Cleveland Clinic

Author Of 3 Presentations

Disease Modifying Therapies – Risk Management Oral Presentation

FC02.02 - Update on the risk estimates of progressive multifocal leukoencephalopathy related to fingolimod

Speakers
Presentation Number
FC02.02
Presentation Topic
Disease Modifying Therapies – Risk Management
Lecture Time
13:12 - 13:24

Abstract

Background

Progressive multifocal leukoencephalopathy (PML) is a serious and potentially fatal complication of some multiple sclerosis (MS) disease-modifying therapies, including fingolimod. Precise estimates and risk stratification tools are not available for fingolimod-related PML.

Objectives

To estimate the global risk of PML in MS patients receiving fingolimod, and to investigate the effect of treatment duration and age on the risk of PML.

Methods

The number of PML cases identified from the manufacturer safety database, attributed to fingolimod by expert adjudication (based on criteria published by Berger et al. in 2014) as of 28 February 2020, was compared with the estimated global number of fingolimod-treated patients at risk (overall, by treatment duration, and by assumed age at fingolimod treatment initiation).

Results

It was estimated that approximately 299,600 patients were treated with fingolimod globally as of 28 February 2020, corresponding to >778,900 patient-years (PYs) of exposure. Of the 188 suspected PML cases reported during fingolimod treatment, 37 confirmed cases were clearly attributed to fingolimod through expert adjudication. In 17 cases, PML was attributed to previous natalizumab treatment. The remaining 134 cases either had inadequate information to confirm the diagnosis of PML or were classified as either possible or not PML. The estimated incidence rate was 4.75 (95% confidence interval [CI]: 3.34; 6.55) per 100,000 PYs. The estimated crude incidence was 0.12 (95% CI: 0.09–0.17) per 1,000 patients. The incidence of PML appears to increase with treatment duration and approach a plateau at approximately 0.13 per 1,000 patients during Year 5, after which data were scarce. Incidence of PML appears to increase between 30 and 50 years of age and then stabilize but the exact shape of the relationship with age is uncertain due to wide CIs, underlying assumptions, and other unknown confounding factors. For both treatment duration and age at treatment initiation, the precision of the incidence estimates was low due to the small number of cases.

Conclusions

PML risk associated with fingolimod is low. Although, the estimated risk of fingolimod-associated PML appears to increase with cumulative exposure, the precise pattern of this relationship remains uncertain. There may be an increase in PML risk with increased age at treatment initiation, although the exact pattern of this possible relationship is also uncertain.

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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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COVID-19 Late Breaking Abstracts

SS02.02 - Comparison of COVID-19 outcomes between racial groups in the COViMS registry

Speakers
Presentation Number
SS02.02
Presentation Topic
COVID-19
Lecture Time
10:57 - 11:09

Abstract

Background

Risk factors previously identified for worse outcomes with SARS-CoV-2 infections include older age, male sex and specific comorbid conditions. An increased risk for poorer COVID-19 outcomes in people with multiple sclerosis (MS) are similar to the general population, but less is known about outcomes in minority groups with MS.

Objectives

To evaluate differences in outcomes of SARS-CoV-2 infection in non-Hispanic White and Black persons with multiple sclerosis.

Methods

COViMS is a North American registry for health care providers to report persons with MS who are infected with SARS-CoV-2, the virus that causes COVID-19 (cases). Cases are reported after 7 days and when the outcome of infection is reasonably certain. MS and clinically isolated syndrome cases were categorized using the Center for Disease Control and Prevention races (non-Hispanic Whites, and Black). Comorbidities related to COVID-19 outcomes were collected. Clinical outcomes examined were mortality alone, mortality and/or admissions to the intensive care unit (ICU) and mortality, ICU admissions and/or hospitalization. Age-adjusted mortality rates as of August 3, 2020 and 95% confidence intervals (CI) were calculated. Multivariable logistic regression was used to assess adjusted differences between races using odds ratios (OR) and 95% CIs. Covariates included sex, age, smoking (current, past, never), MS clinical course (relapsing, progressive), disease duration, ambulation (fully ambulatory, walks with assistance, non-ambulatory), individual comorbidities (cardiovascular disease, cerebrovascular disease, chronic kidney disease, chronic lung disease, diabetes, hypertension, morbid obesity), and disease modifying therapy use (yes vs no).

