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Background: Ublituximab is a novel anti-CD20 monoclonal antibody glycoengineered for enhanced antibody-dependent cellular cytotoxicity. The phase 3 ULTIMATE I and II studies showed significant improvements in annualized relapse rate, total number of gadolinium-enhancing (Gd+) T1 lesions, and total number of new or enlarging T2 at Week 96, as well as improvement in the proportion of participants with no evidence of disease activity (NEDA) from Weeks 24–96 with ublituximab vs. teriflunomide. Methods: In ULTIMATE I (NCT03277261; www.clinicaltrials.gov) (N = 549) and II (NCT03277248; www.clinicaltrials.gov) (N = 545), participants with relapsing multiple sclerosis received ublituximab 450 mg intravenous infusion every 24 weeks (following Day 1 infusion of 150 mg and Day 15 infusion of 450 mg) or teriflunomide 14 mg oral once daily for 96 weeks. Pooled post hoc analyses evaluated NEDA by treatment epoch and participant subtype: age (≤ 38 or >38 years), early or later disease (<3 or ≥3 years following diagnosis), treatment history (treatment naïve or previously treated), 0 or ≥1 Gd+ T1 lesions at baseline, and Expanded Disability Status Scale score ≤ 3.5 or >3.5 at baseline. NEDA was defined as no confirmed relapses, no Gd+ T1 lesions, no new or enlarging T2 lesions, and no disability progression confirmed for ≥12 weeks. Results: NEDA rates in the ublituximab vs. teriflunomide cohorts by treatment epoch were: Weeks 0–96, 44.6% vs. 12.4% (3.6 × improvement); Weeks 24–96 (re-baselined), 82.1% vs. 22.5% (3.6 × improvement); and Weeks 48–96 (re-baselined), 88.2% vs. 30.4% (2.9 × improvement) (all p < 0.0001). The primary driver of disease activity in ublituximab-treated participants was new or enlarging T2 lesions during Weeks 0–24. 41.8% of ublituximab-treated participants who had evidence of disease activity in the first year (Weeks 0–48) experienced NEDA in the second year of treatment (Weeks 48–96) compared with 17.3% of teriflunomide-treated participants. At Weeks 24–96 (re-baselined), rates of NEDA were significantly higher with ublituximab than teriflunomide in all participant subtypes (all p < 0.0001). Conclusions: ULTIMATE I and II pooled post hoc analyses demonstrated a consistent NEDA benefit among ublituximab-treated participants across treatment epochs and key participant subpopulations. [ABSTRACT FROM AUTHOR] more...

BACKGROUND: Ozanimod, an oral sphingosine 1-phosphate receptor 1 and 5 modulator, is approved in multiple countries for the treatment of adults with either relapsing forms of multiple sclerosis (RMS) or moderately to severely active ulcerative colitis. OBJECTIVES: Report the safety and efficacy of extended ozanimod exposure. METHODS: Patients with RMS who completed ozanimod phase 1 to 3 parent trials were eligible for the DAYBREAK open-label extension trial (NCT02576717) of ozanimod 0.92 mg/d. The primary objective was to evaluate safety; treatment-emergent adverse events (TEAEs) were monitored. Annualized relapse rate (ARR) was calculated via negative binomial regression pooled for all parent trial treatment groups. New/enlarging T2- and gadolinium-enhancing (GdE) lesions were reported for patients who entered DAYBREAK from activecontrolled phase 3 trials (database lock: April 7, 2023). RESULTS: In total, 2639 patients completed the parent trials; this analysis includes 2494 patients with mean ozanimod exposure of 60.9 months (range, 0.03-81.5; 12,664.7 patientyears total) in DAYBREAK. In DAYBREAK, 2219 patients (89.0%) had any TEAE, 381 (15.3%) had a serious TEAE (SAE), and 98 (3.9%) discontinued due to a TEAE. Similar rates of TEAEs and SAEs occurred when assessed by parent trial treatment. The most common TEAEs were nasopharyngitis (21.3%), headache (17.1%), COVID-19 infection (16.5%), and upper respiratory tract infection (12.4%), which were similar to those in the parent trials (excluding COVID-19). Adjusted ARR in DAYBREAK was 0.098 (95% CI, 0.082-0.117). At month 72 of DAYBREAK, 67% of patients were relapse free. Confirmed disability progression at 3 and 6 months occurred in 17.2% and 15.2% of patients in DAYBREAK, respectively. At month 60, adjusted mean number of new/enlarging T2 lesions per scan (range, 0.789-0.932) and adjusted mean number of GdE lesions (range, 0.062-0.077) were similar, regardless of parent trial treatment. CONCLUSIONS: The safety profile of ozanimod in DAYBREAK was consistent with prior reports. Ozanimod treatment demonstrated sustained efficacy for measures of disease activity and progression. FUNDING: Bristol Myers Squibb. Writing and editorial assistance was provided by Noud van Helmond of Peloton Advantage, LLC, an OPEN Health company, and was funded by Bristol Myers Squibb. [ABSTRACT FROM AUTHOR] more...

