Author Of 3 Presentations

Disease Modifying Therapies – Risk Management Oral Presentation

FC02.01 - Safety of Alemtuzumab Over 9 Years in Patients With Non-MS Autoimmunity

Speakers
Presentation Number
FC02.01
Presentation Topic
Disease Modifying Therapies – Risk Management
Lecture Time
13:00 - 13:12

Abstract

Background

Alemtuzumab is an anti-CD52 monoclonal antibody therapy approved for treating RRMS. Although alemtuzumab is associated with non–MS-related secondary autoimmune events, the role pre-existing non-MS autoimmunity plays in secondary autoimmunity is unclear.

Objectives

To assess the impact of 1) pre-existing non-MS autoimmunity and 2) post-alemtuzumab thyroid autoimmunity on subsequent onset of new autoimmunity up to 9 years after initiating alemtuzumab.

Methods

In clinical trials (NCT00050778, NCT00530348, NCT00548405, NCT00930553, NCT02255656), patients were monitored for autoimmune adverse events (AEs). All patient- and investigator-reported AEs were recorded. An autoimmune event was pre-existing if it occurred prior to initiating alemtuzumab or was in the medical history database.

Results

A total of 1216 patients from the alemtuzumab clinical development program who received alemtuzumab 12 mg were included in the analysis. Ninety-six had pre-existing non-MS autoimmunity. Up to 9 years after alemtuzumab initiation, the percentage of patients with new autoimmune disease was similar in those with (35.4%) versus without (35.3%) pre-existing autoimmunity; similar percentages of patients with versus without pre-existing autoimmunity had ≥2 new autoimmune events (5.2% vs 8.2%, respectively). Most patients with thyroid disorders at baseline did not experience new autoimmunity after alemtuzumab. Treatment-emergent thyroid autoimmunity after alemtuzumab Course 1 was not associated with subsequent nonthyroid autoimmunity after Course 2 (0% of patients with vs 3.0% of patients without thyroid autoimmunity after Course 1). Similarly, thyroid autoimmunity after Course 2 did not predict nonthyroid autoimmunity after Course 3 (1.8% vs 2.0%, respectively). Among 25,292 patients treated with alemtuzumab in the postmarketing setting as of 31 March 2019, additional events (occurring 18–36 months post treatment) included autoimmune hepatitis (10.7 in 10,000) and hemophagocytic lymphohistiocytosis (2.7 in 10,000).

Conclusions

Over 9 years after alemtuzumab initiation, pre-existing non-MS autoimmunity was not associated with subsequent new autoimmune disease. Emergence of thyroid autoimmunity after Courses 1 and 2 does not appear to predict subsequent serious autoimmune disease.

STUDY SUPPORT: Sanofi and Bayer HealthCare Pharmaceuticals.

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Disease Modifying Therapies – Risk Management Oral Presentation

FC02.05 - Safety and Efficacy in Patients Treated With Dimethyl Fumarate and Followed For 13 Years: Final Results of ENDORSE

Speakers
Presentation Number
FC02.05
Presentation Topic
Disease Modifying Therapies – Risk Management
Lecture Time
13:48 - 14:00

Abstract

Background

DMF is a well-established therapy for relapsing forms of multiple sclerosis (RMS); data from ENDORSE, an extension to phase 3 studies DEFINE and CONFIRM, has enabled >10 years follow-up.

Objectives

We report safety/efficacy of DMF in patients with RMS treated with DMF and followed for 13 years in ENDORSE (NCT00835770) (2 years DEFINE/CONFIRM, and >10 years ENDORSE).

Methods

Incidence of serious AEs (SAEs), discontinuations due to AEs, annualized relapse rate (ARR) and Expanded Disability Status Scale (EDSS) score were assessed. Patients were treated with DMF 240 mg BID: placebo (PBO)/DMF (PBO, years 0–2 /DMF, years 3–10) or continuously (DMF/DMF). Efficacy outcomes were assessed in patients up to 10 years due to sample size considerations. For lymphocyte analysis, data from first DMF exposure were analysed for patients in DEFINE/CONFIRM/ENDORSE.

Results

At 23 January 2020, 1736 patients enrolled/received ≥1 dose DMF. Of 1736 patients, 760 completed. Patients were followed for a median (min,max) of 6.76(0.04,10.98) years in ENDORSE, and 2 years in DEFINE/CONFIRM. Overall, 551 (32%) patients experienced SAEs; most were MS relapse and fall. There was one case of PML in this study. There was no increased incidence of other infections or serious infections. Sixteen percent (n=282) patients discontinued due to AEs; 2% relapse, 2% disease progression, and 4% GI disorders. ALC decreased over the first 48 weeks, and then remained generally stable for the majority of the study. The proportion of patients with other AEs of special interest (including opportunistic infection, malignancy, and serious herpes zoster) was similar regardless of ALC. For patients continuously treated (n=501), overall ARR remained low (0.141[95% CI, 0.119,0.167]), while for PBO/DMF patients (n=249) ARR decreased after initiating DMF (ARR 0–2 years, 0.330[95% CI, 0.266,0.408]; ARR overall, 0.149[95% CI, 0.116,0.190]). Overall, 60% of DMF/DMF and 66% of PBO/DMF patients remained relapse-free; 20% and 17% of patients had 1 relapse, respectively. Walking abilities were maintained throughout the study; the number of patients with EDSS scores ≤3.5 was 413/479(86%) DMF/DMF (179/217[82%] PBO/DMF) at Year 2, and 173/226(77%) DMF/DMF (67/90[74%] PBO/DMF) at Year 10. Seventy-two percent and 73% of DMF/DMF and PBO/DMF patients, respectively, had no 24-week confirmed disability progression over 10 years.

Conclusions

These safety and efficacy data in patients followed for 13 years, support DMF as a long-term option for patients with RMS.

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Invited Presentations Invited Abstracts

PS09.01 - Customized Management of Individuals with MS Using Approved Therapies

Speakers
Authors
Presentation Number
PS09.01
Presentation Topic
Invited Presentations
Lecture Time
09:15 - 09:30

Presenter Of 1 Presentation

Invited Presentations Invited Abstracts

PS09.01 - Customized Management of Individuals with MS Using Approved Therapies

Speakers
Authors
Presentation Number
PS09.01
Presentation Topic
Invited Presentations
Lecture Time
09:15 - 09:30

Invited Speaker Of 1 Presentation

Invited Presentations Invited Abstracts

PS09.01 - Customized Management of Individuals with MS Using Approved Therapies

Speakers
Authors
Presentation Number
PS09.01
Presentation Topic
Invited Presentations
Lecture Time
09:15 - 09:30

Author Of 23 Presentations

Epidemiology Poster Presentation

LB1155 - Vitamin D levels in the UK MS population and COVID-19 susceptibility (ID 1116)

Abstract

Background

Despite the well-described association between vitamin D and MS, little is known about current behaviours surrounding vitamin D and the corresponding vitamin D status in this group at a population level across the UK. During the COVID-19 pandemic, interest in the role that vitamin D might play in reducing susceptibility to and severity of COVID-19 has come to the foreground.

Objectives

To determine the vitamin D status of the UK MS population, understand the factors that influence it, and examine how vitamin D supplementation affects the risk of COVID-19.

Methods

A cohort study using the UK MS Register was performed. Self-reported data surrounding vitamin D and remotely collected biological samples were collected. 1768 people with MS (pwMS) completed a questionnaire regarding vitamin D-influencing behaviours; dried blood spots were collected from 388 of these pwMS and 309 matched controls, and serum 25(OH)D was measured. Subsequently, 592 participants from this MS cohort prospectively completed questionnaires evaluating symptoms suggestive of COVID-19.

