial therapy to another DMT (within 60 days) and discontinuation was defined as no DMT use for at least 60 days after stopping the initial DMT. Breakthrough-disease was defined as occurrence of relapse (characterized via a validated claims algorithm) during the treatment period. Outcomes were evaluated as a combined DMT group and by individual DMTs.

Results

We identified 1,096 patients initiating IFN/GA and 565 patients initiating DMF. Of these, 43.4% experienced treatment failure (29.3% discontinued or 14.1% switched DMTs) within one year of initiation (results for individual DMTs were similar). The median time to discontinuation was 4.8 months, and the median time to switch was 5.6 months. Approximately, 28.2% of patients experienced at least 1 relapse over the 1-year observation period. The median time to relapse was 4.6 months. There was no reduction in annualized relapse rate (ARR) after initiation of IFN/GA/DMF therapy [ARR for 1-year prior to initiation = (0.41) and 1 year post-initiation = (0.42)].

Conclusions

There is an unmet need for early use of high efficacy DMT, as the most frequently used first-line DMTs show treatment failure (discontinuation/switching/disease-breakthrough) and lack of treatment benefit at high rates in a real-world setting.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0410 - Treatment with ocrelizumab during Sars-Cov2 pandemic: efficacy and safety outcomes (ID 1787)

Speakers
Presentation Number
P0410
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Sars-Cov2 pandemic led neurologists to modify the therapeutic approach in Multiple Sclerosis (MS) care setting, especially with regard to immunodepleting treatments.

Objectives

to describe management and outcome of MS patients (pts) treated with ocrelizumab (OCR) during Sars-Cov2 pandemic in the MS Center of University of Genoa.

Methods

we collected data about pts scheduled to undergo OCR infusion from 1st March to 30th June 2020. Pts that previously underwent the first OCR infusion completed the induction cycle. No further OCR cycles during March and April 2020 were performed. Starting from May, we adopted an infusion scheme based on B-cell repopulation, differently applied for Relapsing Remitting (RR) and Progressive (P) pts. RRMS pts performed immunophenotype (IF) and received OCR infusion when B CD19+ cell count overcame the cut-off of 1%. Conversely, for PMS pts OCR infusions were delayed for 3 months. Then, PMS pts underwent OCR infusion based on B CD19+ cell monitoring. For pts with evidence of B CD19+ cells repopulation brain 3T MRI was planned before OCR re-infusion.

Results

77 MS pts were included [45 (58%) RRMS, 32 (41%) PMS; mean age 44.7 (SD: 11.1) years, mean disease duration 21.7 (22.3) years, mean number of previous DMT before OCR: 1.6 (1.6), mean number of previous OCR infusions 3.9 (SD 2.3). 11 (13.1%, 9 RR, 2 PP) of the 49 pts that performed a first IF presented B CD19+ cell repopulation and received OCR re-infusion, with a mean delay from scheduled infusion of 70 (48.9) days. The mean number of previous OCR infusions was 3.0 (1.2) and 3.1 (1.6) for pts with and without evidence of B-cell repopulation respectively. No effect of previous OCR infusions number on the probability to develop B CD19+ cell repopulation at the first IF was detected by ANCOVA analysis, correcting for the delay between the date of scheduled infusion and the date in which the first IF has been performed. Considering the global cohort, 1 pt presented a dubious sensory relapse with no evidence of radiological activity. None of the pts who performed brain MRI before OCR re-infusion showed new T2 or Gd+ enhancing lesions. 3 pts were infected by Sars-Cov2; 2 of them needed hospitalization but recovered completely.

Conclusions

the management of patients treated with OCR during Sars-Cov2 pandemic with a personalized infusion protocol based on B CD19+ cells repopulation was associated with good results in terms of efficacy and safety outcome

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Disease Modifying Therapies – Risk Management Poster Presentation

P0411 - Treatment-emergent adverse events occurring early in the treatment course of cladribine tablets in two phase 3 trials in multiple sclerosis (ID 377)

Speakers
Presentation Number
P0411
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Tolerability and adherence to disease-modifying drugs (DMDs) can be influenced by treatment-emergent adverse events (TEAEs) that start shortly after therapy initiation. One potential advantage of cladribine tablets is its short treatment course which may limit TEAEs; patients who receive the approved 3.5 mg/kg dosage only receive doses for two 4 to 5-day periods per treatment year.

