University of Ottawa and the Ottawa Hospital Research Institute
Medicine

Author Of 20 Presentations

Biomarkers and Bioinformatics Poster Presentation

P0032 - Baseline serum Neurofilament light chain levels predict conversion to McDonald 2005 MS within 2 yrs of a first clinical demyelinating event in REFLEX (ID 1096)

Speakers
Presentation Number
P0032
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Serum Neurofilament light chain (sNfL) is a biomarker of neuronal damage, reflecting disease activity, drug response, and is predictive of future disability in established multiple sclerosis (MS).

Objectives

Post hoc analysis to assess whether baseline (Month [M] 0) sNfL concentration can predict conversion to McDonald (McD) 2005 MS in patients (pts) with a first clinical demyelinating event (FCDE) receiving subcutaneous interferon β-1a (scIFNβ-1a) once (qw) or three (tiw) times weekly, or placebo (PBO) in the phase 3 trial REFLEX.

Methods

Pts randomized to scIFNβ-1a tiw (n=171) or qw (n=175), or PBO (n=171) were followed-up over 2 yrs; converters to 'clinically definite MS' switched to open label scIFNβ-1a tiw. High and low M0 sNfL subgroups were defined by median sNfL concentration (26.1 pg/ml at M0). Median (95% confidence intervals [CI]) time to McD MS (days) by treatment group and M0 sNfL subgroup was calculated by Kaplan Meier. Hazard ratios (HR; 95% CI) to determine factors influencing risk of conversion to McD MS were calculated using a univariate Cox’s proportional hazard model. A stepwise multivariate Cox’s proportional hazard model was performed using factors selected from the univariate model (threshold P<0.15). For both models, variable selection was based on a two-sided Wald test.

Results

High sNfL levels at baseline correlated with the likelihood for conversion to McD MS (low vs high M0 sNfL, HR [95% CI]: 0.58 [0.47; 0.72], P<0.001). Other baseline factors that reduced the risk of conversion to McD MS (univariate model) included: classification of FCDE (mono- vs multifocal: 0.68 [0.55; 0.83], P<0.001) and low numbers of MRI lesions (number of T2 lesions: 1.02 [1.02; 1.03], P<0.001; number of T1 gadolinium-enhancing [Gd+] lesions: 1.14 [1.11; 1.17], P<0.001; number of T1 hypointense lesions: 1.04 [1.02; 1.05]; P<0.001). Furthermore, treatment with scIFNβ-1a tiw (vs PBO: 0.53 [0.41; 0.69], P<0.001) or qw (0.71 [0.56; 0.91], P=0.006) reduced the risk of conversion to McD MS. These findings were confirmed by multivariate models for baseline sNfL subgroup (P=0.024), classification of FCDE (P<0.001), most baseline imaging findings (number of T2 lesions, number of T1 Gd+ lesions; (P≤0.001), and on-study treatment (both P<0.001).

Conclusions

Among other factors, baseline sNfL concentration was identified as a predictor of conversion to McD MS in patients with a FCDE.

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Biomarkers and Bioinformatics Poster Presentation

P0037 - Change in serum neurofilament light chain levels: ENSEMBLE 1-year interim results (ID 945)

Speakers
Presentation Number
P0037
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Early treatment of multiple sclerosis (MS) provides significant long-term benefits. The aim of the Phase IIIb ENSEMBLE study (NCT03085810) is to evaluate the effectiveness and safety of ocrelizumab (OCR) in patients with early-stage relapsing-remitting MS (RRMS). Neurofilament light chain (NfL) is a marker of neuroaxonal injury. OCR reduced elevated NfL levels in patients with relapsing MS and primary progressive MS to those of healthy donors in the OPERA and ORATORIO studies over 96 weeks. NfL levels are assessed yearly in ENSEMBLE.

Objectives

To report 1-year NfL analyses from ENSEMBLE.

Methods

Treatment-naive patients with a diagnosis of early-stage RRMS (age, 18–55 years inclusive; Expanded Disability Status Scale [EDSS] score ≤3.5) per 2010 revised McDonald criteria and a disease duration from the first documented clinical attack consistent with MS disease of ≤3 years and ≥1 clinically reported relapse or ≥1 sign of MRI activity within 12 months of enrollment were included. Patients will receive OCR 600 mg every 24 weeks (first dose, 2×300 mg separated by 14 days) for the 192-week treatment period (maximum 8 doses). Serum NfL levels are measured via the Simoa Quanterix Advantage kit.

Results

A total of 582 patients were included in the NfL evaluation (female, 64.3%; mean [SD]: age, 32.4 [9.2] years; baseline EDSS, 1.70 [0.96]; time since MS symptom onset, 1.08 [0.84] years) with characteristics comparable with the overall population (N=678). The median serum NfL level at baseline was 13.20 pg/mL; 81.8% of patients had levels greater than healthy donors (HDs; 7.1 pg/mL). Median NfL levels at baseline in patients stratified by age, gender and EDSS score were consistent with those of the overall population. The highest median NfL levels at baseline were observed in patients with T1-weighted contrast-enhancing lesions (CELs) at screening (18.71 pg/mL; n=260) and relapses within 3 months of enrollment (14.91 pg/mL; n=217). At Week 48 the median serum NfL level was reduced to 6.35 pg/mL; 60.8% of patients had levels comparable to or lower than the HD level. Decreases in median serum NfL levels were observed, independent of the baseline demographics and disease characteristics of age, gender, EDSS score, CELs, relapses and reason for enrollment.

Conclusions

NfL levels at baseline and patterns of change over 48 weeks were in line with previous evaluations and decreased considerably after 1 year of treatment with ocrelizumab.