Results

Marked differences were observed between supplementation behaviours with pwMS more likely to take supplements (72% vs 26% controls, p<0.001), and at higher doses (median 1600 IU/day vs 600 IU/day in controls, p<0.001). Serum levels of 25(OH)D were higher in pwMS than controls (71nmol/L, IQR 48 vs 49nmol/L, IQR 27, p<0.001). People with MS who did not supplement had lower serum 25(OH)D levels than non-supplementing controls (median 38 nmol/L, IQR 35 vs 44 nmol/L, IQR 21, p<0.001). 71% of those self-diagnosed with COVID-19 reported taking vitamin D vs 72% without COVID-19. Median dose for those with COVID-19 was reported as 1000 IU/day vs 2000 IU/day in those without (p=0.682).

Conclusions

pwMS living in the UK are more likely to have adequate levels of vitamin D than controls, and is driven by the higher rate and dose of supplementation across this population. This has implications on the design and interpretation of any future clinical trials with vitamin D in this population. In addition, we found no evidence that vitamin D supplementation had an impact on susceptibility to COVID-19 in this population.

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Clinical Trials Late Breaking Abstracts

LB1229 - CLASSIC-MS: Long-term efficacy and real-world treatment patterns for patients receiving cladribine tablets - interim data with 8–14 years follow-up (ID 2108)

Speakers
Presentation Number
LB1229
Presentation Topic
Clinical Trials

Abstract

Background

CLARITY, CLARITY Extension, and ORACLE-MS have previously demonstrated the efficacy of cladribine tablets (CT; cumulative dose 3.5 mg/kg over 2 years). CLASSIC-MS (NCT03961204) seeks to explore the long-term efficacy and durability of effect of CT beyond the 2 annual treatment cycles in patients (pts) enrolled to these parent trials, with the aim of informing future treatment approaches.

Objectives

To present interim data on long-term efficacy and durability of effect of CT and real-world treatment patterns in CLASSIC-MS.

Methods

CLASSIC-MS is an exploratory, low-interventional, multicenter, ambispective, Phase IV study of pts with multiple sclerosis (MS), or those with a first clinical demyelinating event, previously enrolled into Phase III parent trials, and who had received ≥1 course of CT or placebo. The primary objective is long-term mobility (no wheelchair use/bedridden; EDSS <7 in the 3 months prior to first visit in CLASSIC-MS). The main secondary objective is long-term disability status (EDSS <6 any time since last parent study dose [LPSD]). Further objectives seek to assess differences in clinical and magnetic resonance imaging characteristics in long-term responders vs non-responders, with long-term responder status defined as: (A) not requiring further disease-modifying drug (DMD) treatment until ≥4 years after LPSD, or (B) no evidence of disease reactivation based on clinical outcomes in the 4 years following LPSD. Analyses are descriptive.

Results

The interim population comprised 147 pts (61% female; 88% exposed to CT in parent studies; mean EDSS 3.3±2.1 at baseline of CLASSIC-MS [vs. 2.6±1.2 at baseline of parent studies]). Median time since LPSD was 10 (range 8–14) years. The proportion of pts not using a wheelchair/bedridden in the 3 months prior to CLASSIC-MS was 94.6% (139/147) and the proportion of pts with no need of ambulatory device at any time since LPSD was 83.7% (EDSS <6; 123/147). Overall, 73.5% of pts (108/147) were long-term responders by definition A and 45.6% by definition B. In addition, 63.3% of pts (93/147) received no subsequent DMD treatment after LPSD, and 59.1% of pts maintained active employment.

Conclusions

Interim data from CLASSIC-MS, with a median of 10 years’ follow-up, suggests sustained efficacy of CT following 2 annual treatment cycles, with a substantial proportion of pts requiring no further treatment with DMDs or assistive ambulatory device.

CLARITY: NCT00213135; CLARITY Extension: NCT00641537; ORACLE: NCT00725985

Funding: This study was sponsored by Merck KGaA, Darmstadt, Germany.

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Biostatistical Methods Poster Presentation

P0013 - Modeling a long-term virtual placebo arm for SPMS population in the EXPAND study: Comparing different statistical methods (ID 1774)

Speakers
Presentation Number
P0013
Presentation Topic
Biostatistical Methods

Abstract

Background

Siponimod significantly reduced the risk of 3-/6-month confirmed disability progression (3m/6mCDP) versus placebo by 21% and 26%, respectively in patients with secondary progressive multiple sclerosis (SPMS), during the core part of the EXPAND study. At the end of EXPAND-Core, patients were offered a switch to open-label siponimod in the ongoing EXPAND-Extension allowing follow-up for up to an additional 7 years; therefore, a long-term comparison between siponimod and placebo was not possible and a modeling for the placebo long-term trajectory was proposed using different statistical methodology.

Objectives

To estimate the long-term effect of siponimod versus placebo by modeling placebo treatment corrected for switch at the end of EXPAND-Core.

Methods

In the EXPAND-Extension part, 6mCDP was analyzed to assess disability. Time to 6mCDP to account for the switch to siponimod in placebo-treated patients was modeled by 3 methods: 1) Rank Preserving Structural Failure Time (RPSFT) model that uses the actual time to 6mCDP for switchers to compute a hypothetical time to 6mCDP as if they had never switched; 2) simulating the hypothetical time from the switch to 6mCDP based on core part data as if patients had never switched (Two-stage method); and 3) a parametrical model (Weibull distribution) to extrapolate a placebo survival curve.

Results

As of 6 April 2019, 878 patients (siponimod, n=593; placebo-siponimod switch, n=285) were still ongoing in the EXPAND-Extension. All 3 methods confirmed the long-term effect of siponimod versus placebo in the EXPAND population. The RPSFT model seems to provide the more accurate estimate for time to 6mCDP (hazard ratio [95% confidence interval]: 0.69 [0.53; 0.90]) vs the Two-stage (0.76 [0.64; 0.92]) and Weibull modeling methods (0.58 [0.49; 0.67]). The RPSFT results were indicative of a persistent treatment effect over 5 years with a ~50–60% increase in the time to 6mCDP in siponimod versus placebo-corrected switch (median time to 6mCDP: 42.5 months for placebo-corrected switch as opposed to 51.7 months for uncorrected placebo; median not reached with siponimod). Accuracy of RPSFT is supported by simulations conducted under conditions similar to the EXPAND study, which included waning and increasing treatment effects, that found very low difference between the true hazard ratio and the hazard ratio obtained with RPSFT.

Conclusions

The results support the reliability of RPSFT to model a virtual placebo arm in the long-term in a SPMS population. RPSFT results confirmed a long-term benefit of siponimod over placebo with a preserved hazard ratio on 6mCDP and ~50‒60% prolongation of time to 6mCDP.