Objectives

To identify TEAEs early in the course of treatment in patients enrolled in the Phase 3 CLARITY and ORACLE-MS clinical trials.

Methods

This was a post hoc analysis of safety populations in CLARITY and ORACLE-MS studies. Patients received cladribine tablets 3.5 mg/kg (cumulative dose over 2 years; N=636) or placebo (N=641). The incidence of early adverse events, TEAEs, serious TEAEs, drug-related TEAEs, and TEAEs leading to discontinuation were summarized based on incidence within 2, 6, and 12 weeks (Wk) after commencement of therapy.

Results

The incidence of TEAEs occurring within the first 2–12Wk of treatment across both trials in both treatment groups was generally low, and the majority of events were mild (placebo: 53.8–68.4%; cladribine tablets: 54.4–68.0%). The most common TEAEs by time epoch after initiating placebo and cladribine tablets 3.5 mg/kg treatment, respectively, were: nausea: 3.3% vs. 4.9% (2Wk), 3.7% vs. 6.4% (6Wk), and 4.5% vs. 8.0% (12Wk); fatigue: 2.0% vs. 1.4% (2Wk), 3.1% vs. 2.5% (6Wk), and 4.4% vs. 3.1% (12Wk); headache: 8.3% vs. 9.0% (2Wk), 11.9% vs. 14.8% (6Wk), and 15.1% vs. 18.4% (12Wk); lymphopenia: 0.0% vs. 2.5% (6Wk) and 0.5% vs. 6.8% (12Wk); leukopenia: 0.0% vs. 1.3% (12Wk). Other endpoints will be shown in the final presentation.

Conclusions

Incidence of TEAEs experienced during the first 12 weeks of treatment with cladribine tablets 3.5 mg/kg in Phase 3 clinical trials was low and mostly mild. Nausea, headache, and lymphopenia were seen more frequently in cladribine tablets-treated patients versus those in the placebo group. These findings suggest that cladribine tablets are generally well tolerated, which may facilitate treatment adherence.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0412 - Treatment-induced BAFF expression alters B cell biology in multiple sclerosis (ID 767)

Speakers
Presentation Number
P0412
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

Although fingolimod and interferon-β are two mechanistically different MS treatments, they both induce B cell activating factor (BAFF), and shift the B cell pool towards a regulatory phenotype.

Objectives

To investigate whether there is a shared mechanism between both treatments in how they influence the B cell compartment.

Methods

We collected a cross-sectional study population of 112 MS patients (41 untreated, 42 interferon-β, 29 fingolimod). We determined B cell subsets, cell-surface and RNA expression of BAFF-receptor (BAFF-R) and transmembrane activator and cyclophilin ligand interactor (TACI) as well as plasma and/or RNA levels of BAFF, BAFF splice forms and interleukin-10 (IL-10) and -35 (IL-35). We added an in vitro B cell culture with four stimulus conditions (Medium, CpG, BAFF and CpG+BAFF) for untreated and interferon-β treated patients including measurement of intracellular IL-10 levels.

Results

Interferon-β and fingolimod induced BAFF protein and mRNA expression (P≤3.15x10-4) without disproportional change in the antagonizing splice form. Protein BAFF correlated with an increase in transitional B cells (P=5.70x10-6) and reduction in B cell-surface BAFF-R expression (P=2.70x10-10), both on TACI-positive and -negative cells. TACI and BAFF-R RNA levels remained unaltered. RNA, plasma and in vitro experiments demonstrated that BAFF was not associated with increased IL-10 and IL-35 levels.