Results

Of 734 patients reported, 421 (57.4%) Whites, and 194 (26.5%) Black patients were reported. Black cases were more likely to be younger (p=0.002), never smokers (p=0.002), have shorter MS duration (p<0.001), a relapsing MS course (p=0.03) and have comorbidities (p<0.001) compared to Whites. A higher proportion of Black patients had hypertension (40.2% vs 19.5%, p<0.001), and morbid obesity (17.0% vs 9.5%, p=0.007). Mortality rates increased with age and were not statistically different between Whites and Blacks (p=0.156). Black race was associated with increased odds of mortality and/or ICU admission (OR 3.8 [95%CI: 1.60, 8.96], p=0.002) and mortality, ICU admission and/or hospitalization (OR 2.0 [95%CI: 1.14, 3.54], p=0.016) after adjustment for covariates.

Conclusions

Within the COViMS registry, Black MS patients were younger and more likely to have comorbidities than White MS patients. Black MS patients had an increased risk for poorer outcomes compared to Whites even after adjusting for comorbidities at the time of COVID-19.

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Presenter Of 1 Presentation

Disease Modifying Therapies – Risk Management Oral Presentation

FC02.02 - Update on the risk estimates of progressive multifocal leukoencephalopathy related to fingolimod

Speakers
Presentation Number
FC02.02
Presentation Topic
Disease Modifying Therapies – Risk Management
Lecture Time
13:12 - 13:24

Abstract

Background

Progressive multifocal leukoencephalopathy (PML) is a serious and potentially fatal complication of some multiple sclerosis (MS) disease-modifying therapies, including fingolimod. Precise estimates and risk stratification tools are not available for fingolimod-related PML.

Objectives

To estimate the global risk of PML in MS patients receiving fingolimod, and to investigate the effect of treatment duration and age on the risk of PML.

Methods

The number of PML cases identified from the manufacturer safety database, attributed to fingolimod by expert adjudication (based on criteria published by Berger et al. in 2014) as of 28 February 2020, was compared with the estimated global number of fingolimod-treated patients at risk (overall, by treatment duration, and by assumed age at fingolimod treatment initiation).

Results

It was estimated that approximately 299,600 patients were treated with fingolimod globally as of 28 February 2020, corresponding to >778,900 patient-years (PYs) of exposure. Of the 188 suspected PML cases reported during fingolimod treatment, 37 confirmed cases were clearly attributed to fingolimod through expert adjudication. In 17 cases, PML was attributed to previous natalizumab treatment. The remaining 134 cases either had inadequate information to confirm the diagnosis of PML or were classified as either possible or not PML. The estimated incidence rate was 4.75 (95% confidence interval [CI]: 3.34; 6.55) per 100,000 PYs. The estimated crude incidence was 0.12 (95% CI: 0.09–0.17) per 1,000 patients. The incidence of PML appears to increase with treatment duration and approach a plateau at approximately 0.13 per 1,000 patients during Year 5, after which data were scarce. Incidence of PML appears to increase between 30 and 50 years of age and then stabilize but the exact shape of the relationship with age is uncertain due to wide CIs, underlying assumptions, and other unknown confounding factors. For both treatment duration and age at treatment initiation, the precision of the incidence estimates was low due to the small number of cases.

Conclusions

PML risk associated with fingolimod is low. Although, the estimated risk of fingolimod-associated PML appears to increase with cumulative exposure, the precise pattern of this relationship remains uncertain. There may be an increase in PML risk with increased age at treatment initiation, although the exact pattern of this possible relationship is also uncertain.

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Author Of 15 Presentations

COVID-19 Late Breaking Abstracts

LB1242 - COViMS Registry: Clinical Characterization of SARS-CoV-2 Infected Multiple Sclerosis Patients in North America (ID 2128)

Speakers
Presentation Number
LB1242
Presentation Topic
COVID-19

Abstract

Background

Emergence of SARS CoV-2 causing COVID-19 provoked the need to gather information on the overall outcomes and potential risks associated with morbidity and mortality in multiple sclerosis (MS) patients with COVID-19 infections. The COViMS registry was initiated as a rapid and efficient means to collect this data from North American health care providers.

Objectives

To describe the spectrum of outcomes in SARS CoV-2 infected North American MS patients and to ascertain characteristics associated with severe COVID-19 outcomes.