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Clinical Trials Poster Presentation

P0196 - Cladribine to halt deterioration in people with advanced multiple sclerosis (ChariotMS) (ID 585)

Abstract

Background

Whilst the introduction of disease modifying treatments (DMTs) has transformed the management of people with early/relapsing MS (pwRMS), the use of DMTs in people with MS who are largely or completely wheel chair-dependent (EDSS>6.5) remains controversial. Evidence suggests that slowing or stopping disease deterioration is possible even past this arbitrary (loss of ambulatory function) threshold. Pathology and anecdotal clinical data support the hypothesis that even at an advanced stage of MS (AMS) inflammatory activity is a key driver of functional decline and that effective immunotherapy may halt this process. Cladribine tablets are a highly effective and central nervous system (CNS) penetrant DMT for people with highly-active RMS. It effectively depletes B cells, particularly memory B cells, a likely key mechanism of disease control in MS. Evidence, suggesting that (i) a significantly higher number of CNS axons supply upper compared to lower limb functions and (ii) longer axons are more vulnerable to the effects of focal inflammatory demyelination than shorter ones, corroborate our hypothesis that upper limb function can be protected even beyond EDSS=6.5.

Objectives

Primary Objective: To investigate whether cladribine tablets over 24 months is an effective DMT in people with AMS (pwAMS; EDSS=6.5-8.5) as measured using the 9-hole peg test (9HPT) peg speed.

Secondary Objectives: To establish whether there is a difference in pwAMS between treatment with cladribine tablets or placebo in (i) blood/serum biomarkers of inflammation (lymphocyte subsets) and/or neurodegeneration (neurofilament light chain), (ii) MRI loss of brain volume and spinal cord cross sectional area, (iii) T2 lesion burden, (iv) hypo-intense lesions on T1 weighted scans, (v) quality of life, and (vi) whether cladribine is a cost-effective treatment for pwAMS.

Methods

Randomised, double-blind, placebo-controlled phase IIb trial. To detect a 15% treatment effect in 9HPT peg speed with 90% power at 5% significance and 20% drop-out over 104 weeks n=200 pwAMS will be recruited across 20 UK MS centres.

Results

Protocol and ancillary documents have been submitted for ethics approval. So far 17 centres have agreed to recruit pwAMS for ChariotMS. Due to the COVID-19 pandemic start of recruitment has been deferred to 04 Jan 2021.

Conclusions

ChariotMS will be the first DMT-trial focussing on pwAMS. If successful, ChariotMS would expand the DMT landscape to include pwAMS and provide a platform for add-on therapies.

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Clinical Trials Poster Presentation

P0201 - Disability improvement in relapsing-remitting multiple sclerosis patients receiving cladribine tablets, evaluated by expanded disability status scale (ID 416)

Speakers
Presentation Number
P0201
Presentation Topic
Clinical Trials

Abstract

Background

In CLARITY, treatment with cladribine tablets 10 mg (cumulative dose 3.5 mg/kg over 2 years [CT3.5]) significantly reduced relapse rates and slowed disability progression versus placebo in RRMS patients. A key question is to evaluate whether and for how long cladribine tablets can improve EDSS scores.

Objectives

To evaluate post hoc long-term prevalence of disability improvement assessed by Expanded Disability Status Scale (EDSS) score in relapsing-remitting multiple sclerosis (RRMS) patients treated with cladribine tablets enrolled into CLARITY Extension.

Methods

Patients enrolled into CLARITY Extension were included and pooled by early (CT3.5 in CLARITY then CT3.5 or placebo in CLARITY Extension; n = 284), versus delayed (placebo in CLARITY then CT3.5 in CLARITY Extension; n = 244) treatment. Disability improvement was defined as a decrease in EDSS from baseline of ≥ 1 point for baseline EDSS < 5.5, or ≥ 0.5 points for baseline EDSS ≥ 5.5, confirmed at 6 months. Improvement was considered lost when EDSS returned to ≥ baseline (regression of improvement confirmed at 6 months). Prevalence of improved EDSS was estimated by a new statistical approach, accounting for not only the onset of improvement but also the duration. Prevalence was estimated as the difference between the Kaplan-Meier (KM) estimators for the probability of having an improvement before time t and the probability of returning to baseline before time t. P values were estimated using a bootstrap technique on the area under the modified KM curve.

Results

The prevalence of disability improvement (KM estimate) for the early versus delayed treatment groups at 2-years post-CLARITY baseline was 15.6% (95% confidence interval [CI]: 11.9–19.3) versus 9.3% (95% CI: 6.1–12.4), respectively and at 5-years was 12.7% (95% CI: 8.8–16.6) versus 8.6% (95% CI: 4.8–12.4), respectively (early versus delayed treatment group: P = 0.048 for 5-years difference).

Conclusions

Patients receiving early treatment with cladribine tablets had a greater prevalence of disability improvement over 5 years versus those with delayed treatment.

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Clinical Trials Poster Presentation

P0202 - Durable efficacy of cladribine tablets: cumulative relapse incidence over 5 years in CLARITY and CLARITY Extension (ID 960)

Speakers
Presentation Number
P0202
Presentation Topic
Clinical Trials

Abstract

Background

In CLARITY and CLARITY Extension (NCT00213135 and NCT00641537, respectively), treatment with cladribine tablets 10 mg (cumulative dose 3.5 mg/kg over 2 years [CT3.5]) significantly reduced relapse rates in patients with relapsing-remitting multiple sclerosis. Moreover, in the CLARITY Extension study, treatment with cladribine tablets for 2 years followed by treatment with placebo for 2 years produced similar clinical benefits to 2 years of cladribine tablets treatment followed by an additional 2 years of treatment, but with a lower risk of higher grade lymphopenia.

Objectives

To assess, post hoc, the temporal occurrence of relapses up to 5 years after treatment initiation with cladribine tablets.

Methods

Patients enrolled into CLARITY treated with CT3.5, and those subsequently receiving CT3.5 (CC7) or placebo (CP3.5) in CLARITY Extension, were included for analysis. The main endpoint was all qualifying relapses reported in CLARITY or CLARITY Extension plus those that occurred during the variable bridging interval (range: 1 day to 118 weeks). A recurrent event analysis was performed to estimate mean cumulative number of relapses over time using a cumulative mean function estimate.

Results

A total of 433 patients from CLARITY treated with CT3.5 were included in this analysis; of these 284 patients entered CLARITY Extension (CP3.5, n=98; CC7, n=186). Recurrent event analysis for the CT3.5 population showed that annual increase in mean cumulative number of relapses was consistently low from Year 2 to Year 5 (range: 0.10–0.15) and was slightly higher in Year 1 (0.17); the 6-month increase in mean cumulative number of relapses was similar in the first 6 months and the second 6 months (0.08 and 0.09, respectively). There were no differences in mean cumulative number of relapses between the CP3.5 and CC7 groups from Year 2 to Year 5. In recurrent event analysis for the CT3.5 population, the yearly increments of mean cumulative function were constant and low from the second treatment to Year 5, supporting the durable efficacy of cladribine tablets (given no increase in relapses following completion of the two courses of cladribine tablets).

Conclusions

Annual increase in mean cumulative number of relapses occurred at a low annualized rate of 0.10 to 0.17 per year to 5 years, almost 4 years after the last dose of cladribine tablets and therefore consistent with durable efficacy. Results also support the early effect of cladribine tablets on relapses, which is apparent in the first year of treatment.

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Clinical Trials Poster Presentation

P0211 - Examination of fenebrutinib, a highly selective BTKi, on disease progression of multiple sclerosis (ID 1225)

Abstract

Background

Preventing multiple sclerosis (MS) disease progression is critical in preserving function and quality of life. Fenebrutinib is a potent, highly selective Bruton’s tyrosine kinase (BTK) inhibitor with a dual mechanism of action. Fenebrutinib targets acute and chronic aspects of MS by decreasing B-cell activation and limiting myeloid proinflammatory responses. This profile and studies of fenebrutinib in patients with other inflammatory diseases suggest a potentially favorable benefit-risk ratio, although there are no studies yet in patients with MS.