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Biomarkers and Bioinformatics Poster Presentation

P0051 - Comparison of serum and CSF fluid biomarkers for predicting long term disease progression in MS
  (ID 1448)

Speakers
Presentation Number
P0051
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

With the availability of more powerful treatments for multiple sclerosis (MS), prognostic biomarkers are badly needed.

Objectives

Our objective was to evaluate the long-term prognostic value of 4 protiens in paired serum and CSF samples obtained early-on following MS diagnosis.

Methods

In this prospective cohort study, we identified patients with serum collected within 5 years of first MS symptom onset (baseline) and more than 15 years of routine clinical follow-up. Neurofilament light Chain (NfL), Glial Fibrillary Acidic Protein (GFAP), Tau and UCHL-1 were quantified in paired serum (s) and CSF (c) samples from patients and matched controls using digital immunoassay (SiMoA HD-1 Analyzer, Quanterix). Outcomes of biomarker performance included conversion to progressive MS phenotype and reaching an EDSS ≥4.

Results

67 patients had a median follow-up of 17.4 years (range:15.1-26.1), by which time 10/67 had been classified as PPMS, 16 SPMS and 41 RRMS. 29 had developed EDSS ≥4. Baseline CSF levels 3 of the candidate markers were higher than MS patients compared to controls: cNfL (Mann Whitney p=0.0001, median 624 vs. 277pg/mL), cGFAP (p<0.0001, 6900 vs. 694pg/mL) and cTau (p=0.0001, 15.4 vs. 8.12pg/mL) but not UCH-L1. Patient-control differences were less marked in serum: sNfL (p= 0.0037, 10.1 vs. 7.3pg/mL), sGFAP (p=0.0011, 68 vs 51pg/mL), no difference in sTau and sUCH-L1. Positive correlations existed between paired serum and CSF samples only for NfL (Spearman r=0.71, p<0.0001) and GFAP (r=0,4, p=0.003). ROC curve analysis showed cUCH-L1 was most predictive of developing EDSS ≥4 after 15 years of follow-up (AUC 0.72, p=0.003) followed by sNfL (AUC 0.70, p=0.012) and cGFAP (AUC 0.66, p=0.03). Similarly, cUCH-L1 was most predictive of developing a progressive phenotype (PP/SPMS, AUC 0.69, p=0.0097), followed by cGFAP (AUC 0.66, p=0.024) and barely by sNfL (AUC 0.64,p=0.057). cNfL (AUC 0.60,p=0.17), sGFAP, sTau, cTau and sUCH-L1 were not predictive of either reaching EDSS ≥4 or converting to a progressive phenotype (PP/SPMS).

Conclusions

This is the first study to report and association of baseline CSF UCH-L1 levels with long term clinical outcomes in MS. This marker was more predictive of EDSS worsening and conversion to a progressive phenotype than well-established markers NfL and GFAP. More generally, CSF biomarker levels better segregating MS patients from controls at baseline compaired to levels in paired serum samples.

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Clinical Outcome Measures Poster Presentation

P0071 - Effect of oral ponesimod on clinical disease activity and MRI-based outcomes in patients with relapsing multiple sclerosis: Phase 3 OPTIMUM study (ID 1570)

Abstract

Background

Ponesimod (PON), an orally active, highly selective and reversible modulator of sphingosine-1-phosphate receptor 1, reduces circulating lymphocytes by sequestration in lymphoid organs. In the phase-3 OPTIMUM study (NCT02425644), PON showed superior efficacy vs teriflunomide (TER) in patients with relapsing multiple sclerosis (RMS).

Objectives

To evaluate prespecified MRI-based endpoints and no evidence of disease activity (NEDA) status in patients with RMS.

Methods

Patients (18-55 years) with RMS (expanded disability status scale scores: 0-5.5) were randomized (1:1) to receive PON 20 mg or TER 14 mg for 108 weeks. MRI endpoints included: percentage change from baseline to week 108 in brain volume (SIENA, Structural Image Evaluation, using Normalization of Atrophy), mean number of new gadolinium-enhancing (Gd+) T1 lesions and volume/count of new/enlarging T2-weighted (T2) lesions. NEDA-3 (absence of confirmed relapse, 12-week confirmed disability accumulation, Gd+T1 and new/enlarging T2 lesions on annual MRIs) and NEDA-4 status (NEDA-3 and no average annual brain volume decrease ≥0.4%) were evaluated from baseline to week 108.

Results

985/1133 (86.9%) randomized patients completed the study. MRI findings for PON vs TER from baseline to week 108, respectively, were: least square (LS) mean percent change from baseline in brain volume: −0.91% vs −1.25% (difference: 0.34%, 95% CLs: 0.17;0.50, p<0.0001); LS mean difference (PON−TER) in change from baseline in total T2 lesion load: −399.2 mm3 (95% CLs: −651.5;−146.8, p=0.002); mean number of new/enlarging T2 lesions per year: 1.40 vs 3.16 (rate ratio [RR]: 0.44, 95% CLs: 0.36;0.54, p<0.0001); PON vs TER odds ratio (OR [95% CL]) for absence of new/enlarging T2 lesions: 1.71 (1.30;2.25, p=0.0001); mean number of new Gd+T1 lesions per scan: 0.18 vs 0.43 (RR: 0.42, 95% CLs: 0.31;0.56, p<0.0001); PON vs TER (OR [95% CL]) for absence of new Gd+T1 lesions: 2.18 (1.61;2.95, p<0.0001). At week 108, 28.2% (159/564) PON vs 18.3% (102/558) TER patients (OR: 1.70, 95% CLs: 1.27;2.28, p=0.0004) achieved NEDA-3; 15.0% (79/526) PON vs 8.5% (45/532) TER patients (OR: 1.85, 95% CLs: 1.24;2.76, p=0.0026) achieved NEDA-4. The most common reason for not achieving NEDA-3 or NEDA-4 status was presence of new/enlarging T2 lesions.