Conclusions

Treatment-induced BAFF prompts a shift towards transitional B cells which are enriched for cells with an immunoregulatory function. However, BAFF does not directly influence the expression of the immunoregulatory cytokines IL-10 and IL-35. Furthermore, the post-translational mechanism of BAFF-induced BAFF-R cell surface loss was TACI-independent. These observations put the failure of pharmaceutical anti-BAFF strategies in perspective and provide insights for targeted B cell therapies.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0413 - Tumefactive demyelinating lesions under fingolimod. A Tunisian case report (ID 579)

Speakers
Presentation Number
P0413
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Fingolimod (FTY) is a second-line treatment which changed the course of remittent recurrent multiple sclerosis (RRMS) in the real world by ensuring an increase in the proportion of NEDA 3 (No Evidence of Disease Activity 3). However, some studies have suggested a worsening MS under FTY with tumefactive demyelinating lesions (TDLs).

Objectives

ours objectives are to show TDLs under FTY and the different possibility of treatments that can be used to avoid the morbidity / mortality then to show long term clinical and radiological evolution of the patient after management of TDLs

Methods

Our patient was admitted at Habib Bourguiba hospital, Sfax, Tunisia. The diagnosis of MS was defined according to McDonald 2017 crietria. The patient was treated initially by interferonB and then by FTY. The TDLs was appeared under FTY with clinically worsening and radiological extensive pseudotumoral lesions in cerebral MRI

Results

Our patient is a 47-year-old who in 2016 had symptomatology evoking a Lhermite syndrome. Neurological examination was normal. Cervical MRI revealed C3/C4 spinal cord hyperintensity without contrast enhancement (CE). A complement by brain MRI showed three white matter hyperintensities (WMH) lesions on T2/FLAIR without CE. Analysis of the cerebrospinal fluid (CSF) shows the presence of oligoclonal bands (OCBs). The diagnosis of RRMS was made. The patient was then put on Interferon Béta-1a. Brain and spinal MRI were done every 6 months for 3 years which was all stable. In 03/2019, he developed a dizziness and left hemiplegia with decrease in bilateral visual acuity. A cerebral and medullary MRI were made objectifying the appearance of active lesions in the brain and brainstem (BS). In front of aggravation under interferon, the the patient was put under FTY in 05/2019 (natalizumab was contraindicated in the face of a high index JCV. Two months later, his wife noticed the appearance of sudden confusion with visual hallucinations, right hemiplegia, language disorder and vigilance disorders. A brain MRI showed multiple WMH with CE. Some of these lesions are confluent, others appear to be infiltrating with a large swelling of the BS. A progressive multifocal leukoencephalopathy under FTY was evoked and the patient was transferred to intensive care. A CSF JCV serology was negative. Infectious serology in the blood and CSF were negative (HIV, HSV, CMV, EBV, VZV). The diagnosis of TDLs under FTY was made. The patient was treated with 4 sessions of plasmapheresis with clinical and radiological improvement. Then, he was treated with mitoxantrone with spectacular clinical and radiological improvement.

Conclusions

The occurrence of TDLs with FTY in our patient was an evolutionary turning point of poor prognosis with a significant risk of neurological sequelae. Its put on mitoxantrone allowed a clinical and radiological recovery suggesting the immunological mechanism of the TDLs. The etiopathogenic association between FTY and TDLs is not clear.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0414 - Tumefactive demyelination in association with B-cell therapy (ID 1823)

Speakers
Presentation Number
P0414
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Tumefactive multiple sclerosis (MS) is a rare entity that occurs in approx. 1 per 1000 cases of MS and presents a significant diagnostic challenge due to clinical and radiologic similarities with several inflammatory, infectious and neoplastic processes. It usually occurs as a first clinical event but has been observed in patients on modern immunosuppressants, such as fingolimod.

Objectives

To report a case of possible adverse effect of a disease-modifying therapy for MS._______________________________

Methods

Case report__________________________________________________________________________________________

Results

A 49-year old male patient was diagnosed with RRMS in 2017 after a brainstem relapse with typical radiologic features on MRI and positive oligoclonal bands in CSF. He started on ocrelizumab in Feb 2018 and was clinically and radiographically stable until spring 2020 with an EDSS of 1.0.

He noticed subtle clumsiness in his left hand at the beginning of April 2020 and presented to our Emergency unit approximately 3 weeks later. Neurological examination revealed mild dysarthria and mild left-sided hemiparesis with hemihypesthesia and an EDSS score of 3.5.