Objectives

To describe the unique design aspects of the Phase III fenebrutinib clinical trial program as they relate to understanding disease progression across the MS spectrum.

Methods

We developed a Phase III program that will assess disease progression in two identical clinical trials in relapsing MS (RMS) and one trial in primary progressive MS (PPMS).

Results

To understand the effects of fenebrutinib on disease progression, all three trials include 12-week composite Confirmed Disability Progression (cCDP12) as a primary endpoint; the RMS trials also include annualized relapse rate as a co-primary endpoint. The cCDP12 requires at least one of the following: (1) an increase in Expanded Disability Status Score (EDSS) score of ≥1.0 point from a baseline (BL) score of ≤5.5 points, or a ≥0.5 point increase from a BL score of >5.5 points; (2) a 20% increase from BL in time to complete the 9-Hole Peg Test; (3) a 20% increase from BL in the Timed 25-Foot Walk Test. The cCDP12 is a more sensitive assessment of disability than the EDSS, especially at early disease stages, as it provides a quantitative assessment of upper limb function. Comparator arms will include active disease-modifying treatments with known effects on disability progression (PPMS=ocrelizumab; RMS=teriflunomide). Treatment assignments will be 1:1, with estimated enrollment of 734 patients in each of the RMS trials and 946 in the PPMS trial. Study durations will be event driven, with the primary analysis occurring after a prespecified number of cCDP12 events (≥96 or ≥120 weeks in the RMS and PPMS trials, respectively).

Conclusions

Fenebrutinib will be investigated in RMS and PPMS and may offer a unique approach to slowing disease progression in MS. Furthermore, the use of the cCDP12 as a primary endpoint may provide a clearer, more complete picture of disability progression or improvement than the EDSS alone.

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Clinical Trials Poster Presentation

P0216 - Long-term reduction of relapse rate and 48-week confirmed disability progression after 6.5 years of ocrelizumab treatment in patients with RMS (ID 844)

Speakers
Presentation Number
P0216
Presentation Topic
Clinical Trials

Abstract

Background

The efficacy and safety of ocrelizumab (OCR) in relapsing multiple sclerosis (RMS) were demonstrated in the 96-week controlled double-blind period (DBP) of the Phase III OPERA I (NCT01247324) and OPERA II (NCT01412333) trials.

Objectives

To assess the efficacy of switching from interferon (IFN) β-1a or maintaining OCR therapy on disease activity and confirmed disability progression (CDP) after 4.5 years of follow-up, in the open-label extension (OLE) of OPERA I and OPERA II.

Methods

In the DBP of OPERA I and OPERA II, patients were randomized to receive OCR or IFN β-1a. Patients completing the DBP either continued OCR (OCR-OCR) or switched from IFN β-1a to OCR (IFN-OCR) when entering the OLE period. Adjusted annualized relapse rate (ARR), time to onset of 48-week CDP (CDP48) and time to 48-week confirmed Expanded Disability Status Scale score ≥6.0 (time to require a walking aid) were analyzed up to Week 336.

Results

Overall, 79.2% of patients who entered the OLE period completed OLE Year 4.5. Adjusted ARR decreased year-on-year from the pre-switch year to OLE Year 4.5 in IFN-OCR switchers (pre-switch, 0.20; OLE Year 4.5, 0.06) and was maintained at low levels in OCR-OCR continuers (pre-switch, 0.12; OLE Year 4.5, 0.04). The rates of CDP48 were lower in OCR-OCR continuers vs IFN-OCR switchers at the end of the DBP (4.1% vs 8.5%; p<0.001) and at OLE Year 4.5 (16.0% vs 20.3%; p=0.05). The rates of patients requiring a walking aid were lower in OCR-OCR continuers vs IFN-OCR switchers at the end of the DBP (0.8% vs 3.1%; p=0.001) and at OLE Year 4.5 (5.1% vs 8.3%; p=0.024). Over the DBP and OLE periods, the risk of CDP48 was 28% lower (HR [95%CI]: 0.72 [0.56–0.93]; p=0.01) and the risk of requiring a walking aid was 46% lower (HR [95%CI]: 0.54 [0.35–0.83];p=0.004) in OCR-OCR continuers vs IFN-OCR switchers. The safety profile in the OLE was generally consistent with the DBP.

Conclusions

Switching from IFN β-1a to ocrelizumab at the start of the OLE period was associated with a rapid and robust reduction in ARR that was maintained through the 4.5-year follow-up of the OLE period. Compared with patients switching to ocrelizumab at the OLE, patients initiating ocrelizumab 2 years earlier accrued significant benefits on CDP48 and time to require a walking aid that were maintained vs the switch group through the 4.5 years of the OLE period.

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Clinical Trials Poster Presentation

P0230 - Rationale and design of two Phase IIIb studies of ocrelizumab at higher than the approved dose in patients with RMS and PPMS (ID 971)

Abstract

Background

Ocrelizumab (OCR) is approved for the treatment of relapsing (RMS) and primary progressive multiple sclerosis (PPMS) at a dose of 600 mg iv twice yearly and showed significant benefit on disability progression (DP). Exposure-response (ER) analyses of the pivotal OCR Phase III studies in patients with RMS or PPMS showed that those with higher exposures (based on individual mean serum concentration [Cmean] exposure quartiles) had a greater benefit on DP vs patients with lower exposure, without an increase in adverse events. While doses of OCR of 1000–2000 mg were studied in a Phase II study, doses >600 mg have not been investigated in Phase III studies in RMS or PPMS patients.

Objectives

To present the OCR higher dose selection rationale and design of two double-blind, parallel-group, randomized Phase IIIb studies (one in RMS and one in PPMS) aiming to explore if a higher dose of OCR will provide even higher benefits vs 600 mg on DP without adversely affecting the established favorable benefit-risk profile.

Methods

The higher dose of OCR in both studies is based on achieving a Cmean of at least that observed in the highest exposure quartile of the Phase III ER analyses while limiting Cmean below that observed with the highest OCR dose of 2000 mg in the Phase II study that had a similar safety profile, except for a slightly higher incidence of infusion-related reactions (pre-medication: methylprednisolone only; no mandatory antihistamine).

Results

Modeling predicts that doses of 1200 mg (patients <75kg) or 1800 mg (patients ≥75kg) twice yearly would fulfill these criteria. Based on data from the pivotal trials, the expected risk reduction vs 600 mg in 12-week composite confirmed DP (cCDP; consisting of time to progression measured by the EDSS, Timed 25-Foot Walk or 9-Hole Peg Test) would be ≥35% in RMS and ≥27% in PPMS. Patients with RMS (EDSS score 0–5.5; N=786) or PPMS (EDSS score ≥3.0–6.5; N=699) will be randomized (2:1) to either the higher dose (above) or OCR 600 mg administered every 24 weeks (first dose divided into 2 infusions separated by 14 days) for ≥120 weeks (minimum 5 doses).

The primary outcome for both trials is risk reduction on cCDP. Immunoglobulin and oligoclonal bands in the CSF will be assessed in a sub-study of up to 288 patients.

Conclusions

These studies will test if higher-dose ocrelizumab provides an even higher benefit on cCDP vs the approved 600 mg dose without adversely affecting the established favorable benefit-risk profile.