Methods

The COViMS registry requested that MS, neuromyelitis optica (NMO), myelin oligodendrocyte glycoprotein antibody disease (MOGAD), and radiographically isolated syndrome (RIS) patients with SARS-CoV-2 infection be reported after the outcome was reasonably certain. Data were de-identified and cross-sectional. Effort was made to harmonize with other international registries for COVID-19. Poor clinical outcomes assessed were: mortality, mortality and/or admission to the intensive care unit (ICU), and mortality, ICU admission and/or hospitalization. Associations between patient characteristics and these outcomes were evaluated using multivariable logistic regression. Covariates included sex, age, race, smoking, MS clinical course (relapsing, progressive), MS disease duration, ambulation (fully ambulatory, walks with assistance, non-ambulatory), individual comorbidities (cardiovascular disease, cerebrovascular disease, chronic kidney disease, chronic lung disease, diabetes, hypertension, morbid obesity), and disease modifying therapy (DMT) use.

Results

As of Aug 3, 2020, 764 patients from over 140 different practices were reported; 734 MS, 21 NMO, 4 MOGAD, and 5 RIS. MS patients were 73.4% female (73.4%), 65.2% Caucasian, with mean (SD) age of 48.2 (±13.5) years. Mean disease duration was 13.8 (±9.9) years. 70.9% were fully ambulatory. Ocrelizumab and dimethyl fumarate (DMF) were the top two DMTs used. Most (77.1%) were laboratory confirmed for SARS-CoV-2. Of MS cases, 6.1% died, 13.8% were admitted to the ICU and/or died, and 31.2% were either hospitalized, admitted to the ICU or died. Older age, non-ambulatory status and cardiovascular disease were associated with increased risk of poor outcomes. No specific DMT was associated with increased odds of mortality and mortality and/or ICU admission. Anti-CD20 DMT use showed an increased odds of mortality, ICU admission and/or hospitalization compared to DMF (OR: 2.53 95%CI [1.17, 5.50]).

Conclusions

The data provide reassurance that the MS registry population aligns with reported COVID-19 outcomes in the general North American population. While reported deaths are few, no clear association between a specific therapy and mortality has been seen after adjustment for age, sex, ambulatory status and comorbidities. Data collection continues.

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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 Outcome Measures Poster Presentation

P0021 - A propensity-matched comparison of long-term disability progression in MS patients treated with dimethyl fumarate or fingolimod (ID 709)

Speakers
Presentation Number
P0021
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Previous comparative effectiveness studies in multiple sclerosis (MS) have shown similar efficacy between dimethyl fumarate (DMF) and fingolimod (FTY) on measures of inflammatory disease activity but most studies did not assess long-term disability.

Objectives

To compare long-term disability progression over 5 years (yrs), as assessed by Patient-Determined Disease Steps (PDDS), in NARCOMS registry participants (pts) treated with DMF or FTY.

Methods

The NARCOMS registry is a voluntary self-report registry of people with MS. Pts provide health-related information at enrollment and every 6 months thereafter. We identified pts with RRMS; living in the US; and initiating index DMT (DMF or FTY) from Spring 2011 through Spring 2018. Pts were included if they had ≥1 yr follow-up on index DMT. DMF pts treated with prior FTY, and FTY pts treated with prior DMF, were excluded. We used 1:1 propensity-score matching (PSM) to match FTY to DMF pts. Baseline factors (at time of index DMT initiation) used for PSM were age, disease duration, sex, number of prior DMTs, education, PDDS, cognition score, depression score, relapses in last 6 months, and cardiovascular comorbidities. Time to 6-month confirmed disability progression (≥1-point increase on PDDS sustained for ≥6 months) was estimated using the Kaplan-Meier method and compared using a Cox proportional hazards regression model with robust sandwich estimators. Pts were censored at last follow-up or at the time of DMT discontinuation.

Results

Overall, 689 DMF and 565 FTY pts were included. After PSM, 468 DMF pts were matched with 468 FTY pts. The survey compliance was high in both groups, with >93% of pts in both groups completing ≥50% of surveys while on treatment. Baseline characteristics were well-balanced after PSM, with standardized differences <0.1 for each covariate. Median treatment duration was 3.0 yrs for DMF and 4.0 yrs for FTY. At 5 yrs, 68.3% (95% CI: 62.4-73.5) of DMF pts and 63.3% (95% CI: 59.6-70.1) of FTY pts were free from 6-month confirmed PDDS progression (hazard ratio: 1.01 [95% CI: 0.79-1.28]; p=0.95).