An emergency brain MRI was performed and revealed 2 new large T2 and FLAIR hyperintense lesions in bilateral frontal white matter with central contrast enhancement, diffuse T2 and FLAIR hyperintense lesions in cerebellar white matter and patchy granular thick leptomeningeal enhancement in cerebellar folia.

CSF examination showed mildly elevated proteins with mild lymphocytosis. JC virus DNA PCR in CSF was negative as were all other initial microbiological tests. CSF cytology revealed reactive lymphocytosis without evidence of malignancy. Follow up MRI showed worsening of the leptomeningeal enhancement in the posterior fossa and persistent large supratentorial lesions. The patient was then empirically treated with steroids yet failed to improve initially.

An extensive CSF and serological panel excluded possible infectious diseases and rheumatic diseases. Antineuronal and paraneoplastic antibodies in CSF and serum were negative. A brain biopsy revealed activated T cells, with no signs of demyelination-possibly due to peripheral sampling. Follow-up MRI showed regression of leptomeningeal enhancement. A repeated lumbar puncture was again negative for malignant cells. He was treated with steroids with signs of improvement which were afterwards withheld for 4 weeks for the second brain biopsy which again revealed inflammatory demyelination with the absence of B cells with activated T cells and no malignant cells. He has been afterwards continuing with steroids with slow improvement of symptoms.

Conclusions

We presented a RRMS patient who developed tumefactive lesions while on B-cell monoclonal antibody therapy, possibly due to immune dysregulation. We cannot fully exclude underlying CNS lymphoma and will continue to follow him closely.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0415 - Updated post-approval safety of cladribine tablets in the treatment of multiple sclerosis, with particular reference to respiratory viral infections (ID 965)

Speakers
Presentation Number
P0415
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Several integrated analyses have reported on the safety of cladribine tablets 10 mg (3.5 mg/kg cumulative dose over 2 years [CT3.5]) during clinical development for the treatment of patients with relapsing multiple sclerosis (RMS). Additional real-life safety data have accrued since the approval of CT3.5 in many countries worldwide. In recent months the COVID-19 pandemic has become a concern for MS patients and their healthcare providers in terms of the associated safety of their disease-modifying therapy.

Objectives

To update on the post-approval safety profile of CT3.5 in patients with RMS, including COVID-19 and other respiratory viral infections.

Methods

Serious and non-serious adverse events (AEs) from post-approval sources (including spontaneous individual case safety reports, non-interventional post-marketing studies, and reports from other solicited sources) are presented to Jan 2020. AE rates are shown as crude incidences (events/number of patients). Up-to-date COVID-19 findings are summarized.

Results

A total of 2570 AEs were reported for the first 14,813 patients who received CT3.5 post-approval; 303 (12%) events were classified as serious and none represented a new safety signal. Crude incidences for AEs of special interest were as follows: severe lymphopenia, 0.002; herpes zoster, 0.008; tuberculosis, 0.0004; severe infections, 0.009; progressive multifocal leukoencephalopathy, 0; opportunistic infections, 0.001; malignancies, 0.0015; and teratogenicity, 0. The majority of opportunistic infections were superficial dermal and mucosal fungal infections that resolved on standard treatments.

The pattern of respiratory viral infections (typically non-serious) with post-approval use of CT3.5 was also consistent with that from the clinical development program; crude incidences were as follows: influenza, 0.005; viral infection, 0.002; and viral upper respiratory tract infection, 0.0004. As of 29 Jun 2020, the Merck safety database included 18 cases of confirmed COVID-19 in CT3.5-treated patients. An update on latest findings on COVID-19 infections will be presented, including analysis of time of infection since treatment where available.

Conclusions

No new safety signals were identified in the real-world post-approval data of CT3.5, cumulative to Jan 2020. The safety profile of CT3.5, including respiratory viral infections, is consistent with previously published integrated safety analyses of the clinical development data.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0416 - Use of Dimethyl fumarate in real clinical practice and strategy to minimize adverse effects and health resources (ID 937)

Speakers
Presentation Number
P0416
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Background: Dimethyl fumarate (DMF) has shown efficacy in reducing relapse rates in patients with multiple sclerosis (MS). However, associated adverse effects (AE) (mainly gastrointestinal [GI] and flushing) are the main cause of treatment discontinuation.