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Clinical Trials Poster Presentation

P0238 - Sustained reduction of disability and cognitive decline with long-term siponimod treatment in patients with active SPMS: EXPAND data up to 5 years (ID 1471)

Abstract

Background

In the EXPAND Core part, in the subgroup of patients with active secondary progressive multiple sclerosis (aSPMS: presence of relapses in the 2 years prior to screening and/or ≥1 T1 gadolinium-enhancing (Gd+) lesion at baseline), siponimod reduced the risk of 3-/6-month confirmed disability progression on Expanded Disability Status Scale (3m/6mCDP) by 31% and 37%, respectively, and the risk of decline in cognitive processing speed (CPS, 6-month confirmed cognition worsening of ≥4-point on Symbol Digit Modalities Test [6mCCW]) by 27% versus placebo.

Objectives

To assess the long-term efficacy and safety of siponimod in patients with aSPMS in the Core and Extension parts of the EXPAND study.

Methods

In patients with aSPMS who had received ≥1 dose of randomized treatment during Core part, and who entered the Extension (36 month extension data cut-off [6 April 2019]; total study duration ≤5 years), time to 3m/6mCDP, 6mCCW, and annualized relapse rate (ARR) were assessed for the Continuous (siponimod in the Core and Extension) and Switch (placebo in the Core and switched to open-label siponimod in the Core/Extension) groups.

Results

Of the 1651 patients randomized in the EXPAND Core part, 779 were with aSPMS (Continuous group: N=516; Switch group: N=263), of which 582 entered the Extension. The risk of 6mCDP was reduced by 29% (0.71 [0.57‒0.90]; p=0.0044) for the Continuous versus Switch group, corresponding to an about 70% delay in time to 6mCDP across the 25th–40th percentile). Median time to 6mCDP was 48 months for the Switch group and was not reached for the Continuous group. The risk of 6mCCW for the Continuous versus Switch group was reduced by 33% (0.67 [0.53‒0.86]); p=0.0018), corresponding to an about 70% delay in time to 6mCCW across the 25th–30th percentile, median time to 6mCCW (55.5 months) was reached only for the Switch group. In patients without active disease, a nonsignificant trend for reduced risk of disability progression and cognitive worsening was observed for the Continuous vs Switch groups. A significant reduction in ARR for the Continuous versus Switch groups was observed in patients with (0.08 vs 0.12; p=0.0023) or without active disease (0.03 vs 0.08; p<0.0001).

Conclusions

In EXPAND, long-term data analyses in the Continuous versus Switch groups showed that siponimod treatment effects on disability, cognitive processing speed, and relapse outcomes in patients with active SPMS are sustained for up to 5 years, and highlight the value of early treatment initiation.

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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

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

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 – 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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Genetics and Epigenetics Poster Presentation

P0522 - Gene-environment interactions in Multiple Sclerosis: a UK Biobank study (ID 1863)

Speakers
Presentation Number
P0522
Presentation Topic
Genetics and Epigenetics

Abstract

Background

Multiple Sclerosis (MS) is a common neuro-inflammatory disorder caused by a combination of environmental exposures and genetic risk factors.

Objectives

To determine which environmental risk factors are associated with MS in UK Biobank, to validate an autosomal polygenic risk score for MS , and to determine whether genetic risk modifies the effect of environmental MS risk factors.

Methods

People with MS were identified within UK Biobank using ICD10-coded MS or self-report. Associations between environmental risk factors, HLA alleles, and MS risk were quantified using multivariable logistic regression. Interaction between environmental and genetic risk factors was quantified using the Attributable Proportion due to interaction (AP). Model fits were quantified using Nagelkerke’s pseudo-R2 metric.

Results

Phenotype data were available for 2151 pwMS and 486,125 controls. Exposures associated with MS risk were childhood obesity (OR=1.39, 95%CI 1.22-1.58), smoking (OR=1.19, 95%CI 1.07-1.33), earlier menarche 0.95, 95%CI 0.92-0.98), HLA-DRB1*15 (ORHomozygote 5.05, 95%CI 4.22-6.05) and lack of the HLA-A*02allele (ORHomozygote=0.57, 95%CI 0.46-0.70). The autosomal polygenic risk score (PRS) was associated with MS disease status (ORTop-vs-bottom-decile=3.96, 95%CI 3.11-5.04). There was evidence of positive (synergistic) interaction between elevated childhood body size and the PRS (AP 0.11, 95% CI 0.008 to 0.202, p = 0.036), and weaker evidence suggesting a possible interaction between smoking status prior to age 20 and the PRS (AP 0.098, 95% CI -0.013 to 0.194, p = 0.082).

Conclusions

This study provides novel evidence for an interaction between childhood obesity and a high burden of autosomal genetic risk. These findings have significant implications for our understanding of MS biology, and inform targeted planning of prevention strategies.

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Imaging Poster Presentation

P0587 - Impact of siponimod on myelination as assessed by MTR across SPMS subgroups: Post-hoc analysis from the EXPAND MRI substudy (ID 1588)

Speakers
Presentation Number
P0587
Presentation Topic
Imaging

Abstract

Background

Changes in magnetization transfer ratio (MTR) are a marker of changes in myelin density and associated tissue integrity in the brain. Siponimod improved MTR recovery in lesions and demonstrated a significant effect on MTR decrease in normal-appearing brain tissue (NABT) and cortical grey matter (cGM) with a more pronounced effect on normal-appearing white matter (NAWM) in the overall EXPAND secondary progressive multiple sclerosis (SPMS) population, as reported previously.

Objectives

To investigate the effect of siponimod vs placebo (PBO) on MTR changes in NABT, cGM, and NAWM in subgroups of SPMS patients.

Methods

This prospective MTR substudy assessed the effect of siponimod versus PBO on median normalized MTR (nMTR) in NABT, cGM and NAWM assessed by absolute change from baseline (BL) to Month (M) 24 using repeated measures models. Patient subgroups were defined by: disease history and severity (age [≤45/>45 years], disease duration [≤15/>15 years], Expanded Disability Status Scale (EDSS) score [≤5.5/≥6.0], Symbol Digit Modalities Test score (≤43/>43); and inflammatory disease activity (active/non-active SPMS, with/without relapse in 2 years before screening, with/without gadolinium-enhancing lesions). Data from the per-protocol set (n=443) are presented.

Results

The subgroup analysis indicated that absolute changes from BL in median nMTR for NAWM ranged from –0.124 to –0.034 in the PBO group and from –0.016 to 0.040 in the siponimod group, which corresponds to 79–198% attenuation in median nMTR decrease versus PBO across all the subgroups studied (all p<0.05 except EDSS≥6 subgroup, p=0.064). The results were consistent for NABT (70–170%) and cGM (44–188%) although slightly less pronounced (p>0.05 for some subgroups). In the active SPMS subgroup, siponimod attenuated median nMTR decrease across NABT, cGM and NAWM by 91–109% (p<0.01 all); and in the non-active SPMS subgroup by 170–198% (p=0.0151 for NAWM, p>0.05 for NABT, cGM).

Conclusions

Over 24 months, siponimod attenuated the decrease in median nMTR in brain tissues across the patient subgroups characterized by disease activity and severity. The effect of siponimod was most pronounced in NAWM. These data support preclinical studies of siponimod, showing direct beneficial CNS effects on myelination.

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Neuropsychology and Cognition Poster Presentation

P0806 - Effect of siponimod on cognitive processing speed in SPMS patients with active and non-active disease (ID 1251)

Speakers
Presentation Number
P0806
Presentation Topic
Neuropsychology and Cognition

Abstract

Background

Siponimod significantly reduced the relative risk of 3-month (m) confirmed disability progression (CDP) by 21% and 6mCDP by 26% versus placebo in the EXPAND core study. Siponimod also showed a significant benefit on cognitive processing speed (CPS) as measured by change in the Symbol Digit Modalities Test (SDMT).