Conclusions

PON showed benefit vs TER for all MRI outcomes including brain volume loss and a significantly higher proportion of patients achieved NEDA-3 and NEDA-4 status, supporting the effects observed on clinical endpoints.

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Biomarkers and Bioinformatics Poster Presentation

P0088 - Identification of putative multiple sclerosis biomarkers in CSF by targeted-mass spectrometry (ID 913)

Speakers
Presentation Number
P0088
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

The individual expression of Multiple Sclerosis (MS) is highly heterogeneous. One of the greatest potential benefits of biomarkers is to predict disease severity and guide therapeutic choices.

Objectives

Our objective is to evaluate the predictive value of soluble brain-specific proteins of 10-year MS clinical outcomes.

Methods

This retrospective study analyzed cerebrospinal fluid (CSF) from 35 MS patients (mean age: 42; 79% female) and 23 non-MS controls (mean age: 35.5; 68% female) collected within 5 years of disease onset. We quantified 63 brain-specific proteins in the CSF of these patients using a targeted liquid-chromatography tandem mass spectrometry assay. This assay was previously developed in-house by mining of the Human Protein Atlas database and experimental search of CSF to establish brain-enriched proteins.

Results

Our parallel reaction monitoring assay (PRM) used in this study had high assay reproducibility (median across peptides CV = 5.7%). Twelve proteins significantly differentiated MS from controls (p<0.05). The levels of 6 proteins at baseline were significantly associated with CIS, RRMS or PPMS. We also observed a trend with a number of proteins negatively predicting evolution of CIS to RRMS or SPMS. Finally, we observed an association between 3 proteins and the rate of EDSS progression rate over 10 years (Spearman rank correlation: r=-0.59, r=-0.36, r=-0.44; p=0.0006, p=0.046, p=0.0151 respectively).

Conclusions

We identified 12 CSF brain-specific proteins that are unique to MS patients and 3 proteins that seem to predict disease course over the next decade. These proteins also highlight putative pathways implicated in MS pathogenesis and can be targets for future therapeutic regimes.

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Biomarkers and Bioinformatics Poster Presentation

P0105 - Longitudinal proteomic analysis of MS patients before and after autologous hematopoietic stem cell transplantation (ID 1549)

Speakers
Presentation Number
P0105
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Serum markers which reflect MS disease activity could help personalize MS therapeutics. Longitudinal samples from patients undergoing autologous haematopoetic stem cell transplantation (HSCT) for aggressive MS represent a valuable cohort to search for such biomarkers, as these patients had very active disease prior to treatment followed by durable supression of inflammatory disease activity after treatment.

Objectives

To investigate changes in candidate serum proteins in patients with active MS compared to controls as well as before and after HSCT in relation to clinical and MRI outcomes.

Methods

97 proteins of interest were identified including established markers of inflammation and neurodegeneration. Levels were quantified using an in-house antibody colocalization microarray in 24 MS patients with aggressive relapsing MS at baseline compared to 10 controls. Pre-post HSCT changes were analyzed over 10 timepoints pre and up to 36 months post HSCT. We used principal componant analysis for data reduction prior to correlation as well as mixed effects models of individual proteins to compare changes in levels to clinical and MRI covariates of interest (age, EDSS score, relapses, sustained progression, lesional and volumetric MRI measures).

Results

Levels of 19 proteins differed between MS patients at baseline and controls and 17 proteins differed comparing baseline and 12-months post HSCT (simple t tests, p<0.1); we focused on the levels of these proteins for subsequent analyses. 7 proteins were identified in both comparisons including amphiregulin, cathepsin, CRP, GRO, HAI-1 and leptin, which may indicate normalization post HSCT. 8/24 patients developed sustained EDSS progression in the absence of ongoing relapses post HSCT; using mixed effects models, of the 17 candidate proteins, the longitudinal trajectory of CRP levels differed in patients who developed sustained progression compared to those who did not (B=-0.003, p=0.045). Component analysis was used to summarize clusters of proteins into a single value based on internal correlation/discordance. At baseline, one cluster of proteins (CRP, KLK14, PAI-1, IGFBP-7, PDGF) correlated with preceding rapid progression from diagnosis to EDSS 6 (p=0.011, r=0.80) and EDSS worsening in the preceding 24 months (p=0.047, r=0.46). A different cluster of proteins (HAI-1, amhiregulin, FAS, capthespsin B, e-cadherin, GFAP) correlated with the pretreatment rate of brain atrophy. Comparing pre-post changes, one cluster correlated with rate of brain atrophy in the first year post HSCT (p=0.024, r=0.059).

Conclusions

This exploratory analysis of longitudinal serum biomarkers changes pre and post HSCT provides hypothesis generating observations worthy of future investigation.

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Biomarkers and Bioinformatics Poster Presentation

P0132 - Prediction of 15-year MS outcomes in BENEFIT trial patients using serum neurofilament light chain concentrations (ID 1726)

Speakers
Presentation Number
P0132
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Serum neurofilament light chain (sNfL) levels are a promising biomarker for quantifying neuro-axonal injury in multiple sclerosis (MS). Recent studies showed sNfL levels relate to disease activity and treatment response.

Objectives

To analyze the predictive capacity of baseline (BL) sNfL levels for disease outcomes in the 15-year BENEFIT study long-term follow-up

Methods

Monofactorial regression analyses were conducted on outcomes at Year 15, including sNfL age-adjusted percentiles (80th, 90th, 95th, 97.5th and 99th; Disanto et al., 2017).

