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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 (3.5 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.

BACKGROUND: Spinal cord atrophy and whole brain volume (WBV) loss are associated with physical disability in patients with multiple sclerosis (MS). Medulla oblongata volume (MOV) as a surrogate for spinal cord volume and lateral ventricular volume (LVV) as a surrogate for WBV are easy-to-measure, validated biomarkers. LVV expansion of > 3.5% per year, which corresponds to WBV loss of > 0.4% per year, has been proposed to represent a pathological change in MS. A cutoff has not yet been identified for MOV. OBJECTIVES: To evaluate change at 1 year in MOV, LVV, and measures of physical disability among patients with early relapsing MS (RMS) treated with ozanimod in the ongoing ENLIGHTEN trial. METHODS: ENLIGHTEN (NCT04140305) is a prospective, multicenter, open-label study of ozanimod 0.92 mg in patients with early RMS. Participants are aged 18 to 65 years; are taking ≤ 1 MS disease-modifying therapy (DMT); have received a diagnosis of RMS within ≤ 5 years; and have an Expanded Disability Status Scale (EDSS) score of ≤ 3.5, no relapses within 30 days of screening, and ≤ 10 gadolinium-enhancing lesions on baseline brain MRI. For this analysis, MOV, LVV, Nine-Hole Peg Test (9-HPT), Timed 25-Foot Walk test (T25W), and EDSS scores at baseline and year 1 were evaluated (data cutoff: February 14, 2023). Change at 1 year was analyzed descriptively in the subset of patients with assessments at both time points. RESULTS: ENLIGHTEN participants (N = 185) were mostly women (78.4%), White (85. 9%), and DMT naive (72.4%), with a mean (SD) age of 39.5 (10.7) years at baseline, 4.1 (5.5) years since MS symptom onset, 1.1 (1.3) years since MS diagnosis, and a mean (SD) 0.8 (0.8) relapses in the year before the study. At baseline, the median MOV (n = 99) was 6.0 cm3, and LVV (n = 100) was 35.7 cm3. After 1 year of ozanimod, the change from baseline in these measures was small (median % change: MOV, --0.11%; LVV, 0.14% [n = 98 for both]). Patients' median time for completion of the 9-HPT (n = 106) was 22.0 seconds at baseline, and they completed it a median of 0.5 seconds faster after 1 year of ozanimod. For the T25W, (n = 105), median time at baseline was 5.2 seconds, with little change at year 1 (median change: 0.05 seconds). The median EDSS score (n = 122) was 2.0 at baseline and remained so at year 1 (median change: 0.0). CONCLUSIONS: During treatment with ozanimod, patients with early RMS had relatively stable MOV, LVV, and levels of physical disability over 1 year and improved their speed on the 9-HPT. The median percent change in LVV (0.14%) remained well below the 3.5% cutoff that is suggestive of pathologic change. 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]