Objectives

To evaluate the effect of siponimod on CPS in subgroups of patients with active (aSPMS) and non-active (naSPMS) disease from the EXPAND core study.

Methods

EXPAND (N=1651) was a double-blind Phase 3 study that randomized a broad range of SPMS patients to siponimod or placebo (2:1). This subgroup post-hoc analysis included patients with aSPMS (siponimod, n=516; placebo, n=263; defined as presence of relapses in the 2 years before screening and/or ≥1 T1 gadolinium-enhancing lesions at baseline) and naSPMS (siponimod, n=557; placebo, n=270; counterpart of aSPMS). The outcomes analyzed were change in SDMT score from baseline to M24 derived from the mixed model for repeated measures; time to 6m confirmed ≥4-points cognitive worsening/improvement (6mCW/6mCI) on SDMT and a categorical analysis showing the proportion of patients with worsened, stable and improved SDMT scores (worsened/improved by ≥4 points since baseline and until the end of the trial, or otherwise stable) at M24.

Results

Change in SDMT (95% CI) versus placebo from baseline to M24 in the aSPMS and naSPMS groups was 2.34 (0.66; 4.02) and 2.44 (0.67; 4.22; p<0.01 for both), respectively, consistent with the overall EXPAND core population (2.28 [1.09; 3.48]; p<0.001). In patients with aSPMS, siponimod reduced the risk of 6mCW by 27% (hazard ratio [95% CI]: 0.73 [0.53; 1.01]; p=0.06) and improved the chance of 6mCI by 62% (1.62 [1.14; 2.29]; p=0.007) versus placebo. Corresponding values in the naSPMS group were: 6mCW, 24% (0.76 [0.53; 1.09]; p=ns) and 6mCI, 19% (1.19 [0.86; 1.65]; p=ns). In the aSPMS group, a lower proportion of patients worsened (27.3% vs 38.2%, p=0.002) and a higher proportion of patients improved (34.1% vs 22.9%, p=0.001) on SDMT versus placebo. Corresponding proportions for the naSPMS group were: worsened, 21.2% vs 23.7%, p=ns; improved, 35.6 vs 31.2%, p=ns.

Conclusions

Siponimod was associated with relevant benefits in CPS as measured by change in SDMT in patients with active and non-active SPMS. In patients with active disease, both a reduced risk for clinically relevant worsening and an increased chance for clinically relevant improvement were observed.

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Observational Studies Poster Presentation

P0850 - Cladribine personalised dosing to treat multiple sclerosis: observations in 208 patients (ID 1521)

Abstract

Background

Oral cladribine (Mavenclad®) was approved as a disease-modifying treatment (DMT) for highly active relapsing multiple sclerosis (RMS) in August 2017. We have treated a large cohort of people with MS (pwMS) using a personalised dosing schedule of subcutaneous cladribine (Litak®) (CPD) since 2014.

Objectives

To report safety and efficacy of cladribine personalised dosing (CPD) as an immunotherapy in people with multiple sclerosis.

Methods

CPD was offered to pwMS irrespective of their disease course, provided they had MRI-detectable inflammatory activity (gadolinium-enhancing T1 and/or more T2 lesions over past ≤2 years) or an elevated neurofilament light chain (NfL) level in their cerebrospinal fluid (CSF). Litak® 10 mg was given on three consecutive days (four in pwMS >90kg) during week 1. Based on total lymphocyte count at week 4, patients were given another 0-3 doses at week 5. A second cycle of CPD was administered 11 months later. Follow-up included recording of adverse events and relapses, annual EDSS, 9-hole-peg, Timed-25-foot-walking, Symbol-Digit-Modalities tests, and full blood counts. Proportions of pwMS with no evidence of disease activity (NEDA), and of progression or active disease (NEPAD), were calculated where complete clinical datasets were available.

Results

208 pwMS (100 relapsing, 108 progressive) underwent CPD. 192/208 received a second treatment cycle. Baseline age 44 (17-72) years, EDSS 0-8.5. Tolerability was very good. One myocardial infarction and one breast cancer occurred. Two severely disabled pwMS died (one influenza, one encephalitis). 12/208 had transient skin reactions. Lymphopenia ≥ grade 3 was detected in <3%. At 2 years, 66% (95% CI 49%, 80%) of pwRMS (total n=38) had NEDA and 62% (95% CI 32%, 86%) of pwPMS (total n=13) NEPAD. Of 23 pwMS with elevated baseline CSF-NfL, 22 had normal levels at follow-up. Median CSF-NfL levels were 652 pg/mL (IQR 458-1063) and 344 pg/mL (IQR 186-505) at baseline and follow-up, respectively.

Conclusions

CPD is a promising and well-tolerated alternative for pwMS not eligible for licensed DMTs. Efficacy in pwRMS was similar to controlled trial data. NEPAD rates in the proportion of pwPMS with full datasets was promising, underpinning the rationale of multi-centre, placebo-controlled trial ChariotMS (Oral cladribine to halt deterioration in people with advanced MS; n=200), starting recruitment of pwMS with EDSS 6.5-8.5 from January 2021.

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Observational Studies Poster Presentation

P0885 - MSProDiscussTM is a useful tool to aid discussion of multiple sclerosis disease progression: Results from a large, real-world qualitative survey (ID 1177)

Abstract

Background

MSProDiscussTM is a validated, physician-completed tool aimed at facilitating physician–patient conversation on signs of progression in multiple sclerosis (MS). A set of weighted questions on relapses, symptoms and their impacts as experienced by the patient generate a traffic light system output to aid the discussion. The tool is available online at www.msprodiscuss.com.

Objectives

Evaluate the usability and usefulness of MSProDiscuss in discussing disease progression in daily clinical practice.

Methods

An online qualitative survey consisting of individual questionnaires completed by healthcare professionals (HCPs) after using MSProDiscuss in patient consultations and a final questionnaire to capture overall experience on the tool was conducted in 34 countries. General feedback and recommendations for improving the tool were also collected.

Results

In total, 301 HCPs participated in the survey. The HCPs first completed individual questionnaires after using MSProDiscuss on 6974 MS patients and then a final questionnaire. In 97% (initial questionnaire, i) and 98% (final questionnaire, f) of the time MSProDiscuss was used, the time taken to complete the tool was considered satisfactory (1-4min). The questions were found to be comprehensible in 94% (i) to 97% (f) of cases, and HCPs are willing to use the tool again in the same patient 91% (i) of the time. MSProDiscuss was also useful in discussing MS symptoms and its impact on daily activities (88% i / 92% f) and cognitive function (79% both i and f) and in discussing progression in general (88% i / 90% f).

Moreover, in the final questionnaire, 95% agreed that the questions were similar to those asked by a HCP in a regular consultation. MSProDiscuss was also found to be helpful for understanding the impact of MS symptoms on daily activities (91%) and cognitive function (80%). Overall, 92% of the HCPs would recommend MSProDiscuss to a colleague; 92% think that it is feasible and 86% are willing to integrate MSProDiscuss into their clinical practice. Key recommendations were to allow for longitudinal follow-up, expand on cognitive assessments, and provide a patient-completed version. These have been considered for implementation in the updated version of MSProDiscuss.

