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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]

Introduction: In EVOLVE-MS-1 (NCT02634307), mean absolute lymphocyte count (ALC) on diroximel fumarate (DRF) declined from baseline by approximately 28% in year 1, then stabilized, similar to ALC decline observed with dimethyl fumarate (DMF). Prior studies reported that clinical efficacy of DMF was not substantially different in patients with and without lymphopenia. Methods: EVOLVE-MS-1—an open-label, 96-week, phase 3 study—assessed DRF safety and exploratory efficacy in patients with relapsing–remitting multiple sclerosis. This study analyzes efficacy-related outcomes comparing (1) patients with lymphopenia (≥ 1 ALC below lower limit of normal [LLN]) and without (all ALCs ≥ LLN); (2) across quartiles stratified by week 96 ALC decline from baseline: Q1 (≥ 47% decline); Q2 (30% to < 47% decline); Q3 (12% to < 30% decline); Q4 (< 12% decline). Results: Baseline characteristics were similar between patients without (n = 593) and with lymphopenia (n = 452). At week 96, adjusted annualized relapse rate (ARR; 95% confidence interval) was 0.14 (0.11–0.17) without lymphopenia and 0.12 (0.09–0.15) with lymphopenia. Estimated proportions with 12-week confirmed disability progression (CDP12) at week 96 were 10.2% without and 9.3% with lymphopenia. When stratified by quartiles (Q1–Q4), ARR at week 96 was 0.11 (Q1), 0.09 (Q2), 0.13 (Q3), and 0.17 (Q4). Estimated proportions with CDP12 at week 96 were 9.6% (Q1), 10.2% (Q2), 5.7% (Q3), and 10.9% (Q4). At week 96, no evidence of disease activity was achieved by 47.2% (Q1), 47.8% (Q2), 45.4% (Q3), and 37.3% (Q4) of patients. Conclusion: In DRF-treated patients in EVOLVE-MS-1, clinical and radiological measurements indicated reduced disease activity regardless of lymphopenia or magnitude of ALC decline from baseline; however, patients who had greater ALC declines appeared to have numerically lower ARR and higher proportions free from relapses and gadolinium-enhancing lesions compared with those with smallest decline. This supports prior evidence that, while lymphopenia may contribute to fumarate efficacy outcomes, it is not the primary mechanism of action. Trial Registration: ClinicalTrials.gov identifier NCT02634307. [ABSTRACT FROM AUTHOR]

BACKGROUND: Ofatumumab, a fully human anti-CD20 monoclonal antibody, demonstrated superior efficacy vs teriflunomide in the phase 3 ASCLEPIOS I/II (NCT02792218/ NCT02792231) trials in people with relapsing multiple sclerosis (PwRMS). Previously reported data for up to 5 years demonstrated sustained efficacy and a favorable safety profile in PwRMS. OBJECTIVES: To assess ofatumumab's longer-term safety and efficacy for up to 6 years in PwRMS. METHODS: Efficacy analyses will include all participants randomly assigned to cohorts in ASCLEPIOS I/II and their data from the first dose in ASCLEPIOS I/ II, whereas safety analyses will include all participants who received at least 1 dose of ofatumumab in ASCLEPIOS I/II, APOLITOS (NCT03249714), APLIOS (NCT03560739), or ALITHIOS (NCT03650114; cutoff: September 25, 2023). Efficacy will be analyzed by the randomized treatment in the core study, with those randomly assigned to ofatumumab being referred to as the continuous group and those randomly assigned to teriflunomide as the switch group. RESULTS: Mean baseline age in ASCLEPIOS I/II (N = 1882) was 38 years, 67.6% were female, and mean Expanded Disability Status Scale score was 2.9 in both groups. Previously reported 5-year data (cutoff: September 25, 2022) for ofatumumab showed a sustained, low annualized relapse rate (ARR) and sustained and almost complete suppression of MRI lesion activity in the continuous group. In the switch group, ARR was markedly reduced from years 2-3 (0.16- 0.06) and remained low through years 3-5 (0.05). MRI lesion activity was almost completely suppressed through years 3-5. At year 5, 9 of 10 patients reached no evidence of disease activity in both groups. Exposure-adjusted incidence rate of adverse events (AEs), serious AEs, serious infections, and malignancies remained consistent, with no increased risk over 5 years. Mean immunoglobulin (Ig) G levels remained stable (above the lower limit of normal [LLN]: 5.65 g/L), whereas mean IgM levels decreased but remained above the LLN (0.4 g/L). Updated 6-year efficacy and safety results will be presented at the annual meeting. CONCLUSIONS: These analyses will help inform physicians on the longer-term safety and efficacy profile of ofatumumab in PwRMS. [ABSTRACT FROM AUTHOR]