Further BL covariates included sex; age; lowest EDSS up to Month 6; mono/multifocal onset; presence of optic nerve, brainstem, or spinal cord lesions; Paced Auditory Serial Addition Test 3 (PASAT-3), Timed 25 Foot Walk (T25W), and 9 Hole PEG test (9HPT) scores; number/volume of hypointense T1, gadolinium-enhancing T1, and T2 lesions; cerebral volume; and initial treatment assignment. On-study covariates at Years 1, 2, and 5 were annualized relapse rate; EDSS change; PASAT-3, T25W, and 9HPT scores; annualized rate of new lesions; lesion number/volume; brain volume change; and relative duration of treatment. Covariates with p≤0.1 (at ≥2 time points for on-study covariates) were entered into multifactorial models.

We assessed the predictive capacity of BL sNfL levels for the following outcomes: EDSS ≥4, clinically silent disease, T2 lesion volume, and cerebral volume.

Results

Patients with sNfL values at screening (N=258) above the 90th (n=176), 95th (n=157), 97.5th (n=149), and 99th (n=129) percentiles (adjusted for other relevant covariates) had a significantly higher risk of EDSS≥4 at Year 15 for BL model (odds ratio 2.45 [95% CI: 1.05,5.68] p=0.0376; 2.60 [1.18,5.75] p=0.0181; 2.61 [1.20,5.66] p=0.0154; 2.47 [1.19,5.13] p=0.0150, for the 90th, 95th, 97.5th and 99th percentiles, respectively), and for on-study models at Year 1 (3.86 [1.16,12.78] p=0.0272; 3.38 [1.13,10.14] p=0.0296; 2.92 [1.02,8.35] p=0.0461; 2.98 [1.11,8.00] p=0.0305, respectively) and Year 2 (5.36 [1.26,22.85] p=0.0231; 4.88 [1.34,17.77] p=0.0163; 3.86 [1.18,12.66] p=0.0259; 3.34 [1.17,9.48] p=0.0237, respectively). Covariates that remained statistically significant with EDSS≥4 as the endpoint in most percentile models were lowest EDSS value up to Month 6 for BL and Year 1, and change in brain volume at Year 1, 2, and 5.

Conclusions

Findings in this unique long-term BENEFIT study suggest that higher sNfL values in early MS disease stages are independent predictors of long-term disability.

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Clinical Trials Poster Presentation

P0194 - Cardiac Safety of Ponesimod in Relapsing Multiple Sclerosis in the Randomized, Active-Controlled, Double-Blind, Parallel-Group Phase 3 OPTIMUM Study (ID 565)

Abstract

Background

Ponesimod (PON) is a sphingosine-1-phosphate receptor 1 modulator. Activation of these receptors on cardiomyocytes during treatment initiation cause transient effects on heart rate (HR) and antrioventicular (AV) conduction. The OPTIMUM phase 3 study assessed efficacy, safety, and tolerability of PON and teriflunomide (TER) in relapsing multiple sclerosis.

Objectives

We report on the cardiac safety profile of ponesimod versus teriflunomide in the phase 3 OPTIMUM study (NCT02425644).

Methods

Patients (18-55 years) were randomized 1:1 to PON (20 mg) or TER (14 mg) for 108 weeks. For PON, a gradual 14-day up-titration starting with 2 mg was implemented to address 1st-dose cardiac effects. Cardiac safety was assessed by blood pressure (BP) and 12-lead ECG measurements. Cardiac treatment-emergent adverse events (TEAEs), major adverse cardiovascular (CV) events (MACE; defined as CV death, non-fatal myocardial infarction [MI], and non-fatal stroke), and TEAEs of special interest (AESIs) are reported.

Results

Of 1131 patients who received treatment (PON: n=565, TER: n=566), baseline mean HR was 70.6 bpm (PON), 70.3 bpm (TER), range 45-126 bmp. Cardiac TEAEs leading to treatment discontinuation occurred in 1 (0.2%) patient on PON (cardiomyopathy) and 2 (0.4%) patients on TER (1 atrial fibrillation, 1 coronary artery insufficiency). No MACE were reported on PON; 3 MACE occurred on TER. HR and rhythm AESIs were reported in 29 (5.1%) PON patients vs. 24 (4.2%) TER patients. Incidence of HR and rhythm AESIs on Day 1 in the PON group (2 mg) was 2.1%, and included bradycardia (HR<50bpm) in 0.7% and 1st degree AV block in 0.5%; vs. 0.4% in TER. Max mean reduction in HR from pre- to post-dose on Day 1 was observed at 2h post-dose for PON at -8.7bpm compared with -1.7bpm for TER. On Day 1, 3 patients on PON had post-dose asymptomatic HR≤40bpm, all had pre-treatment HR<55bpm. On Day 1, new ECG findings of sinus bradycardia was 20.0% in patients at risk for symptomatic bradyarrhythmia, compared to 3.0% (all asymptomatic) in patients who were not at-risk. The up-titration was not associated with clinically significant bradyarrhythmia events; none were serious or leading to discontinuation of treatment, no 2nd degree or higher AV blocks were reported.

Conclusions

In the 2-year OPTIMUM study, PON treatment was not associated with an increased risk for major CV events such as MI, stroke, or CV death compared to TER. The up-titration regimen successfully mitigates 1st-dose effects and supports removing the requirement for 1st-dose cardiac monitoring in patients without risk factors of symptomatic bradycardia.

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Clinical Trials Poster Presentation

P0204 - Effect on disability measures and MSFC in patients with relapsing multiple sclerosis from the phase 3 ponesimod versus teriflunomide optimum study (ID 1667)

Abstract

Background

OPTIMUM was a multicenter, double-blind, active-comparator phase 3 superiority trial that assessed efficacy, safety, and tolerability of ponesimod 20 mg (PON) vs teriflunomide 14 mg (TER) in patients with relapsing multiple sclerosis (RMS). The primary endpoint of annualized relapse rate was met demonstrating PON’s superiority vs TER.