Conclusions

The survey results established MSProDiscuss as useful and easy to use tool to facilitate patient-physician discussion of MS progression by structured capturing of patient clinical profile. Most HCPs were willing to integrate MSProDiscuss into their daily clinical practice.

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Pathogenesis – Immunology Poster Presentation

P0986 - Online Medical Education Improves Knowledge of Age-Related Immune System Changes in Patients with MS Among Neurologists (ID 313)

Speakers
Presentation Number
P0986
Presentation Topic
Pathogenesis – Immunology

Abstract

Background

Multiple sclerosis (MS) is a chronic inflammatory disease affecting an estimated 2.5 million people worldwide. The autoimmune basis of MS remains a key target of therapeutics designed to stop or slow disease progression. It is important therefore, that clinicians are aware of the precise immune mechanisms involved in the disease. Emerging data is starting to show age-related changes in immune function, which may have important consequences for treatment decisions as patients get older.

Objectives

A study was undertaken to evaluate the effectiveness of an online educational intervention to improve knowledge among neurologists on age-related immune changes and how those changes may impact treatment decisions.

Methods

The online continuing medical education (CME) activity format consisted of a 15-minute video discussion with two expert faculty in MS. Educational effect was assessed by comparing a matched sample of neurologists’/PCPs’ responses to four identical questions presented before and directly after exposure to the intervention. A chi-square test was used to identify significant differences between pre- and post-assessment responses. Cramer’s V was used to calculate the effect size of the online education (0.06-0.15 is a noticeable effect, 0.16-0.26 considerable, and >0.26 extensive). Data from the participants were collected between May 24, 2019 and August 5, 2019.

Results

Participation in the CME intervention resulted in a considerable educational effect size among neurologists (n=200; V=.220, P<.001). The following areas showed significant (P <.05 for all) pre- vs post-educational improvements: identification of age-related changes to B- and T-cell function (28% relative improvement among neurologists); consequences of immunosenescence to consider when selecting a disease-modifying therapy (DMT) in MS (24% relative improvement); and selection of an appropriate DMT in older adults with MS (128% relative improvement). After participating in the activity, 50% of neurologists reported that participation in this educational activity improved their confidence in understanding the impact of immunosenescence on selecting a DMT for the management of MS.

Conclusions

The results indicated that the CME-certified 15-minute video discussion was effective at improving knowledge regarding the impact of age-related changes in immune function on the management of MS. Future education should continue to provide updates on immunosenescence in MS and how this impacts the selection of DMTs.

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Symptom Management Poster Presentation

P1106 - Postprandial somnolence in multiple sclerosis: the invisible is real. (ID 1469)

Speakers
Presentation Number
P1106
Presentation Topic
Symptom Management

Abstract

Background

Some invisible symptoms of multiple sclerosis (MS) are more important to the individual’s sense of wellbeing than physical disability. Patients with MS (pwMS) may be more sensitive to the effects of postprandial somnolence (PPS) than the general population, but this has not been confirmed yet.

Objectives

To evaluate the association between MS and PPS. To evaluate the impact of lifestyle modifications on the improvement of PPS in pwMS.

Methods

A cross-sectional study was conducted among pwMS (n=107) and age- and sex-matched people without MS (n=107) at The Royal London Hospital, London, UK. Participants were asked to complete an online survey including demographics, a description of their most recent meal and the Stanford Sleepiness Scale (SSS) one hour after lunch. A chi-square test was used to assess group differences for binary and nominal variables. For ordinal variables, a Mann-Whitney U test was used. Kendall's tau correlation test was performed to measure the correlation between MS and SSS scores.

Results

64.2% of pwMS subjectively reported PPS, compared to 49.5% of people without MS (p=0.044). The median SSS for pwMS was 3 (IQR 2-5) and for people without MS was 2 (IQR 2-3) (p=0.009). There was minimal association between patient characteristics and PPS. Symptoms of PPS were improved by eating smaller portions (p<0.001), consuming less carbohydrates (p<0.001), consuming less fat (p=0.026) and by exercising (p=0.008).

Conclusions

PwMS suffer from PPS more than people without MS and symptoms can be improved through dietary adjustments. These findings can be adopted in clinical practice to manage PPS in pwMS.

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Rehabilitation and Comprehensive Care Poster Presentation

P1111 - Timely Intervention, Monitoring and Education MATTERS in MS (TIME MATTERS in MS): global piloting of the MS Brain Health quality improvement tool (ID 1386)

Speakers
Presentation Number
P1111
Presentation Topic
Rehabilitation and Comprehensive Care

Abstract

Background

A strategy for timely multiple sclerosis (MS) care was described in the policy report, Brain health: time matters in multiple sclerosis. Building on this report, multiple stakeholder groups participated in a modified Delphi process to define acceptable, good and high-quality brain health-focused MS care. These benchmarks were incorporated into an Excel-based quality improvement (QI) tool. The first prototype of this tool was piloted in three MS centers; local analysis of results led to improvements in clinical practice in those centers.

Objectives

We aimed to improve the clinical usability of the QI tool and to test the applicability of a refined version in different healthcare settings.

Methods

The recommendations from all three centers that participated in the initial pilot study were gathered and used to prepare a refined prototype of the QI tool (prototype II). MS centers worldwide have been invited to conduct a service evaluation using prototype II as part of a larger pilot study of 10–20 MS centers across a broad geographical area. Each participating site will review the medical records of 36 adults with MS (at representative stages of the care pathway) and input the data requested into the tool. To assess whether the QI tool can be applied in MS centers globally, study sites will be asked to complete a survey following their service evaluation. The survey asks about ease of use of the tool, its usefulness for facilitating local change, relevance of the data captured and key data for repeated use.

Results

Prototype II has separate spreadsheets for entering information on patients at different stages of the care pathway; fields are tailored to the different patient populations so there is less data to input per patient. Data validation programming prevents the insertion of invalid information. To assist MS centers in analyzing their findings, improved visual summaries of clinic-level and patient-level results are generated within the tool; these auto-populate when the required fields in the data input spreadsheets are completed. Prototype II will also support future language translations. More than 18 MS centers have so far expressed interest in trialing prototype II of the QI tool; preliminary insights from selected study sites will be presented.

Conclusions

Following further refinements, widespread roll-out of the QI tool will enable MS centers to collect data to benchmark their clinical standards and to support service improvement.

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Invited Presentations Invited Abstracts

TC15.01 - Presentation 01 (ID 632)

Speakers
Authors
Presentation Number
TC15.01
Presentation Topic
Invited Presentations

Presenter Of 5 Presentations

Clinical Trials Poster Presentation

P0202 - Durable efficacy of cladribine tablets: cumulative relapse incidence over 5 years in CLARITY and CLARITY Extension (ID 960)

Speakers
Presentation Number
P0202
Presentation Topic
Clinical Trials

Abstract

Background

In CLARITY and CLARITY Extension (NCT00213135 and NCT00641537, respectively), treatment with cladribine tablets 10 mg (cumulative dose 3.5 mg/kg over 2 years [CT3.5]) significantly reduced relapse rates in patients with relapsing-remitting multiple sclerosis. Moreover, in the CLARITY Extension study, treatment with cladribine tablets for 2 years followed by treatment with placebo for 2 years produced similar clinical benefits to 2 years of cladribine tablets treatment followed by an additional 2 years of treatment, but with a lower risk of higher grade lymphopenia.

Objectives

To assess, post hoc, the temporal occurrence of relapses up to 5 years after treatment initiation with cladribine tablets.