BACKGROUND: Ozanimod treatment was associated with significantly fewer relapses than interferon beta-1a (IFN) in phase 3 relapsing multiple sclerosis (RMS) trials and provided sustained control of disability progression for up to 5 years in an open-label study. OBJECTIVES: To determine the incidence and predictors of relapse-associated worsening (RAW) and progression independent of relapse activity (PIRA) in participants in the RADIANCE and DAYBREAK trials. METHODS: Participants in phase 3 RADIANCE (NCT02047734) were randomly assigned oral ozanimod 0.46 mg/day or 0.92 mg/day or intramuscular IFN 30 μg/week for 24 months, and completers were eligible to enroll in an ozanimod 0.92-mg open-label extension trial (DAYBREAK [phase 3; NCT02576717]; data cutoff: February 1, 2022). In participants continuously treated with ozanimod 0.92 mg or those who initially received IFN, we assessed 6-month confirmed disability progression (CDP; ≥ 1-point increase in Expanded Disability Status Scale [EDSS] score from baseline, confirmed after 6 months), and participants were considered to have RAW if CDP onset occurred ≤ 90 days of a relapse or PIRA if CDP onset occurred without relapse or > 90 days after a relapse. For relapse with incomplete recovery, baseline EDSS was reset > 90 days after relapse onset to identify the next PIRA event. Kaplan-Meier analysis and univariable Cox proportional hazards regression assessed incidence over time and predictors, respectively. P values were determined via Wald χ2 test. RESULTS: A total of 363 participants who received continuous ozanimod 0.92 mg and 346 who switched from IFN were included. In up to 8 years of follow-up, 75.9% of participants were free of 6-month CDP. Among participants with CDP, 44.3% and 54.5% of those treated with continuous ozanimod had RAW or PIRA, respectively; 8% had both. Of the participants who switched from IFN to ozanimod, 57.8% and 43.4% had RAW or PIRA, respectively; 4.8% had both. RAW was observed in 10.7% of participants treated with continuous ozanimod and 13.9% of those who switched from IFN to ozanimod; PIRA was observed in 13.2% of participants treated with continuous ozanimod and 10.4% of those who switched from IFN to ozanimod. In both treatment groups, predictors of RAW with nominal P < .05 included RADIANCE baseline EDSS score (positive association) and whole brain, cortical gray matter, and thalamic volumes (negative associations); these variables were not predictors of PIRA. CONCLUSIONS: In ozanimod-treated participants with RMS, RAW and PIRA contributed similarly to disability progression over 8 years. Higher baseline EDSS scores and lower baseline whole brain, cortical gray matter, and thalamic volumes were predictive of RAW. FUNDING: Bristol Myers Squibb. Writing and editorial assistance was provided by Noud van Helmond, MD, PhD, of Peloton Advantage, LLC, an OPEN Health company, and was funded by Bristol Myers Squibb. [ABSTRACT FROM AUTHOR] more...