Conclusions

In this propensity-matched analysis of MS pts from the NARCOMS registry, there was no significant difference between DMF and FTY on confirmed disability (PDDS) progression over 5 yrs. These results are consistent with previous studies that have shown similar effectiveness between DMF and FTY on relapse and MRI outcomes.

Supported by: Biogen; NARCOMS is a project of the CMSC

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Clinical Outcome Measures Poster Presentation

P0068 - Disability Progression in MS Participants Treated with Delayed-release Dimethyl Fumarate: Age-related Subgroup Analysis of the NARCOMS Registry (ID 397)

Speakers
Presentation Number
P0068
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Dimethyl fumarate (DMF) clinical trials excluded relapsing-remitting multiple sclerosis (RRMS) patients aged >55 years (yrs). The limited data on DMF use in this age group evaluated relapses but not disability. Unlike relapses, which often decrease as MS patients age, disability progression often increases.

Objectives

To characterize long-term disability outcomes over 4.5 yrs of DMF treatment in RRMS participants based on age at time of DMF initiation.

Methods

We identified NARCOMS participants (pts) with RRMS, living in the US, and initiating DMF from Fall 2013–Spring 2018 with ≥1 yr follow-up. We dichotomized age at DMF initiation as <55 (younger) and ≥55 yrs (older). Disability was measured using the Patient Determined Disease Steps (PDDS). Time to 6-month confirmed PDDS progression (≥1-point increase) and conversion to SPMS were estimated using the Kaplan-Meier method and compared using a log rank test. Cox proportional hazards regression models were adjusted for sex and initial PDDS level. Pts were censored at last follow-up or DMF discontinuation, whichever came first. Safety data were not collected.

Results

647 RRMS pts initiated DMF. In the younger subgroup (n=351, 54%), median age was 47 yrs, 88% female, and 24% reported a relapse in the last 6 months. In the older subgroup (n=296, 46%), median age was 60 yrs, 82% female, and 22% reported a relapse in the last 6 months. Compared to the younger subgroup, older pts had longer MS disease duration (11 vs 17 yrs, p<0.001) and significantly greater disability at baseline as measured by PDDS. Median treatment duration was 2.5 yrs in younger pts and 2 yrs in older pts. At last follow-up, 283 (81%) younger pts and 236 (80%) older pts remained on DMF. Most pts in both groups were estimated to remain free of disability progression over 4.5 yrs: 64% (95%CI: 57-71) of younger pts vs 74% (95%CI: 67-80) of older pts (p=0.12). Most pts in both subgroups also were estimated to remain free from conversion to SPMS over 4.5 yrs: 90% (95%CI: 85-94) of younger pts vs 86% (95%CI: 79-91) of older pts (p=0.17).

Conclusions

Conclusions: As expected, older pts (≥55 yrs) had significantly longer MS disease duration and higher baseline disability compared with younger pts (<55 yrs). Despite these baseline differences, most pts in both groups remained free of PDDS progression and free from conversion to SPMS over 4.5 yrs of DMF treatment.

Supported by: Biogen; NARCOMS is a project of the CMSC

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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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Clinical Outcome Measures Poster Presentation

P0144 - Real-world outcomes in patients with relapsing forms of multiple sclerosis treated with intramuscular interferon beta-1a or peginterferon beta-1a (ID 794)

Speakers
Presentation Number
P0144
Presentation Topic
Clinical Outcome Measures

Abstract

Background

In clinical trials, the probability of confirmed disability worsening (CDW) is significantly lower with intramuscular (IM) interferon beta-1a (IFNβ1a) and peginterferon beta-1a (PEG) treatment than with placebo in patients with relapsing forms of multiple sclerosis (RMS). Registry data provides information on disability outcomes with long-term treatment.

Objectives

To examine the long-term effects of IM IFNβ1a and PEG on real-world effectiveness in participants with RMS from the North American Research Committee on Multiple Sclerosis (NARCOMS) registry.