Objectives

Objective: The aim of this study was to evaluate the efficacy of DMF, and to explore how to reduce treatment discontinuation rates in routine clinical practice.

Methods

Methods: Ninety patients initiated DMF treatment between August 2015 and February 2020. Prior to DMF therapy, patients received written information including guidelines for DMF administration, dose administration schedule and description of treatment-associated AE along with medical prescriptions for proper AE management. Clinical and analytical data were collected at least at every 6-monthly clinical visit, and disease progression was evaluated by brain magnetic resonance imaging (MRI).

Results

Results: At final follow-up of DMF treatment, both annual relapse rate (ARR) and median Expanded Disability Status Scale (EDSS) score were significantly reduced: ARR = 0.09 (p < 0.001); median EDSS = 0 (interquartile range: 0-1.625; p < 0.001) and 26.7% of patients with baseline brain MRI showed improvement. 53 patients reported incidence of DMF-associated EA during follow-up, 96.2% of them did it already during the first clinical visit. Most frequent EA were flushing (n = 39 patients; 43.3%) and GI EA (n = 34; 37.7%). Twelve patients (13.5%) abandoned DMF treatment but none because of GI AE or flushing.

Conclusions

Conclusions: In our series, DMF showed high efficacy at clinical and radiological levels. More important, we found that providing patients with complete information prior to treatment on the management of associated AE helped them to better understand what to expect, improved tolerance and reduced discontinuation rate and clinical and telephone consultations. The use of this strategy in real world clinical practice may allow to maximize the benefits of DMF treatment and diminish the use and cost of healthcare resources.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0417 - Utilization, safety, and tolerability of ocrelizumab: year 3 data from the Providence Ocrelizumab Registry (ID 475)

Speakers
Presentation Number
P0417
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Ocrelizumab (OCR), a humanized anti-CD20 monoclonal antibody, was approved in the US in 2017 for the treatment of relapsing MS (RMS) and primary progressive MS (PPMS). The Providence OCR Registry (POR) was established to monitor long-term treatment and safety outcomes.

Objectives

To evaluate OCR treatment outcomes including clinical and radiographic changes as well as safety issues using real-world data from a diverse, community-based MS population.

Methods

Adult MS patients who have been prescribed OCR were eligible. Chart reviews at OCR start date and every 6 months thereafter were done by a trained RN. Expanded Disability Status Scale (EDSS) scores were determined by the treating provider on the start date and then yearly. Descriptive statistics and paired t-tests were used.

Results

Of the 355 patients enrolled from March 2017 to March 2020, 71.9% were female; mean (SD) age was 51.8 (12.5) years; 78.3% had RMS, 13.2% had SPMS, and 8.5% had PPMS. Median baseline EDSS [interquartile range (IQR)] was 3.0 [2.0, 4.0], 6.5 [6.0, 7.5], and 6.5 [6.0, 7.0] respectively. The RMS cohort had an annualized relapse rate (ARR) of 0.34 prior to starting OCR. Among all patients who had > 1 dose of OCR (n=332), ARR was 0.09 with 4 patients having 2 relapses and 1 patient having 3 relapses. Median EDSS scores at 12 months were 3.0 [2.0, 5.5] (n=151) for RMS patients, 6.5 [6.5, 7.5] (n=31) for SPMS, and 6.5 [5.6, 7.5] (n=16) for PPMS. Infusion reactions occurred in 32.9% of patients during dose one, becoming less frequent with subsequent doses. Respiratory infections occurred in 40.1% of patients followed by urinary tract infections (UTI) (33.1%). Of 34 patients hospitalized, 11 patients had multiple hospitalizations. 25 hospitalizations were due to infections, 14 (56%) of which were due to UTIs. Sixty-five percent of these patients were 55 years or older. Forty-three (12.0%) patients have stopped OCR with a median time to discontinuation [IQR] of 10.8 [6.1,18.9] months; 24 patients stopped due to side effects, 15 patients stopped due to a relapse or clinical progression, and four patients died one each due to septic shock from pneumonia, urosepsis, suicide, and respiratory distress. There were no significant changes in Beck Depression Inventory (BDI), but 87 patients who had baseline and 12 month Modified Fatigue Inventory (MFIS), had significant improvement at 12 months (mean difference -3.7 (±14.1), (p=0.02).