BACKGROUND: Disease-modifying therapies may attenuate the response to SARS-CoV-2 vaccination in participants with relapsing multiple sclerosis (RMS). OBJECTIVES: Describe the extended serologic response to SARS-CoV-2 vaccination and/or infection during ozanimod treatment in participants with RMS enrolled in the open-label extension (OLE) trial DAYBREAK (NCT02576717) and compare serologic responses in healthy volunteers. METHODS: Participants with RMS who completed a phase 1 to 3 ozanimod trial could enter the singlearm DAYBREAK OLE trial of ozanimod 0.92 mg/d. This analysis included DAYBREAK participants who received a full SARS-CoV-2 vaccination course and/ or reported a COVID-19 adverse event between January 13, 2020, and August 25, 2022. Healthy controls were commercially sourced. SARS-CoV-2 spike receptor-binding domain (RBD) and nucleocapsid antibodies were measured with the Elecsys anti--SARS-CoV-2 assay and cobas e analyzer; seroconversion was defined as IgG levels ≥ 0.8 U/mL for spike RBD; nucleocapsid antibody seroconversion was defined as IgG levels ≥ 1 U/mL. Predictors of RBD antibody levels were assessed. RESULTS: Baseline characteristics of 369 participants in this analysis included median age of 39.1 years (range, 19-56), 70% women, and ozanimod exposure of 74.1 months (range, 48-110); 30 healthy controls were aged 43.4 years (range, 18-66) and were 77% women. Postvaccination samples (n = 253) in DAYBREAK participants without evidence of SARS-CoV-2 exposure (nucleocapsid antibody--negative result) showed 94% RBD antibody seroconversion; all postvaccination samples (n = 112) with evidence of exposure (nucleocapsid antibody--positive result) showed seroconversion. All healthy control samples demonstrated seroconversion post vaccination with (n = 6) or without (n = 22) evidence of exposure. Samples from unvaccinated DAYBREAK participants with evidence of exposure (n = 92) showed 99% seroconversion. In vaccinated participants, spike RBD antibody levels were maintained over 28 weeks with or without boosting. Spike RBD antibody levels were not associated with absolute lymphocyte count (ALC) in participants without (R = -0.12; P = .05) or with SARS-CoV-2 exposure (R = -0.06; P = .26). Time on ozanimod treatment was not associated with spike RBD antibody levels in participants without (R = 0.05; P = .55) or with exposure (R = 0.02; P = .81). CONCLUSIONS: The majority of participants with RMS receiving ozanimod developed and maintained a serologic response to SARS-CoV-2 vaccination for at least 28 weeks, whereas healthy controls had 100% seroconversion. There was no significant association between spike RBD antibody levels and ALC or ozanimod exposure. FUNDING: Bristol Myers Squibb. Writing and editorial assistance were provided by Noud van Helmond, MD, PhD, of Peloton Advantage, LLC, an OPEN Health company, and were funded by Bristol Myers Squibb. [ABSTRACT FROM AUTHOR] more...

Objective: Rates of worsening and evolution to secondary progressive multiple sclerosis (MS) may be substantially lower in actively treated patients compared to natural history studies from the pretreatment era. Nonetheless, in our recently reported prospective cohort, more than half of patients with relapsing MS accumulated significant new disability by the 10th year of follow-up. Notably, "no evidence of disease activity" at 2 years did not predict long-term stability. Here, we determined to what extent clinical relapses and radiographic evidence of disease activity contribute to long-term disability accumulation.Methods: Disability progression was defined as an increase in Expanded Disability Status Scale (EDSS) of 1.5, 1.0, or 0.5 (or greater) from baseline EDSS = 0, 1.0-5.0, and 5.5 or higher, respectively, assessed from baseline to year 5 (±1 year) and sustained to year 10 (±1 year). Longitudinal analysis of relative brain volume loss used a linear mixed model with sex, age, disease duration, and HLA-DRB1*15:01 as covariates.Results: Relapses were associated with a transient increase in disability over 1-year intervals (p = 0.012) but not with confirmed disability progression (p = 0.551). Relative brain volume declined at a greater rate among individuals with disability progression compared to those who remained stable (p < 0.05).Interpretation: Long-term worsening is common in relapsing MS patients, is largely independent of relapse activity, and is associated with accelerated brain atrophy. We propose the term silent progression to describe the insidious disability that accrues in many patients who satisfy traditional criteria for relapsing-remitting MS. Ann Neurol 2019;85:653-666. [ABSTRACT FROM AUTHOR] more...