Methods

This analysis included NARCOMS participants diagnosed with RMS who initiated IM IFNβ1a treatment between April 2004 and October 2019 (N=760) or PEG between October 2014 and October 2019 (N=116). Patient-reported outcomes were collected every 6 months. The primary endpoint was 6-month CDW, defined as a ≥1-point increase in Patient Determined Disease Steps (PDDS) score sustained for ≥6 months. Separate analyses were conducted in the IM IFNβ1a and PEG cohorts. A Kaplan-Meier analysis assessed the cumulative probability of CDW; participants were censored if they discontinued treatment or had no additional follow-up. Only participants who completed ≥2 surveys with treatment history and ≥3 surveys with PDDS history were included in the CDW analysis (IM IFNβ1a: N=760; PEG: n=81). Progression to secondary progressive multiple sclerosis (SPMS) was analysed in IM IFNβ1a participants who completed ≥50% of their surveys (n=630) and in PEG participants (n=102).

Results

At the first survey on treatment in IM IFNβ1a and PEG participants, the mean age was 49.7 and 53.0 years, respectively, the mean (standard deviation [SD]) disease duration was 11.1 (8.6) and 15.8 (7.9) years, respectively, and 8.4% and 91.2% had prior disease modifying therapy (DMT) use, respectively. The median PDDS score at the first survey was 2.0 for both populations, indicating moderate disability. The cumulative probability of remaining free of CDW was 77.6% and 43.6% at 2 and 11 years of IM IFNβ1a treatment, respectively, and 84.4% at 2 years of PEG treatment. The cumulative probability of participant-reported progression to SPMS was 1.2% and 12.0% at 2.5 and 11 years in IM IFNβ1a participants, respectively, and 3.3% at 2.5 years in PEG participants.

Conclusions

These results support clinical trial data showing the effectiveness of IM IFNβ1a and PEG in preventing CDW and demonstrate their long-term effectiveness in RMS patients.

This study is funded by Biogen. Biogen funded the analyses and writing support for this abstract. Writing support was provided by Ashfield Healthcare Communications (Middletown, CT, USA).

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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

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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Clinical Trials Poster Presentation

P0241 - Top-line Results of EMPhASIS, a Phase 2 Clinical Trial of Vidofludimus Calcium (IMU-838) in Relapsing-Remitting Multiple Sclerosis (ID 1409)

Speakers
Presentation Number
P0241
Presentation Topic
Clinical Trials

Abstract

Background

Dihydroorotate dehydrogenase (DHODH) inhibition is an established mode of action for disease-modifying treatment of relapsing-remitting multiple sclerosis (RRMS). Vidofludimus calcium (IMU-838) is a selective and potent second-generation DHODH oral immunomodulator being developed for the treatment of several immune-mediated diseases including MS and COVID-19. The inhibition of the DHODH enzyme leads to metabolic stress in stimulated lymphocytes with subsequent reduction of pro-inflammatory cytokines and induction of apoptosis. Due to IMU-838’s pharmacological selectivity and lack of relevant off-target effects on kinases, increased rates of typical antiproliferative effects (neutropenia, alopecia and gastrointestinal disturbances) have not been observed in clinical trials. The serum half-life of approximately 30 hours allows quick on- and off-dosing.

Objectives

To report top­line efficacy, safety, and tolerability of IMU-838 in the relapsing MS EMPhASIS trial (NCT03846219), the first trial of IMU-838 in MS.

Methods

EMPhASIS is a phase 2 multicenter, double-blind, placebo-controlled, randomized, parallel-group trial to assess the efficacy and safety of two once-daily oral doses of IMU-838 (30 and 45 mg/day) in patients with RRMS. Inclusion criteria are age 18-55 years, active RRMS defined by the evidence of clinical and radiological disease activity, and Expanded Disability Status Scale (EDSS) 0-4. The primary endpoint is the cumulative number of combined unique active MRI lesions over 24 weeks. Secondary endpoints include efficacy, safety and tolerability parameters. The study also includes a subsequent optional, open-label treatment period to evaluate long-term safety and tolerability.

Results

210 subjects (65% women) were enrolled in 36 centers across four European countries. The mean age at baseline was 36.8 years (SD 8.8). 198 subjects (94%) completed the 24-week main treatment period, with the last follow-up visit in April 2020. Database lock will be in July 2020 and top-line data will be available shortly thereafter. Primary outcome and several secondary outcomes (including safety data) will be presented.

Conclusions

IMU-838 is an orally available, next-generation selective immunomodulator with a potentially more favorable profile than first-generation DHODH inhibitors. Top-line results of IMU-838 on primary and several secondary endpoints in patients with RRMS in the EMPhASIS trial will be presented.