Conclusions

Our study showed that OCR was effective in controlling relapse and disability worsening and reported similar rates of infusion reactions compared to earlier phase III clinical trials. Although only a small percentage of patients have stopped OCR, infections resulting in hospitalization are a concern, especially in older patients.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0418 - Withdrawal of fingolimod treatment: results from a single-cohort observational study (ID 1604)

Speakers
Presentation Number
P0418
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Management of multiple sclerosis (MS) patients who discontinue fingolimod (FTY) is not established yet and breakthrough disease activity has been reported following fingolimod withdrawal. However, data regarding this phenomenon and its possible impact in the long-term are still sparse.

Objectives

To explore frequency of disease reactivation after FTY cessation in a single-center cohort and clinical/radiological characteristics of patients (pts) discontinuing FTY during (I) the wash-out period and (II) the first 12-months following a new treatment onset.

Methods

Data regarding relapses, Expanded Disability Status Scale (EDSS), MRI activity (new T2 and/or Gd-enhancing lesion) and lymphocyte count before and during FTY treatment, the wash-out period and the first 12-moths of a new treatment were retrospectively collected. Pts were grouped according to (I) discontinuation reason (inefficacy/adverse events/other reasons) and (II) disease activity during wash-out (no disease activity/at least one relapse or MRI activity/rebound). Differences in clinical/radiological characteristics or time to NEDA3-failure between groups were assessed with ANOVA, Chi-square and Kaplan-Meier estimator as appropriate.

Results

We included 71 pts [females:70%; mean age and disease duration at FTY start:37.6±8.4 and 11±7.6 years; median EDSS:3 (0-7); mean treatment duration:2.3 year]. 70% discontinued for inefficacy, 22% for adverse events, 8% for other reasons (pregnancy/pts’s choice). During the wash-out 69% of pts remained stable, 21.2% had clinical/radiological activity, 9.8% had a rebound (mean wash-out period: 2.3, 8.2, 4.1 months, respectively; p=0.03). Age was lower in rebound vs stable pts (28.5±4.9vs39.4±8.3; p=0.006). Discontinuation for inefficacy was observed in 70% of stable, 93% of clinically/radiologically active and 42% of pts with a rebound during wash-out (p<0.0001). No differences in time to NEDA3-failure during the first 12-months following a new treatment start were observed according to discontinuation reason or disease activity during wash-out (Log-Rank test: p=0.67 and p=0.23, respectively). Disease duration, EDSS, lymphocytes’ count at FTY stop and lymphocytes’ increase during wash-out did not differ according to disease activity during wash-out or response to following treatment.

Conclusions

Younger pts were more likely to have a rebound, while more frequent discontinuation for inefficacy and longer wash-out period were observed in pts with clinical/radiological activity during wash-out. Time to NEDA3-failure within the 12-months following a new treatment onset was not influenced by discontinuation reason or disease activity during wash-out

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Epidemiology Poster Presentation

P0419 -   Racial inequalities in multiple sclerosis research participation: underreporting and underrepresentation (ID 1751)

Speakers
Presentation Number
P0419
Presentation Topic
Epidemiology

Abstract

Background

MS affects minority communities differently with more rapid disability accumulation described in African American and Hispanic patients. These patients are also negatively impacted by social determinants of health further worsening disparities in outcomes. To best care for minority patients, the safety and efficacy of MS treatments in these populations must be known and reliably reported.

Objectives

To evaluate how representation of minority patients in manufacturer-sponsored phase 3 trials is reported in medical journals and on patient- and healthcare provider (HCP)-facing websites for approved disease-modifying therapies (DMTs). To assess the representation of minority patients in DMT trials and trends over time.

Methods

The Medline and clinicialtrials.gov databases were searched from 1995 to 1 June 2020, to identify manufacturer-sponsored phase 3 trials for FDA-approved MS DMTs. We explored how race and ethnicity were reported in the trial outcomes publications. Using studies where information was available, we analyzed representation of minority patients. Additionally, we reviewed patient-and HCP-facing websites of available DMTs to assess the availability of information on racial representation in trials. Finally, we searched for publications presenting either post-hoc analyses of clinical trial data or post-marketing studies aiming to evaluate safety and efficacy of DMTs in minority patients.