Objectives

To assess treatment effect on disability progression using time to worsening of timed 25-foot walk (T25FW), 9-Hole Peg Test (9HPT), Symbol Digit Modalities Test (SDMT), Paced Auditory Serial Addition Test [PASAT-3] , Expanded Disability Status Scale (EDSS) and composites of these endpoints.

Methods

OPTIMUM enrolled patients with RMS (EDSS:0-5.5), randomized (1:1) to daily PON or TER for 108 weeks. Change in MS functional composite (MSFC) Z-score (mean of T25FW, 9HPT, PASAT-3 Z-scores), and SDMT from baseline to Week 108 was assessed using Mixed-Effect Model Repeated Measures. Analyses of time to first confirmed (12-week) disability event were conducted post-hoc; disability was defined as 4-point worsening in SDMT, 20% worsening in T25FW or 9HPT, in addition to EDSS (as defined for the secondary endpoint).

Results

Of 1133 patients (PON=567, TER=566), 86.9% completed study. Changes from baseline in overall MSFC Z‑score: 0.02 PON vs −0.039 TER (mean difference, 0.059; p=0.047); for the 3 individual components of MSFC Z-score, mean differences (p-values) were: T25FW, 0.20 sec (p=0.37); 9HPT, –0.93 sec (p<0.0001); PASAT-3, 0.55 number correct (p=0.16). The PON vs TER worsening events up to EOS were, respectively: confirmed 20% worsening in T25FW, 9.2% vs 13.1% (hazard ratio [HR]:0.70; p=0.045); 4-point worsening in SDMT, 22.1% vs 26.4% (HR:0.82; p=0.12)], composite EDSS/SDMT, 26.3% vs 32.7% (HR:0.80; p=0.045)]; composite EDSS/9HPT/T25FW, 18.2% vs 24.0% (HR:0.76; p=0.035); numerical differences in favour of PON in time to confirmed worsening in 9HPT and SDMT assessed individually were not statistically significant.

Conclusions

Measures of worsening of impairment and disability in this exploratory analysis indicated benefits for PON vs TER. Composite endpoints provide more power to statistical assessments owing to greater number of events analyzed, making them particularly useful in RMS trials.

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Clinical Trials Poster Presentation

P0210 - Elezanumab in patients with different disease courses of multiple sclerosis: study design and baseline analysis from two phase 2 studies (ID 404)

Speakers
Presentation Number
P0210
Presentation Topic
Clinical Trials

Abstract

Background

Background: Multiple sclerosis (MS) treatment involves disease-modifying therapies (DMTs) and symptom management. There is an unmet need for MS treatments that reverse demyelination and neuronal damage. Elezanumab (formerly ABT-555) is a monoclonal antibody that neutralizes repulsive guidance molecule A (RGMa), a neurite outgrowth inhibitor thought to be involved in MS.

Objectives

Objective: Present the study design and baseline data from 2 studies investigating elezanumab efficacy and safety in patients with progressive MS (PMS) and relapsing MS (RMS).

Methods

Methods: RADIUS-R (NCT03737851) and RADIUS-P (NCT03737812) are 2 ongoing, 52-week, proof-of-concept, RAndomized, Double-blind, placebo-controlled, multIple-dose phase 2 stUdies investigating efficacy and safety of elezanumab added to Standard of care in patients with RMS and PMS, respectively. RADIUS-R includes patients with relapsing-remitting MS (RRMS; no relapse 6 months before screening), or active secondary-progressive MS (SPMS; relapse 6 to 24 months before screening). RADIUS-P includes patients with primary-progressive MS (PPMS) or non-active SPMS (no relapses 24 months before screening). Patients in both studies were randomized 1:1:1 to receive 1 of 2 doses of elezanumab or placebo intravenously every 4 weeks through week 48. The primary endpoint for both studies is mean overall response score (ORS; based on Expanded Disability Status Scale [EDSS], Timed 25-Foot Walk [T25FW], and 9-hole Peg Test [9HPT]-dominant and nondominant) at week 52.

Results

Results: Overall, 208 patients enrolled in RADIUS-R and 123 in RADIUS-P. In RADIUS-R, 199 (96%) patients were diagnosed with RRMS, while 9 (4%) were diagnosed with SPMS. In RADIUS-P, 59 (48%) patients were diagnosed with PPMS, and 63 (52%) were diagnosed with SPMS. Baseline mean (SD) age was 45.7 (8.4) years (RADIUS-R) and 52.6 (7.0) years (RADIUS-P). Overall, 66% of RADIUS-R and 48% of RADIUS-P patients were women. Mean (SD) ORS components for RADIUS-R were: T25FW, 7.3 (4.0); 9HPT-dominant, 28.0 (22.5); and 9HPT-nondominant, 30.0 (23.5); EDSS (median [range]), 3.5 (1.0, 6.5). ORS components for RADIUS-P were: T25FW, 12.5 (11.2); 9HPT-dominant, 31.4 (27.6); and 9HPT-nondominant, 38.1 (37.3); EDSS, 6.0 (2.0, 7.0). Most patients used concomitant DMTs (RADIUS-R, 75%; RADIUS-P, 69%), most commonly ocrelizumab (RADIUS-R, 45%; RADIUS-P, 59%).

Conclusions

Conclusion: RADIUS-R and RADIUS-P are ongoing phase 2 studies investigating safety and efficacy of elezanumab as a remyelination agent.

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Clinical Trials Poster Presentation

P0215 - Long-term efficacy and safety of ponesimod: Results from randomized phase II core and extension studies in relapsing‑remitting multiple sclerosis (ID 470)

Speakers
Presentation Number
P0215
Presentation Topic
Clinical Trials

Abstract

Background

Ponesimod, an orally active, selective sphingosine 1-phosphate receptor-1 (S1P) modulator, showed benefits in clinical and MRI outcomes in a double-blind, placebo controlled, phase 2b Core Study (NCT01006265). Patients rolled-over into an ongoing Extension Study (NCT01093326).