Methods

Patients enrolled into CLARITY treated with CT3.5, and those subsequently receiving CT3.5 (CC7) or placebo (CP3.5) in CLARITY Extension, were included for analysis. The main endpoint was all qualifying relapses reported in CLARITY or CLARITY Extension plus those that occurred during the variable bridging interval (range: 1 day to 118 weeks). A recurrent event analysis was performed to estimate mean cumulative number of relapses over time using a cumulative mean function estimate.

Results

A total of 433 patients from CLARITY treated with CT3.5 were included in this analysis; of these 284 patients entered CLARITY Extension (CP3.5, n=98; CC7, n=186). Recurrent event analysis for the CT3.5 population showed that annual increase in mean cumulative number of relapses was consistently low from Year 2 to Year 5 (range: 0.10–0.15) and was slightly higher in Year 1 (0.17); the 6-month increase in mean cumulative number of relapses was similar in the first 6 months and the second 6 months (0.08 and 0.09, respectively). There were no differences in mean cumulative number of relapses between the CP3.5 and CC7 groups from Year 2 to Year 5. In recurrent event analysis for the CT3.5 population, the yearly increments of mean cumulative function were constant and low from the second treatment to Year 5, supporting the durable efficacy of cladribine tablets (given no increase in relapses following completion of the two courses of cladribine tablets).

Conclusions

Annual increase in mean cumulative number of relapses occurred at a low annualized rate of 0.10 to 0.17 per year to 5 years, almost 4 years after the last dose of cladribine tablets and therefore consistent with durable efficacy. Results also support the early effect of cladribine tablets on relapses, which is apparent in the first year of treatment.

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Clinical Trials Poster Presentation

P0216 - Long-term reduction of relapse rate and 48-week confirmed disability progression after 6.5 years of ocrelizumab treatment in patients with RMS (ID 844)

Speakers
Presentation Number
P0216
Presentation Topic
Clinical Trials

Abstract

Background

The efficacy and safety of ocrelizumab (OCR) in relapsing multiple sclerosis (RMS) were demonstrated in the 96-week controlled double-blind period (DBP) of the Phase III OPERA I (NCT01247324) and OPERA II (NCT01412333) trials.

Objectives

To assess the efficacy of switching from interferon (IFN) β-1a or maintaining OCR therapy on disease activity and confirmed disability progression (CDP) after 4.5 years of follow-up, in the open-label extension (OLE) of OPERA I and OPERA II.

Methods

In the DBP of OPERA I and OPERA II, patients were randomized to receive OCR or IFN β-1a. Patients completing the DBP either continued OCR (OCR-OCR) or switched from IFN β-1a to OCR (IFN-OCR) when entering the OLE period. Adjusted annualized relapse rate (ARR), time to onset of 48-week CDP (CDP48) and time to 48-week confirmed Expanded Disability Status Scale score ≥6.0 (time to require a walking aid) were analyzed up to Week 336.

Results

Overall, 79.2% of patients who entered the OLE period completed OLE Year 4.5. Adjusted ARR decreased year-on-year from the pre-switch year to OLE Year 4.5 in IFN-OCR switchers (pre-switch, 0.20; OLE Year 4.5, 0.06) and was maintained at low levels in OCR-OCR continuers (pre-switch, 0.12; OLE Year 4.5, 0.04). The rates of CDP48 were lower in OCR-OCR continuers vs IFN-OCR switchers at the end of the DBP (4.1% vs 8.5%; p<0.001) and at OLE Year 4.5 (16.0% vs 20.3%; p=0.05). The rates of patients requiring a walking aid were lower in OCR-OCR continuers vs IFN-OCR switchers at the end of the DBP (0.8% vs 3.1%; p=0.001) and at OLE Year 4.5 (5.1% vs 8.3%; p=0.024). Over the DBP and OLE periods, the risk of CDP48 was 28% lower (HR [95%CI]: 0.72 [0.56–0.93]; p=0.01) and the risk of requiring a walking aid was 46% lower (HR [95%CI]: 0.54 [0.35–0.83];p=0.004) in OCR-OCR continuers vs IFN-OCR switchers. The safety profile in the OLE was generally consistent with the DBP.

Conclusions

Switching from IFN β-1a to ocrelizumab at the start of the OLE period was associated with a rapid and robust reduction in ARR that was maintained through the 4.5-year follow-up of the OLE period. Compared with patients switching to ocrelizumab at the OLE, patients initiating ocrelizumab 2 years earlier accrued significant benefits on CDP48 and time to require a walking aid that were maintained vs the switch group through the 4.5 years of the OLE period.

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Clinical Trials Poster Presentation

P0238 - Sustained reduction of disability and cognitive decline with long-term siponimod treatment in patients with active SPMS: EXPAND data up to 5 years (ID 1471)

Abstract

Background

In the EXPAND Core part, in the subgroup of patients with active secondary progressive multiple sclerosis (aSPMS: presence of relapses in the 2 years prior to screening and/or ≥1 T1 gadolinium-enhancing (Gd+) lesion at baseline), siponimod reduced the risk of 3-/6-month confirmed disability progression on Expanded Disability Status Scale (3m/6mCDP) by 31% and 37%, respectively, and the risk of decline in cognitive processing speed (CPS, 6-month confirmed cognition worsening of ≥4-point on Symbol Digit Modalities Test [6mCCW]) by 27% versus placebo.

Objectives

To assess the long-term efficacy and safety of siponimod in patients with aSPMS in the Core and Extension parts of the EXPAND study.

Methods

In patients with aSPMS who had received ≥1 dose of randomized treatment during Core part, and who entered the Extension (36 month extension data cut-off [6 April 2019]; total study duration ≤5 years), time to 3m/6mCDP, 6mCCW, and annualized relapse rate (ARR) were assessed for the Continuous (siponimod in the Core and Extension) and Switch (placebo in the Core and switched to open-label siponimod in the Core/Extension) groups.

Results

Of the 1651 patients randomized in the EXPAND Core part, 779 were with aSPMS (Continuous group: N=516; Switch group: N=263), of which 582 entered the Extension. The risk of 6mCDP was reduced by 29% (0.71 [0.57‒0.90]; p=0.0044) for the Continuous versus Switch group, corresponding to an about 70% delay in time to 6mCDP across the 25th–40th percentile). Median time to 6mCDP was 48 months for the Switch group and was not reached for the Continuous group. The risk of 6mCCW for the Continuous versus Switch group was reduced by 33% (0.67 [0.53‒0.86]); p=0.0018), corresponding to an about 70% delay in time to 6mCCW across the 25th–30th percentile, median time to 6mCCW (55.5 months) was reached only for the Switch group. In patients without active disease, a nonsignificant trend for reduced risk of disability progression and cognitive worsening was observed for the Continuous vs Switch groups. A significant reduction in ARR for the Continuous versus Switch groups was observed in patients with (0.08 vs 0.12; p=0.0023) or without active disease (0.03 vs 0.08; p<0.0001).

Conclusions

In EXPAND, long-term data analyses in the Continuous versus Switch groups showed that siponimod treatment effects on disability, cognitive processing speed, and relapse outcomes in patients with active SPMS are sustained for up to 5 years, and highlight the value of early treatment initiation.

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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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Invited Presentations Invited Abstracts

TC15.01 - Presentation 01 (ID 632)

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Authors
Presentation Number
TC15.01
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

TC15.01 - Presentation 01 (ID 632)

Speakers
Authors
Presentation Number
TC15.01
Presentation Topic
Invited Presentations