Results

A total of 41 phase 3 trials were reviewed, among which 14 (34%) did not report race, 15 (37%) reported race as proportion of white participants only, and 12 (29%) reported detailed information on race. People identifying as black were underrepresented in all trials, with decreased representation over time. Ethnicity was only reported in 1/41 publication, and trends in representation of Hispanics could not be assessed. No patient- or HCP-facing website reported demographic data on race and ethnicity. Four post-hoc analyses and three post-marketing studies that addressed DMT efficacy and safety in minority patients were found.

Conclusions

Race is underreported in phase 3 trial outcomes publications for MS DMTs and race/ethnicity representation is omitted from patient- and HCP-facing websites. When available, data show that minority patients are underrepresented in MS trials. Finally, few post-marketing studies assessed safety and efficacy of DMTs in minority populations. The availability of this information is crucial for patients and their HCPs to make informed decisions about their care.

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Prognostic Factors Poster Presentation

P0420 -  Performance on Symbol Digits Modalities Test preceding conversion to Secondary Progressive Multiple Sclerosis (ID 1254)

Speakers
Presentation Number
P0420
Presentation Topic
Prognostic Factors

Abstract

Background

In an era of emerging new therapies for SPMS, neurologist are searching for robust tools to predict and identify conversion to SPMS. Cognitive impairment is prevalent in 40-75% of MS patients and supposedly more common in SPMS as it increases with age. Symbol Digits Modalities Test (SDMT) is a sensitive, easy administrated test of information processing speed and predicts driving capacity and future income in MS populations.

Objectives

In this pilot study we test if SDMT absolute values could be used to predict SPMS conversion, hypothesizing that SPMS patients prior to conversion have lower scores on SDMT compared to age and gender matched RRMS patients.

Methods

This is a Swedish MS Registry-based study. We extracted first SDMT score and age at testing, available for MS patients included in the registry. Then we selected RRMS patients with first SDMT value at least 4 years (mean ± SD, 6.5 ± 1.98) before SPMS onset n=192 (SPMS converters) and gender matched RRMS patients (n=192) that performed their first SDMT at the same age as SPMS converters. We performed a linear regression analysis using SDMT as dependent variable and age, gender, disease course (SP convert) as independent variables.

Results

RRMS patients that later converted to SPMS, had statistically significant lower SDMT values compared to age and gender matched RRMS patients, p=3.43x10-13. Overall, SDMT decreased with age and was lower for men compared to women (p=0.0002 and p=0.024).

Conclusions

Differences in SDMT absolute values correlate with and precede SPMS conversion at the group level. High variation of inter-individual SDMT performance is likely to limit the usefulness of SDMT to predict SPMS by itself, but SDMT could be an integrated component of a more complex prediction algorithm.

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Comorbidities Poster Presentation

P0421 -  SARS-CoV-2 infection in multiple sclerosis patients: a single center experience in the province of Bergamo, Italy (ID 1461)

Speakers
Presentation Number
P0421
Presentation Topic
Comorbidities

Abstract

Background

In Europe, the first case of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was reported in Lombardy region; the highest number of cases identified was in Eastern Lombardy , in particular in Bergamo’s province with 11,313 confirmed COVID19 patients up to April 30th 2020. The pandemic represents a challenge for neurologists treating Multiple Sclerosis (MS) because of the higher risk of infections of this population and for disease modifyng treatment (DMT) used. We report the experience of the MS center of Papa Giovanni XXIII Hospital in Bergamo, Italy.

Objectives

To evaluate the risk of SARS-CoV-2 infection and the outcome of the disease in MS patients treated with first and second line DMT.

Methods

We retrospectively and prospectively collected all MS patients who reported symptoms suggestive of SARS-CoV-2 infection since the beginning of February 2020. We considered for the analysis patients with a diagnosis confirmed by real-time reverse-trascriptase polymerase-chain-reaction (RT-PCR) on nasopharyngeal specimens as well as patients with suggestive symptoms and signs of SARS-CoV-2 infection who did not performed swab test and/or serological test. Since the begnning of pandemic , according to Italian reccomandation, we postponed the majority of treatment with depleting therapies whereas all the other drugs were usually continued.