Objectives

Evaluate the long-term efficacy and safety of ponesimod in patients with relapsing-remitting multiple sclerosis (RRMS).

Methods

A total of 435 patients with RRMS received ≥1 dose of ponesimod (10, 20, or 40-mg/day) during the Core and/or Extension Study. The 40 and 10-mg doses were subsequently discontinued during Treatment Period 1 (TP1) and TP2 of the Extension Study. All patients received 10 or 20-mg during TP2, followed by open-label 20-mg in TP3. Key efficacy parameters: annualized relapse rate (ARR), 6-month confirmed disability accumulation (CDA), and MRI outcomes. Safety parameters: frequencies of adverse events (AEs) and serious AEs (SAEs). Results of combined analyses of Core and Extension studies are presented.

Results

As of 31 March 2019, 214 patients were still on ponesimod treatment; median exposure in 20-mg group was 8.02 years; Cumulative exposure across all doses was 2372.47 patients-years. In 20-mg group, ARR (95% CI) for confirmed relapses was 0.154 (0.111‒0.214); 64.1% patients remained free of confirmed relapse; Kaplan-Meier estimate of 6- month CDA at Week 432 was 20.4% (13.7‒29.7); Mean number of T1 gadolinium enhancing lesions per patient per scan was 0.448 (0.305‒0.657); Mean number of new or enlarging T2 lesions per year was 0.718 (0.523‒0.985). In ponesimod-treated patients, the most common treatment-emergent AEs were nasopharyngitis (30%), headache (24%) and upper respiratory tract infection (21%). Most SAEs were reported in a single patient, no SAE was reported at an incidence of >1%.

Conclusions

Long-term treatment with ponesimod 20 mg showed consistently low levels of disease activity across relevant clinical and MRI outcomes in patients with RRMS. No new safety signals were identified.

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Clinical Trials Poster Presentation

P0220 - Ocrelizumab Phase IIIb efficacy: 1-year NEDA rates (with MRI re-baselining) from the ENSEMBLE study in early-stage relapsing-remitting MS patients (ID 849)

Abstract

Background

Early treatment of multiple sclerosis (MS) has been shown to provide significant long-term benefits in terms of Expanded Disability Status Scale (EDSS) score versus delayed treatment (patients switching from placebo to active treatment). ENSEMBLE (NCT03085810) is a Phase IIIb study evaluating the effectiveness and safety of ocrelizumab (OCR) in patients with early-stage relapsing-remitting multiple sclerosis (RRMS). Assessments of effectiveness in ENSEMBLE include composite endpoint measures, e.g. the proportion of patients with no evidence of disease activity (NEDA).

Objectives

To report ENSEMBLE 1-year interim NEDA rates.

Methods

Treatment-naive patients with a diagnosis of early-stage RRMS (age, 18–55 years inclusive; EDSS score ≤3.5) per 2010 revised McDonald criteria and a disease duration from the first documented clinical attack consistent with MS disease of ≤3 years and ≥1 clinically reported relapse or ≥1 sign of MRI activity within 12 months of enrollment were included. Patients received OCR 600 mg every 24 weeks (first dose 2×300 mg separated by 14 days) throughout the 192-week (4-year) treatment period (max 8 doses). Clinical assessments will be conducted every 24 weeks. NEDA is defined as absence of: protocol-defined relapses (PDRs), 24-week confirmed disability progression (24W-CDP), T1-weighted contrast-enhancing (CEL) and new/enlarging T2-weighted (T2w) lesions. The effects of OCR are not immediate. MRI measures were re-baselined at Week 8 (prespecified) so that the calculation of NEDA would reflect a more accurate treatment effect.

Results

A total of 678 patients (female, 64.6%) were enrolled (74.6% of patients based on the presence of reasons of both MS relapse and MRI activity) and analyzed. Baseline demographics and disease characteristics reflected a population with early-stage disease (mean [SD]: age, 32.4 [9.1] years; baseline EDSS, 1.71 [0.95]; time since RRMS diagnosis, 0.36 [0.40] years; time since MS symptom onset, 1.10 [0.84] years). At Week 48 most patients (84.8% [n/N=545/643]) reached NEDA. Most patients were free of PDR (98.1%), 24W-CDP (94.1%), CEL (94.2%; re-baselined) and new/enlarging T2w (95.2%; re-baselined) lesions. NEDA calculated without MRI re-baselining was achieved by 62.1% of patients (n/N=404/651). Safety results were consistent with prior studies.

Conclusions

In ENSEMBLE, the Year 1 NEDA rate with MRI re-baselining was high (84.8%) in patients with early-stage disease. No new safety signals were observed.

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Clinical Trials Poster Presentation

P0221 - Ocrelizumab treatment in patients with RRMS who had a suboptimal response with one or more prior disease-modifying therapies: CHORDS 2-year results (ID 1216)

Presentation Number
P0221
Presentation Topic
Clinical Trials

Abstract

Background

In the pivotal trials of ocrelizumab (OCR) in patients with relapsing-remitting multiple sclerosis (RRMS; OPERA I, OPERA II), ≈75% of participants had no previous disease-modifying therapy (DMT).

Objectives

To report 2-year findings from the Phase IIIb CHORDS study (NCT02637856) investigating OCR in patients with RRMS who had a suboptimal response with previous DMT.