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Disease Modifying Therapies – Risk Management Poster Presentation

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

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

Abstract

Background

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

Objectives

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

Methods

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

Results

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

Conclusions

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

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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

P0927 - Treatment discontinuation and restart among patients with multiple sclerosis using disease-modifying therapies (ID 699)

Speakers
Presentation Number
P0927
Presentation Topic
Observational Studies

Abstract

Background

Patients with multiple sclerosis (MS) change and discontinue disease-modifying therapies (DMTs) for a variety of reasons. Relatively little is known about the dynamics of these changes across different DMTs.

Objectives

This objective of this study examined patterns of DMT change, discontinuation, and restart in patients with newly diagnosed MS.

Methods

Adults with newly diagnosed MS were identified in the IBM MarketScan Commercial and Medicare databases. Eligible patients had ≥12 months of continuous enrollment prior to their initial MS diagnosis and ≥2 years of follow-up from January 2007 to October 2017. Patients with evidence of pregnancy or any malignancy during the study period were excluded. Up to 3 courses of DMTs were reported during a follow-up period of 2 to 10.5 years. Discontinuation was defined as having a gap in therapy of ≥60 days. Restarting was defined as reinitiating the same DMT after a 60-day gap.

Results

In total, 14,627 newly diagnosed MS patients were treated with DMTs and had ≥2 years of follow-up. Of these, 25% had 2 DMT courses and 27% had 3 DMT courses during follow-up. Half of treated patients discontinued their first DMT course, but 52% of those who discontinued their first course restarted the same DMT for their second course. Mean time to restart was 165 days (median: 93 days). Patients taking glatiramer acetate (GA) and interferon beta-1b (IFN β-1b) had the highest rates of discontinuation during the first DMT course (52% and 55%, respectively) and the highest rates of restart among those who discontinued (57% and 56%, respectively). Of all patients who discontinued, those taking oral DMTs (dimethyl fumarate, fingolimod, and teriflunomide) had discontinuation rates of 43%–50% and restart rates of 31%–38%. Natalizumab had the lowest rate of discontinuation (37%) and restart (20%). Among the 7,510 patients with any second treatment course, the overall discontinuation rate increased to 56% and the rate of those who restarted their second DMT as their third course increased to 56%. Similarly, GA and IFN β-1b had the highest discontinuation and restart rates among those with a second course.

Conclusions

Over 2 to 10.5 years of follow-up, treatment discontinuation and extended treatment gaps occurred frequently among DMT-treated patients with MS. Returning to the same DMT was surprisingly common.

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Patient-Reported Outcomes and Quality of Life Poster Presentation

P1009 - Characteristics and patient-reported outcomes of patients initiating ocrelizumab in the NARCOMS Registry from 2017 to 2019 (ID 1221)

Speakers
Presentation Number
P1009
Presentation Topic
Patient-Reported Outcomes and Quality of Life

Abstract

Background

Ocrelizumab (OCR) was approved for relapsing and primary progressive forms of multiple sclerosis (MS) in 2017. Patient-reported outcome data among patients initiating OCR in clinical practice is limited.

Objectives

To evaluate the characteristics, experience and outcomes of participants in the North American Research Committee on Multiple Sclerosis (NARCOMS) registry who initiated OCR.

Methods

NARCOMS is a voluntary registry enrolling persons with MS who update their information using semi-annual surveys. This analysis included participants initiating OCR between April 2017 and April 2019, including a subset of participants who completed 1-year follow-ups. Outcomes included Patient Determined Disease Steps (PDDS), relapses, health care utilization and employment (i.e. employed/unemployed status, absenteeism). Changes from baseline for the subgroup who completed 1-year surveys were evaluated using the nonparametric Wilcoxon-Signed Rank or McNemar’s tests.