Objective: Primary progressive multiple sclerosis (PPMS) causes accumulation of neurological disability from disease onset without clinical attacks typical of relapsing multiple sclerosis (RMS). However, whether genetic variation influences the disease course remains unclear. We aimed to determine whether mutations causative of neurological disorders that share features with multiple sclerosis (MS) contribute to risk for developing PPMS.Methods: We examined whole-genome sequencing (WGS) data from 38 PPMS and 81 healthy subjects of European ancestry. We selected pathogenic variants exclusively found in PPMS patients that cause monogenic neurological disorders and performed two rounds of replication genotyping in 746 PPMS, 3,049 RMS, and 1,000 healthy subjects. To refine our findings, we examined the burden of rare, potentially pathogenic mutations in 41 genes that cause hereditary spastic paraplegias (HSPs) in PPMS (n = 314), secondary progressive multiple sclerosis (SPMS; n = 587), RMS (n = 2,248), and healthy subjects (n = 987) genotyped using the MS replication chip.Results: WGS and replication studies identified three pathogenic variants in PPMS patients that cause neurological disorders sharing features with MS: KIF5A p.Ala361Val in spastic paraplegia 10; MLC1 p.Pro92Ser in megalencephalic leukodystrophy with subcortical cysts, and REEP1 c.606 + 43G>T in Spastic Paraplegia 31. Moreover, we detected a significant enrichment of HSP-related mutations in PPMS patients compared to controls (risk ratio [RR] = 1.95; 95% confidence interval [CI], 1.27-2.98; p = 0.002), as well as in SPMS patients compared to controls (RR = 1.57; 95% CI, 1.18-2.10; p = 0.002). Importantly, this enrichment was not detected in RMS.Interpretation: This study provides evidence to support the hypothesis that rare Mendelian genetic variants contribute to the risk for developing progressive forms of MS. Ann Neurol 2018;83:51-63. [ABSTRACT FROM AUTHOR] more...

Background: ‘No evidence of disease activity’ (NEDA), defined as absence of magnetic resonance imaging activity (T2 and/or gadolinium-enhanced T1 lesions), relapses and disability progression (‘NEDA-3’), is used as a comprehensive measure of treatment response in relapsing multiple sclerosis (RMS), but is weighted towards inflammatory activity. Accelerated brain volume loss (BVL) occurs in RMS and is an objective measure of disease worsening and progression. Objective: To assess the contribution of individual components of NEDA-3 and the impact of adding BVL to NEDA-3 (‘NEDA-4’) Methods: We analysed data pooled from two placebo-controlled phase 3 fingolimod trials in RMS and assessed NEDA-4 using different annual BVL mean rate thresholds (0.2%–1.2%). Results: At 2 years, 31.0% (217/700) of patients receiving fingolimod 0.5 mg achieved NEDA-3 versus 9.9% (71/715) on placebo (odds ratio (OR) 4.07; p < 0.0001). Adding BVL (threshold of 0.4%), the respective proportions of patients achieving NEDA-4 were 19.7% (139/706) and 5.3% (38/721; OR 4.41; p < 0.0001). NEDA-4 status favoured fingolimod across all BVL thresholds tested (OR 4.01–4.41; p < 0.0001). Conclusion: NEDA-4 has the potential to capture the impact of therapies on both inflammation and neurodegeneration, and deserves further evaluation across different compounds and in long-term studies. [ABSTRACT FROM AUTHOR] more...