Methods

CHORDS enrolled patients who had a suboptimal response (≥1 relapse, ≥1 T1 gadolinium [Gd]-enhancing lesion or ≥2 new/enlarging T2 lesions) after ≥6 months of treatment with 1 to 3 previous DMTs. All participants received OCR 600 mg every 24 weeks for 96 weeks and were included in the intention-to-treat (ITT) population. Annualized relapse rate (ARR), changes in Expanded Disability Status Scale (EDSS) and safety were assessed in the ITT population. The primary endpoint was the proportion of patients free of any protocol-defined event (i.e. relapse, T1 Gd-enhancing lesion, new/enlarging T2 lesion, 24-week confirmed disability progression [CDP] on the EDSS) and was evaluated using a modified ITT (mITT) population, which imputed as having an event those patients who terminated early for lack of efficacy or death and excluded patients who discontinued for reasons other than an event.

Results

The ITT population included 608 patients with a mean (SD) time since diagnosis of 4.2 (3.03) years. The most frequently used DMTs prior to enrollment included glatiramer acetate (49.3%), dimethyl fumarate (35.4%) and fingolimod (20.1%). In the mITT population (576 [94.7%]), 48.1% of patients were free of all protocol-defined events, and most experienced freedom from individual events (relapse, 89.6%; T1 Gd-enhancing lesions, 95.5%; new/enlarging T2 lesions, 59.5%; 24-week CDP, 89.6%) over 96 weeks. Similar results were observed for the primary endpoint in those who received 1 vs >1 prior DMT (50.9% vs 44.5%) as well as for individual events (relapse, 90.0% vs 89.2%; T1 Gd-enhancing lesion, 95.8% vs 95.1%; new/enlarging T2 lesion, 61.4% vs 57.1%; 24-week CDP, 90.9% vs 87.9%). The adjusted ARR over 96 weeks was 0.046. Most patients had stable (<1-point change; 61.5%) or improved (≥1-point decrease; 22.7%) EDSS scores. There were no deaths or new safety signals.

Conclusions

This analysis demonstrates the potential benefits of ocrelizumab treatment over 2 years in patients with RRMS who are relatively early in the disease course and have experienced suboptimal response on prior DMTs.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0284 - Age-related efficacy of cladribine tablets in patients with relapsing-remitting MS in the CLARITY Extension study (ID 867)

Speakers
Presentation Number
P0284
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

Abstract

Background

In the CLARITY study, treatment with cladribine tablets 10 mg (3.5 mg/kg cumulative dose over 2 years [yr]) demonstrated significance over placebo on clinical and MRI efficacy outcomes in patients (pts) with relapsing-remitting multiple sclerosis. Pts who completed CLARITY were eligible to participate in CLARITY Extension (EXT).

Objectives

This post hoc analysis explored efficacy outcomes at the end of the core part of CLARITY EXT (Week 96) in pts who were ≤30yr vs >30yr at CLARITY enrollment.

Methods

Analyses were performed by age and treatment (CC7.0 [cladribine-cladribine]: cladribine tablets 3.5 mg/kg in CLARITY and CLARITY EXT; CP3.5 [cladribine-placebo]: cladribine tablets 3.5 mg/kg in CLARITY and placebo in CLARITY EXT). Endpoints included relapse, 3- and 6-month (mo) confirmed disability progression (CDP, based on Expanded Disability Status Scale), MRI activity, and no evidence of disease activity (NEDA; no relapse, 3- or 6-mo CDP, and MRI activity) at Week 96 of CLARITY EXT.

Results

Data from 284 pts were included: ≤30yr: CC7.0 N=49, CP3.5 N=23; >30yr: CC7.0 N=137, CP3.5 N=75. Annualized relapse rate (95% confidence interval [CI]) was similar between age groups for pts receiving CC7.0 (≤30yr, 0.08 [0.04; 0.15]; >30yr, 0.08 [0.05; 0.12]) and numerically higher in younger pts receiving CP3.5 (≤30yr, 0.27 [0.16; 0.47]; >30yr, 0.06 [0.03; 0.11]). The probabilities (Kaplan-Meier estimates) of being free of 3-mo CDP for CC7.0 were 0.98 for ≤30yr and 0.86 for >30yr; and for CP3.5 were 0.79 for ≤30yr and 0.88 for >30yr. The probabilities of being free of 6-mo CDP were similar to those of 3-mo CDP. Mean (95% CI) cumulative numbers of T1 gadolinium-enhancing lesions were similar between age groups for pts receiving CC7.0 (≤30yr, 0.02 [0.01; 0.08]; >30yr, 0.02 [0.01; 0.06]) or CP3.5 (≤30yr, 0.54 [0.16; 1.79]; >30yr, 0.27 [0.10; 0.73]). Mean (95% CI) numbers of active T2 lesions were similar between age groups for pts receiving CC7.0 (≤30yr, 1.36 [0.75; 2.45]; >30yr, 1.12 [0.78; 1.61]) and numerically lower in older pts receiving CP3.5 (≤30yr, 2.95 [1.22; 7.10]; >30yr, 1.40 [0.88; 2.22]). The proportion of pts achieving NEDA based on 3-mo CDP was numerically higher in younger pts receiving CC7.0 (≤30yr, 36.7%; >30yr, 28.5%) and older pts receiving CP3.5 (≤30yr, 21.7%; >30yr, 30.7%). NEDA results based on 6-mo CDP were similar to those based on 3-mo CDP.

Conclusions

Cladribine tablets result in similar clinical and MRI outcomes at Week 96 of CLARITY EXT in both older (>30yr) and younger (≤30yr) pts, providing further evidence of efficacy across age groups.

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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 – 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 – 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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Observational Studies Poster Presentation

P0880 - Low discontinuation rate and side-effect burden after switching to cladribine tablets: Canadian experience from the adveva® patient support program (ID 1083)

Speakers
Presentation Number
P0880
Presentation Topic
Observational Studies

Abstract

Background

Cladribine tablets were approved in Canada in November 2017. All patients prescribed cladribine tablets in Canada are enrolled upon their consent in the adveva patient support program (PSP), which provides drug education, assistance with reimbursement and patient support services.