Results

During the study period 829 participants initiated OCR. They had a mean [SD] age of 56.6 [10.6] years and time since diagnosis of 18.7 [9.9] years. Most participants were female (75.3%). The most common clinical course was relapsing-remitting (45.4%) followed by secondary progressive (32.1%) and primary progressive (22.6%). The median (interquartile range [IQR]) PDDS was 5.0 [3.0–6.0]. Similar baseline characteristics were observed in the subgroup of 435 participants who had ≥1 year of follow-up (median [IQR] follow-up, 1.5 [1.0–2.0] years). In this subgroup, participants were less likely to report a steroid-treated relapse at 1 year (7.7%) compared with baseline (1-year lookback, 4.7%; p=0.04), although no differences were observed with respect to emergency room or hospital admissions. More than half of participants reported either improvement (40.7%) or no change (15.3%) on the PDDS; 44% reported worsening. Among employed participants at baseline (n=139), 8% reported leaving the workforce during follow-up; among those who remained employed, fewer reported missing work in the follow-up year (33.9%) compared with baseline (1-year lookback; 46.5%; p=0.003).

Conclusions

Participants initiating ocrelizumab in the NARCOMS registry are representative of a prevalent MS population, consistent with the full registry population. Patients with longitudinal follow-up on ocrelizumab reported fewer relapses and lower work absenteeism, with no differences in health resource utilization compared to baseline.

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Presenter Of 4 Presentations

Clinical Outcome Measures Poster Presentation

P0021 - A propensity-matched comparison of long-term disability progression in MS patients treated with dimethyl fumarate or fingolimod (ID 709)

Speakers
Presentation Number
P0021
Presentation Topic
Clinical Outcome Measures

Abstract

Background

Previous comparative effectiveness studies in multiple sclerosis (MS) have shown similar efficacy between dimethyl fumarate (DMF) and fingolimod (FTY) on measures of inflammatory disease activity but most studies did not assess long-term disability.

Objectives

To compare long-term disability progression over 5 years (yrs), as assessed by Patient-Determined Disease Steps (PDDS), in NARCOMS registry participants (pts) treated with DMF or FTY.

Methods

The NARCOMS registry is a voluntary self-report registry of people with MS. Pts provide health-related information at enrollment and every 6 months thereafter. We identified pts with RRMS; living in the US; and initiating index DMT (DMF or FTY) from Spring 2011 through Spring 2018. Pts were included if they had ≥1 yr follow-up on index DMT. DMF pts treated with prior FTY, and FTY pts treated with prior DMF, were excluded. We used 1:1 propensity-score matching (PSM) to match FTY to DMF pts. Baseline factors (at time of index DMT initiation) used for PSM were age, disease duration, sex, number of prior DMTs, education, PDDS, cognition score, depression score, relapses in last 6 months, and cardiovascular comorbidities. Time to 6-month confirmed disability progression (≥1-point increase on PDDS sustained for ≥6 months) was estimated using the Kaplan-Meier method and compared using a Cox proportional hazards regression model with robust sandwich estimators. Pts were censored at last follow-up or at the time of DMT discontinuation.

Results

Overall, 689 DMF and 565 FTY pts were included. After PSM, 468 DMF pts were matched with 468 FTY pts. The survey compliance was high in both groups, with >93% of pts in both groups completing ≥50% of surveys while on treatment. Baseline characteristics were well-balanced after PSM, with standardized differences <0.1 for each covariate. Median treatment duration was 3.0 yrs for DMF and 4.0 yrs for FTY. At 5 yrs, 68.3% (95% CI: 62.4-73.5) of DMF pts and 63.3% (95% CI: 59.6-70.1) of FTY pts were free from 6-month confirmed PDDS progression (hazard ratio: 1.01 [95% CI: 0.79-1.28]; p=0.95).

Conclusions

In this propensity-matched analysis of MS pts from the NARCOMS registry, there was no significant difference between DMF and FTY on confirmed disability (PDDS) progression over 5 yrs. These results are consistent with previous studies that have shown similar effectiveness between DMF and FTY on relapse and MRI outcomes.

Supported by: Biogen; NARCOMS is a project of the CMSC

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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

P0241 - Top-line Results of EMPhASIS, a Phase 2 Clinical Trial of Vidofludimus Calcium (IMU-838) in Relapsing-Remitting Multiple Sclerosis (ID 1409)

Speakers
Presentation Number
P0241
Presentation Topic
Clinical Trials

Abstract

Background

Dihydroorotate dehydrogenase (DHODH) inhibition is an established mode of action for disease-modifying treatment of relapsing-remitting multiple sclerosis (RRMS). Vidofludimus calcium (IMU-838) is a selective and potent second-generation DHODH oral immunomodulator being developed for the treatment of several immune-mediated diseases including MS and COVID-19. The inhibition of the DHODH enzyme leads to metabolic stress in stimulated lymphocytes with subsequent reduction of pro-inflammatory cytokines and induction of apoptosis. Due to IMU-838’s pharmacological selectivity and lack of relevant off-target effects on kinases, increased rates of typical antiproliferative effects (neutropenia, alopecia and gastrointestinal disturbances) have not been observed in clinical trials. The serum half-life of approximately 30 hours allows quick on- and off-dosing.