Background: Neuromyelitis optica spectrum disorder (NMOSD) is a rare, disabling autoimmune disorder of the central nervous system. Clinical trials in NMOSD present unique design and statistical challenges to adequately determine treatment effect and to minimize risk. Methods: The N-MOmentum trial (NCT02200770) is evaluating the efficacy and safety of MEDI-551, an anti-CD 19 B-cell depleting monoclonal antibody, in patients with NMOSD and employs a number of unique design features. Patients are randomized (3:1) to receive MEDI-551 or placebo for up to 197 days. NMOSD attacks are evaluated by the investigator and confirmed by an independent adjudication committee. The primary endpoint is time to first relapse as determined by adjudication committee. Sample size re-estimation and futility analyses are planned interim analyses. Novel multiplicity adjustment methods are developed to control the study-wise type I error. Methods for assessing inter- and intrarater reliability are proposed. Conclusions: The N-MOmentum study minimizes exposure to placebo for individual patients. The application of several statistical methods in the N-MOmentum trial is novel in NMOSD and aims to achieve a balance between minimizing risk and maintaining scientific integrity. [ABSTRACT FROM AUTHOR] more...

Background: In phase 3 trials using the Expanded Disability Status Scale (EDSS), fingolimod and siponimod reduced disability worsening in patients with relapsing-remitting (RRMS) and secondary progressive multiple sclerosis (SPMS), respectively. However, EDSS components may differentially contribute to worsening, and contribution of each component may depend on disease stage. Also, EDSS assessments can be burdensome for patients and clinicians. Using factor analysis, different EDSS functions can be allocated to 2 novel subscales, including parameters most relevant to disease worsening. Objectives: Evaluate the effects of fingolimod and siponimod using EDSS subscales derived by factor analysis of phase 3 trial data. Methods: PROC FACTOR procedure was used to determine best fit of baseline EDSS data to the following subscales: Motor Integration (MI: ambulation, cerebellar, and pyramidal functions) and Collateral (C: bowel and bladder, brainstem, cerebral, sensory, and visual functions). Treatment effect sizes (ESs) on disability (mean change from baseline vs placebo) were determined overall and by each subscale up to 24 months (M) in patients with RRMS from FREEDOMS and up to 27M in patients with SPMS from EXPAND. Statistical significance was assessed using rank analysis of covariance (FREEDOMS) and a covariance mixed-effect, repeat-measurement model (EXPAND). Subgroup analyses of patients in EXPAND with/without lesion activity or relapses prior to screening were also performed and will be presented. Analyses were for hypothesis generation without multiple comparison adjustment. Results: Treatment ESs in FREEDOMS (N = 843: fingolimod, n = 425; placebo, n = 418) at 24 months were -0.14, P = .002 (EDSS); -0.18, P = .002 (MI); and -0.07, P = .081 (C). Significant effects (P < .05) were seen on MI from M6; effects on C were mostly nonsignificant. In EXPAND (N = 1645: siponimod, n = 1099; placebo, n = 546), overall treatment effects were detected over 27M for EDSS (P = .020), MI (P = .014), and C (P = .021). Significant ESs were seen on MI (all P < .01) at M9 (-0.28), M15 (-0.34), and M18 (-0.34), and on C at M18 (-0.24, P < .05) and M27 (-0.54, P < .001). Conclusions: The benefits of fingolimod in patients with RRMS mainly affected the MI subscale. For patients with SPMS, the benefits of siponimod were seen on both MI and C. In SPMS, effects on MI appeared earlier than on C, however the largest ES was seen later on C. Defining EDSS subscales with factor analyses may help improve their clinical usefulness. [ABSTRACT FROM AUTHOR] more...

Gil-Perotin et al ask whether the relapsing patients we identified as having silent progression are identical to the previously described category of bout onset progressive multiple sclerosis (BOPMS). The authors also raise an interesting question with respect to the long-term fate of persons living with multiple sclerosis (MS): are there two groups of RRMS patients, one whose fate is to develop progression and a second who will not? Ocrelizumab reduces disability progression independent of relapse activity in patients with relapsing multiple sclerosis. [Extracted from the article] more...