Objectives

To examine the demographics and treatment history of patients initiating cladribine tablets in Canada, assess the discontinuation rate over the two-year treatment and describe reported adverse events (AEs).

Methods

Analysis of data routinely collected by adveva nurses and all reported AEs from Dec2017 to Jan2020. Patients were included if they consented to enroll in the adveva PSP. They were contacted at enrollment and periodically therafter. Follow-up stopped when treatment was completed/discontinued.

Results

Overall, 1864 patients enrolled in the program; 1373 were female (74.4%) and mean age was 41.54 years (standard deviation [SD]: 10.34). None of the patients were treatment naïve; most (n=1191; 63.9%) had received only one prior disease modifying drug (DMD). The most recent prior DMDs were glatiramer acetate (23.1%), dimethyl fumarate (20.4%), teriflunomide (16.5%), fingolimod (10.9%), and subcutaneous interferon beta-1a (10.4%). Of 1864 enrolled, 1679 (90.1%) had completed pre-treatment evaluation. Of those, 1415 (84.3%) started year-1. Among those, 483 (34.1%) started year-2 and 394 (27.8%) completed it. Mean time to year-2 initiation was 12.75 (SD: 1.27) months. Among all patients who had started year-1 treatment, 38 (2.69%) reported discontinuation. Among those, 26.3% discontinued within <6 months, 52.6% between 6-12 months and 21.1% at ≥12 months. Main reported reasons were: 28.9% unknown, 21.1% AE other than flu-like syndrome and lymphopenia, 18.4% worsening disease, 10.5% patients decision, and 10.5% family planning/pregnant. A total of 843 patients (59.6%) reported at least one AE. Among the total AEs report (n= 3525)the most frequent were fatigue (8.0%), headache (5.4%), nausea (4.7%), and lymphocytopenia (2.5%).

Conclusions

The Canadian adveva program presented a high enrolment rate. Cladribine tablets were associated with a high continuation rate and most patients successfully self-adminstered the drug. Reported adverse events were not severe.

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Invited Presentations Invited Abstracts

TC02.01 - Presentation 01 (ID 590)

Speakers
Authors
Presentation Number
TC02.01
Presentation Topic
Invited Presentations
Invited Presentations Invited Abstracts

TC02.02 - Quantifying therapy response in MS by neurofilaments? (ID 591)

Speakers
Presentation Number
TC02.02
Presentation Topic
Invited Presentations

Abstract

Abstract

Neurofilaments: towards application in clinical practice

1. Do neurofilaments predict MS disease course?

Mark Freedman

3. Quantifying therapy response in MS by neurofilaments?

Jens Kuhle

3. Neurofilament applications outside the MS field

Roberto Furlan

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Presenter Of 2 Presentations

Clinical Trials Poster Presentation

P0215 - Long-term efficacy and safety of ponesimod: Results from randomized phase II core and extension studies in relapsing‑remitting multiple sclerosis (ID 470)

Speakers
Presentation Number
P0215
Presentation Topic
Clinical Trials

Abstract

Background

Ponesimod, an orally active, selective sphingosine 1-phosphate receptor-1 (S1P) modulator, showed benefits in clinical and MRI outcomes in a double-blind, placebo controlled, phase 2b Core Study (NCT01006265). Patients rolled-over into an ongoing Extension Study (NCT01093326).

Objectives

Evaluate the long-term efficacy and safety of ponesimod in patients with relapsing-remitting multiple sclerosis (RRMS).

Methods

A total of 435 patients with RRMS received ≥1 dose of ponesimod (10, 20, or 40-mg/day) during the Core and/or Extension Study. The 40 and 10-mg doses were subsequently discontinued during Treatment Period 1 (TP1) and TP2 of the Extension Study. All patients received 10 or 20-mg during TP2, followed by open-label 20-mg in TP3. Key efficacy parameters: annualized relapse rate (ARR), 6-month confirmed disability accumulation (CDA), and MRI outcomes. Safety parameters: frequencies of adverse events (AEs) and serious AEs (SAEs). Results of combined analyses of Core and Extension studies are presented.

Results

As of 31 March 2019, 214 patients were still on ponesimod treatment; median exposure in 20-mg group was 8.02 years; Cumulative exposure across all doses was 2372.47 patients-years. In 20-mg group, ARR (95% CI) for confirmed relapses was 0.154 (0.111‒0.214); 64.1% patients remained free of confirmed relapse; Kaplan-Meier estimate of 6- month CDA at Week 432 was 20.4% (13.7‒29.7); Mean number of T1 gadolinium enhancing lesions per patient per scan was 0.448 (0.305‒0.657); Mean number of new or enlarging T2 lesions per year was 0.718 (0.523‒0.985). In ponesimod-treated patients, the most common treatment-emergent AEs were nasopharyngitis (30%), headache (24%) and upper respiratory tract infection (21%). Most SAEs were reported in a single patient, no SAE was reported at an incidence of >1%.

Conclusions

Long-term treatment with ponesimod 20 mg showed consistently low levels of disease activity across relevant clinical and MRI outcomes in patients with RRMS. No new safety signals were identified.

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Invited Presentations Invited Abstracts

TC02.01 - Presentation 01 (ID 590)

Speakers
Authors
Presentation Number
TC02.01
Presentation Topic
Invited Presentations

Moderator Of 1 Session

Teaching Course Fri, Sep 11, 2020
Session Type
Teaching Course
Date
Fri, Sep 11, 2020

Invited Speaker Of 1 Presentation

Invited Presentations Invited Abstracts

TC02.01 - Presentation 01 (ID 590)

Speakers
Authors
Presentation Number
TC02.01
Presentation Topic
Invited Presentations