Background: Ublituximab, a novel monoclonal antibody (mAb) targeting a unique epitope on the CD20 antigen, is glycoengineered for enhanced B-cell targeting through antibody-dependent cellular cytotoxicity (ADCC). Greater ADCC may allow lower doses and shorter infusion times versus other anti-CD20 mAbs. Objective: The objective was to determine optimal dose, infusion time, and activity of ublituximab in relapsing multiple sclerosis. Methods: This is a phase 2, placebo-controlled study. Patients received three ublituximab infusions (150 mg over 1–4 hours on day 1 and 450–600 mg over 1–3 hours on day 15 and week 24) in six dosing cohorts. The primary endpoint was B-cell depletion. Results: In all cohorts (N = 48), median B-cell depletion was >99% by week 4, maintained at weeks 24 and 48. Most common adverse events (AEs) were infusion-related reactions (all grade 1–2), with no apparent increased incidence at shorter infusion times. There were no AE-related discontinuations. At weeks 24 and 48, no T1 gadolinium-enhancing lesions (p = 0.003) and a 10.6% decrease in T2 lesion volume (p = 0.002) were detected. The annualized relapse rate was 0.07; 93% remained relapse free on study. Overall, 74% of patients had no evidence of disease activity (NEDA). Conclusion: Ublituximab was safely infused as rapid as 1 hour, producing robust B-cell depletion and profound reductions in magnetic resonance imaging (MRI) activity and relapses. [ABSTRACT FROM AUTHOR]

Background: In CARE-MS II (trial registration: NCT00548405), alemtuzumab (12 mg/day; baseline: 5 days; 12 months later: 3 days) significantly improved clinical/magnetic resonance imaging (MRI) outcomes vs subcutaneous interferon beta-1a (SC IFNβ-1a) over 2 years (y) in patients with RRMS with inadequate response to prior therapy. Efficacy was maintained in a 4-year extension study (NCT00930553), wherein patients could receive additional alemtuzumab courses (12 mg/ day on 3 days, ≥12 months apart) as needed for disease activity, or receive other disease-modifying therapy (DMT) per investigator discretion. Further follow-up was available in an additional 5-year extension, TOPAZ (NCT02255656). Objectives: Evaluate the efficacy and safety of alemtuzumab in CARE-MS II patients over 9 years. Methods: At investigator discretion, patients in TOPAZ can receive additional as-needed alemtuzumab (≥12 months apart, no criteria) or receive other DMT (at any time). Results: From core study baseline through year 9, 288/435 (66%) CARE-MS II alemtuzumab-treated patients remained on study; 41% received neither additional alemtuzumab nor another DMT through year 9. Annualized relapse rate was 0.19 in years 3-9. From core study baseline through year 9, 68% of patients had stable/improved Expanded Disability Status Scale (EDSS) scores, and mean change in EDSS was +0.32. Over 9 years, 60% of patients were free of 6-month confirmed disability worsening and 49% achieved 6-month confirmed disability improvement. On average, 69% of patients were free of MRI disease activity, 89% were free of new gadolinium-enhancing lesions, and 69% were free of new/enlarging T2 hyperintense lesions, annually from year 3-9. From core study baseline through year 9, median percent cumulative brain volume (BV) change was --1.22%; median percent BV change was ≤--0.19% annually over years 3-9. Incidence of overall adverse events (AEs) and infections declined through year 9; cumulative thyroid AE incidence was 43.7% and immune thrombocytopenia (ITP) incidence was 3.7% (1 new case of ITP, 14 months after the fourth alemtuzumab course, was observed at year 9). No new cases of nephropathy were reported. Efficacy and safety in SC IFNβ-1a--treated patients from the core study who switched to alemtuzumab in the extension were consistent with those treated with alemtuzumab both in the core and extension. Conclusions: Efficacy of alemtuzumab on clinical, MRI, and BV loss outcomes was maintained over 9 years in CARE-MS II patients, with 41% receiving no further treatment through year 9. Safety in year 9 in this study was consistent with that of previous years. [ABSTRACT FROM AUTHOR]