Background: Fingolimod inhibits sphingosine 1-phosphate receptor--mediated lymphocyte egress from lymph nodes, reducing lymphocytic infiltration of the central nervous system in multiple sclerosis (MS). However, characterization of immune cell changes in relation to patient outcomes in MS remains incomplete. Objectives: The FLUENT studyexplored fingolimod-mediated immune-cell subset changes in the innate and adaptive immune systems and their association with efficacy and safety outcomes in relapsing MS. Methods: FLUENT was a 12-month, prospective, multicenter, nonrandomized phase 4 study in adults with relapsing MS receiving fingolimod 0.5 mg/day (trial registration: NCT03257358). Patients were stratified as fingolimod-naive (cohort 1) or previously treated with fingolimod for ≥2 years (cohort 2). The primary outcome was change from baseline in immune cell subsets. Secondary outcomes included anti--John Cunningham virus (JCV) antibody status, neurofilament light-chain (NfL) concentrations, Patient-Determined Disease Steps (PDDS) score, and incidence of adverse events (AEs). Analyses were in patients completing month-12 follow-up. Results: At baseline, proportions of CD4+ T cells, CD8+ T cells, and B cells were higher in cohort 1 (n = 163) than in cohort 2 (n = 217). Cell counts in these immune subsets were substantially reduced at month 12 compared with baseline in cohort 1, with naive and central memory T cells affected more than effector memory T cells and regulatory B cells; changes in these subsets were less pronounced in cohort 2 than in cohort 1. At baseline, 54% of cohort 1 and 64% of cohort 2 were anti-JCV positive, and anti-JCV antibody index was unchanged at month 12. Mean (SD) NfL concentration in cohort 1 was 12.16 (11.05) pg/mL at baseline and 8.57 (5.32) at month 12; Nfl concentrations in cohort 2 were similar at baseline (9.59 [7.55]) and month 12 (9.78 [8.88]). Baseline PDDS scores were low (cohort 1, 1.7; cohort 2, 1.8) and unchanged at month 12. Respective rates of treatment-emergent AEs (54.6% vs 44.2%) and AEs leading to treatment discontinuation (12.3% vs 5.5%) were higher in cohort 1 than cohort 2; rates of serious AEs (5.5% vs 5.5%) were similar between cohorts. Conclusions: These findings expand understanding of temporal changes in immune cell subtype profiles and biomarkers in patients with relapsing MS receiving fingolimod. [ABSTRACT FROM AUTHOR] more...

Objective Methods Results Conclusion B‐cell–depletion via CD20 antibodies is a safe and effective treatment for active relapsing multiple sclerosis (RMS). Both ocrelizumab (OCR) and ofatumumab (OFA) have demonstrated efficacy in randomized controlled trials and are approved for treatment of RMS, yet nothing is known on their comparative effectiveness, especially in the real‐world setting.This prospective cohort study includes patients that were started on either OCR or OFA between September 2021 and December 2023. Patients were followed until June 2024 and recruited at 3 large tertiary centers in Germany (Duesseldorf, Essen, and Giessen). Propensity‐score‐matching was used to address baseline imbalances among patients. Clinical relapses, presence of new or enlarging MRI lesions and 6‐month confirmed disability worsening were evaluated. Non‐inferiority of OFA compared to OCR was evaluated through comparison of Kaplan–Meier‐estimates.A total of 1,138 patients were initially enrolled in the cohort. Following patient selection and propensity‐score‐matching, 544 OCR and 417 OFA patients were included in the final analysis. In our primary analysis, OFA was non‐inferior to OCR in terms of relapses, disability progression, and accrual of MRI lesions. Subgroup analyses confirmed findings in previously naïve and platform‐treated patients. Potential differences between OFA and OCR were seen in patients switching from S1P receptor modulators or natalizumab.We here provide comparative data on the effectiveness of OCR and OFA in patients with active RMS. OFA was non‐inferior to OCR in the overall cohort. Potential differences observed in patients switching from S1P receptor modulators or natalizumab require further validation. ANN NEUROL 2024 [ABSTRACT FROM AUTHOR] more...