Results

Between February 1st and and June 30, 153 patients with suspected SARS-CoV-2 infection were identified, which represent the 18% of the whole population regoularly followed at our MS center. The mean age was 45 years (range 20-71) and the mean EDSS was 2,5 ( range 1-8,5). The 81% of patients were female. A first line DMT was used in 92 patients (60%) while 51 patients (33%) were treated with second line DMT. Overall only 11 patients performed a nasopharyngeal swab during the symptomatic phase and a positivity was found in 7 patients. In an additional patient the diagnosis was confirmed on bronchoalveolar lavage fluid obtained by bronchoscopy. Only 3 patients (2%) presented a severe distress respiratory syndrome and were hospitalized in Intensive Care Unit. Two of these patients were female of 43 and 46 years old treated with Natalizumab and Ocrelizumab respectively both with mild disability (EDSS 2,5). The third patient was a disabled male of 56 years with a progressive form of MS (EDSS of 6.5). None of these patients had additional comorbidities and they all showed a complete recovery without sequaele.

Conclusions

In our experience the course of infection was mild in the large majority of patients independently of the ongoing DMT and no deaths were reported . The good outcome observed in our cohort might support a possible protective role of immunomodulation during SARS-CoV-2 infection. However, the diagnosis was confirmed only in a minority of our patients, therefore we cannot draw definitive conclusion and more data are needed to confirm our results.

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Comorbidities Poster Presentation

P0422 - A Case of Multiple Sclerosis in an 18-year-old Female with Juvenile Idiopathic Arthritis on Abatacept (ID 207)

Speakers
Presentation Number
P0422
Presentation Topic
Comorbidities

Abstract

Background

To date there are few case reports regarding the concurrence of Multiple Sclerosis (MS) and Juvenile Idiopathic Arthritis (JIA). Anti-tumor necrosis factor (TNF) agents, a staple of JIA treatment, have been associated with optic neuritis, MS, cranial nerve palsies, and peripheral neuropathies. In contrast, other biologic therapies – including anakinra, tocilizumab, and abatacept – are not thought to play a significant role in precipitating demyelinating disease.

Objectives

To describe a case of MS concurrent with JIA. To suggest a potential role for remote anti-TNF agents and current abatacept therapy in progression of demyelinating disease. To discuss the selection of disease-modifying therapy (DMT) for both MS and JIA in a patient who progressed to MS on abatacept.

Methods

We describe a case study of one patient. We also review the literature regarding the coincidence of JIA and MS and the occurence of demyelinating events with biological agents.

Results

We propose a case suggesting a potential role for abatacept in precipitating demyelinating disease. Our patient was diagnosed with JIA at age 15 and received methotrexate and etanercept without benefit. She was transitioned to infliximab briefly prior to abatacept monotherapy at age 16. She suffered a mild traumatic brain injury after a motor vehicle collision at age 17. MRI brain with and without contrast, obtained due to seizure, demonstrated multiple T2 hyperintensities in the periventricular and juxtacortical white matter without enhancement. Neurologic exam and workup at that time were unremarkable. One year later, she presented with left vision loss. MRI brain and spine without contrast revealed left optic neuritis and extensive new cortical, juxtacortical, basal ganglia, corpus callosum, and brainstem lesions, some with diffusion restriction suggesting active demyelination. Lab workup revealed 8 cerebrospinal fluid oligoclonal bands; aquaporin-4 and myelin oligodendrocyte glycoprotein antibodies were negative. Rheumatologic workup was negative. Abatacept was discontinued; she received methylprednisolone and was transitioned to ocrelizumab.

Conclusions

In a patient with concurrent JIA, we report the second described case of progression to MS on abatacept. While demyelinating syndromes are classically described as temporally related to initiation of anti-TNF agents, our patient had discontinued infliximab two years prior. Further investigation is needed in JIA to determine if remote anti-TNF therapy or non-TNF agents such as abatacept may also preclude an increased risk of demyelinating events.