Objectives

To report top­line efficacy, safety, and tolerability of IMU-838 in the relapsing MS EMPhASIS trial (NCT03846219), the first trial of IMU-838 in MS.

Methods

EMPhASIS is a phase 2 multicenter, double-blind, placebo-controlled, randomized, parallel-group trial to assess the efficacy and safety of two once-daily oral doses of IMU-838 (30 and 45 mg/day) in patients with RRMS. Inclusion criteria are age 18-55 years, active RRMS defined by the evidence of clinical and radiological disease activity, and Expanded Disability Status Scale (EDSS) 0-4. The primary endpoint is the cumulative number of combined unique active MRI lesions over 24 weeks. Secondary endpoints include efficacy, safety and tolerability parameters. The study also includes a subsequent optional, open-label treatment period to evaluate long-term safety and tolerability.

Results

210 subjects (65% women) were enrolled in 36 centers across four European countries. The mean age at baseline was 36.8 years (SD 8.8). 198 subjects (94%) completed the 24-week main treatment period, with the last follow-up visit in April 2020. Database lock will be in July 2020 and top-line data will be available shortly thereafter. Primary outcome and several secondary outcomes (including safety data) will be presented.

Conclusions

IMU-838 is an orally available, next-generation selective immunomodulator with a potentially more favorable profile than first-generation DHODH inhibitors. Top-line results of IMU-838 on primary and several secondary endpoints in patients with RRMS in the EMPhASIS trial will be presented.

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Observational Studies Poster Presentation

P0927 - Treatment discontinuation and restart among patients with multiple sclerosis using disease-modifying therapies (ID 699)

Speakers
Presentation Number
P0927
Presentation Topic
Observational Studies

Abstract

Background

Patients with multiple sclerosis (MS) change and discontinue disease-modifying therapies (DMTs) for a variety of reasons. Relatively little is known about the dynamics of these changes across different DMTs.

Objectives

This objective of this study examined patterns of DMT change, discontinuation, and restart in patients with newly diagnosed MS.

Methods

Adults with newly diagnosed MS were identified in the IBM MarketScan Commercial and Medicare databases. Eligible patients had ≥12 months of continuous enrollment prior to their initial MS diagnosis and ≥2 years of follow-up from January 2007 to October 2017. Patients with evidence of pregnancy or any malignancy during the study period were excluded. Up to 3 courses of DMTs were reported during a follow-up period of 2 to 10.5 years. Discontinuation was defined as having a gap in therapy of ≥60 days. Restarting was defined as reinitiating the same DMT after a 60-day gap.

Results

In total, 14,627 newly diagnosed MS patients were treated with DMTs and had ≥2 years of follow-up. Of these, 25% had 2 DMT courses and 27% had 3 DMT courses during follow-up. Half of treated patients discontinued their first DMT course, but 52% of those who discontinued their first course restarted the same DMT for their second course. Mean time to restart was 165 days (median: 93 days). Patients taking glatiramer acetate (GA) and interferon beta-1b (IFN β-1b) had the highest rates of discontinuation during the first DMT course (52% and 55%, respectively) and the highest rates of restart among those who discontinued (57% and 56%, respectively). Of all patients who discontinued, those taking oral DMTs (dimethyl fumarate, fingolimod, and teriflunomide) had discontinuation rates of 43%–50% and restart rates of 31%–38%. Natalizumab had the lowest rate of discontinuation (37%) and restart (20%). Among the 7,510 patients with any second treatment course, the overall discontinuation rate increased to 56% and the rate of those who restarted their second DMT as their third course increased to 56%. Similarly, GA and IFN β-1b had the highest discontinuation and restart rates among those with a second course.

Conclusions

Over 2 to 10.5 years of follow-up, treatment discontinuation and extended treatment gaps occurred frequently among DMT-treated patients with MS. Returning to the same DMT was surprisingly common.

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Moderator Of 1 Session

Burning Debate Fri, Sep 11, 2020