Background: Clinical trials of alemtuzumab have demonstrated its 9-year efficacy and safety, but real-world data are limited. PRO-ACT assesses patient-reported outcomes (PROs), safety, and treatment sequencing in adults with relapsing-remitting multiple sclerosis (RRMS) transitioning from prior disease-modifying therapy to alemtuzumab in the United States and Canada. Objectives: To report the 1-year interim results of the realworld PRO-ACT study. Methods: PRO-ACT is an ongoing 24-month, prospective, multicenter, noninterventional, single-arm, observational study. The primary end point evaluates change in overall satisfaction on the Treatment Satisfaction Questionnaire for Medication v1.4 (TSQM; scale 0-100; higher scores indicate greater satisfaction), after transitioning to alemtuzumab. Other PROs evaluated (lower scores indicate improved outcomes) are the MS Impact Scale-29 (MSIS-29; scale 0-100), Modified Fatigue Impact Scale-5 (MFIS-5; scale 0-20), Patient-Determined Disease Steps (PDDS; scale 0-8), and Health-Related Productivity Questionnaire (HRPQ)-MS v2. Results: As of September 2019, enrollment was complete (N = 200 patients) and PRO data were evaluable in 170 patients. Patients transitioned from natalizumab (37%), dimethyl fumarate (14%), fingolimod (13%), teriflunomide (12%), or other therapies (24%) to alemtuzumab. Mean TSQM scores improved from baseline to year (Y) 1 for overall satisfaction (50.3 vs 66.5; P < .0001) and effectiveness (49.3 vs 60.7; P < .0001) domains; scores were unchanged for side effects (77.6 vs 76.5) and convenience (70.3 vs 70.7). Mean scores for other PROs showed improvement at Y1 vs baseline: MSIS-29 physical impact scale (52.4 vs 47.8; P < .001), MSIS-29 psychological impact scale (53.4 vs 47.9; P < .001), and MFIS-5 (12.8 vs 11.7; P < .001). Scores remained stable on the PDDS (3.1 vs 3.2). Mean hours of weekly employment productivity lost decreased from 11.4 at baseline to 7.4 at Y1 (P < .05). Incidence of adverse events was 92% and serious adverse events was 11%. One death occurred (suicide). Conclusions: PROs improved during the first year of alemtuzumab treatment after transitioning from another therapy. Alemtuzumab safety in Y1 was consistent with the pivotal studies. [ABSTRACT FROM AUTHOR]

Background: Adherence to therapy in multiple sclerosis (MS) leads to improved clinical outcomes. Persistence to therapy and discontinuation rates contribute to adherence. Diroximel fumarate (DRF) is a novel oral fumarate recently approved in the United States for relapsing forms of MS, administered as 2 capsules twice daily. Objectives: To compare adherence with DRF vs dimethyl fumarate (DMF) in EVOLVE-MS-2 and describe long-term adherence and efficacy outcomes with DRF in EVOLVEMS-1. Methods: Adherence was assessed in patients with relapsing- remitting MS who received DRF or DMF in the 5-week, randomized EVOLVE-MS-2 study (trial registration: NCT03093324) and in those who received DRF in the ongoing, 96-week, open-label EVOLVE-MS-1 study (NCT02634307). All EVOLVE-MS-2 patients received 2 capsules twice daily. Adherence was determined by pill count (number taken divided by the number prescribed x 100). In patients who discontinued treatment, adherence was based on duration of treatment and not the full study period. Efficacy outcomes were assessed in EVOLVE-MS-1. Results: In the completed EVOLVE-MS-2 study, mean adherence was high (DRF 97.1%, n = 252; DMF 97.0%, n = 251); 97.4% of patients were ≥80% adherent to therapy. Discontinuation rates were lower with DRF (3.2%) than DMF (7.2%), primarily due to differences in gastrointestinal tolerability. In EVOLVE-MS-1 as of November 30, 2018 (median [range] exposure, 84 [0-100] weeks; n = 888), mean adherence was 93.4% (n = 877); 92.0% of patients were ≥80% adherent. Overall, 16.3% of patients discontinued treatment. Median (range) exposure for patients with ≥80% vs <80% adherence was 84 (1-100) and 22 (0-97) weeks, respectively. In patients with ≥80% adherence, adjusted annualized relapse rate was 0.15 (95% CI 0.13-0.19), representing a 79.4% (95% CI 75.0-83.0; P < .0001) reduction from the 12 months before study entry. Mean (SD) change in Expanded Disability Status Scale score from baseline to week 96 in patients with ≥80% adherence was 0.07 (0.59; n = 310). The small sample size (n = 70 at baseline, n = 2 at week 96) of patients with <80% adherence limits the ability to draw conclusions on the correlation between adherence and efficacy outcomes. Conclusions: High adherence and low discontinuation rates demonstrate documented treatment adherence and persistence to DRF. Adherence rates with DRF and DMF in EVOLVE-MS-2 were sustained in DRF-treated patients from EVOLVE-MS-1 for up to 96 weeks, demonstrating little impact of a 2-capsules-twice-daily dosing regimen. DRF-treated patients in EVOLVE-MS-1 had improved effi- cacy outcomes from baseline. [ABSTRACT FROM AUTHOR]