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 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., Competing Interests: EA has received compensation for advisory boards, lectures, and consultancy with Actelion/Janssen, Alexion, Bayer, Biogen, Celgene/BMS, EMD Serono/Merck, Genentech/Roche, Genzyme, Novartis, Sanofi, and TG Therapeutics; research support from Biogen, Genentech/Roche, Novartis, TG Therapeutics, Patient-Centered Outcomes Research Initiative, National Multiple Sclerosis Society, National Institutes of Health, and Rocky Mountain MS Center. LS has received compensation for consulting from TG Therapeutics. H-PH has received honoraria for serving on steering or data monitoring committees or speaker fees from Bayer, Biogen, Boehringer Ingelheim, BMS Celgene, GeNeuro, Merck, Novartis, Sanofi, TG Therapeutics, and Roche with approval by the Rector of Heinrich-Heine-Universität. PQ has received speaking and consulting honoraria from Biogen, BMS, Genzyme, Genentech, Viela Bio, and TG Therapeutics. SW has received compensation for consulting from TG Therapeutics; has been a consultant, speaker, and research participant for Celgene/BMS, Biogen, EMD Serono, Genentech/Roche, and Genzyme/Sanofi; has conducted research/been a consultant for Novartis, and has conducted research for Alkermes and TG Therapeutics. DR has received consultancy fees from Greenwich Biosciences, Mallinckrodt, and Novartis; honoraria or speaker fees and consultancy fees from Alexion, Amgen, Biogen, Bristol Myers Squibb, EMD Serono, Genentech, Horizon, ImmPACT Bio, Janssen, Sanofi Genzyme, and TG Therapeutics; research grant support from Anokion, Atara Biotherapeutics, Biogen, CorEvitas, EMD Serono, Genentech, GW Pharmaceuticals, Janssen, Novartis, PCORI, PRIME CME, Sanofi Genzyme, TG Therapeutics, and UCB. KS has received honoraria for speaking, consulting, and serving on advisory boards from Merck, Novartis, Roche, Biogen, Celgene, BMS, and TG Therapeutics. DW's employer has received research funding, speaking fees, or he has served as expert witness for AbbVie, Adamas, Allergan, ANI Pharma, Avanir, Banner Life, Biogen, Bristol Myers Squibb, Chugai, Eli Lilly, EMD Serono, Genentech, GW Therapeutics, Immunic, InnoCare, Janssen, Jazz Pharmaceuticals, Mallinckrodt, MAPI Therapeutics, Mylan, National MS Society, Novartis, SanBio, Sanofi Genzyme, UCB Biopharma, Viela Bio, Teva Pharmaceuticals, and TG Therapeutics and was employed by Consultants in Neurology. EF, KM, YX, KB, and HM are employees of TG Therapeutics. BC has received personal compensation for consulting from Alexion, Atara, Autobahn, Avotres, Biogen, Boston Pharma, EMD Serono, Gossamer Bio, Hexal/Sandoz, Horizon, Immunic AG, Kyverna, Neuron23, Novartis, Sanofi, Siemens, and TG Therapeutics and received research support from Genentech and Kyverna. The authors declare that this study received funding from TG Therapeutics. The funder was involved in the study design, collection, analysis, interpretation of data, the writing of this article, and the decision to submit for publication. All authors had full editorial oversight of the manuscript and provided final approval for all content. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Alvarez, Steinman, Fox, Hartung, Qian, Wray, Robertson, Selmaj, Wynn, Mok, Xu, Bodhinathan, Miskin and Cree.)

Background: Interferon beta-1a remains an important treatment option for multiple sclerosis, particularly when safety or tolerability concerns may outweigh the benefits of higher-efficacy disease-modifying therapies. The five-year phase 4 Plegridy Observational Program (POP) study (NCT02230969) collected data on real-world safety and effectiveness of Plegridy® (peginterferon beta-1a) treatment in patients with relapsing multiple sclerosis., Objective: To explore the real-world safety and effectiveness of peginterferon beta-1a in patients with relapsing multiple sclerosis, including factors influencing treatment discontinuation., Methods: Data were collected prospectively from patients ≥ 18 years old with relapsing multiple sclerosis for overall population analysis and for subpopulations including newly/previously diagnosed patients, age, and experience with peginterferon beta-1a. Outcome measures included annualized relapse rates, adverse events, and predictors of time to treatment discontinuation., Results: Mean (SD) treatment duration in the overall population ( N  = 1172) was 896.0 (733.15) days. Incidence of adverse events was higher in new than experienced users (79.4% vs. 57.0%). New users were more likely than experienced users to discontinue (hazard ratio = 1.60; P  < 0.0001). The adjusted annualized relapse rate was 0.09, and at the end of 5 years, 77.1% of patients were relapse-free., Conclusions: Peginterferon beta-1a is an effective therapy for managing relapsing multiple sclerosis. The identification of predictors of discontinuation can help inform strategies to enhance treatment persistence., Competing Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: MS has received grant support and/or speaker honoraria from Biogen, Merck, Novartis, Roche, Sanofi, and Teva Neuroscience. SW is a paid consultant, speaker, and/or contract researcher for Biogen, Celgene/Bristol Myers Squibb, EMD Serono, Genentech/Roche, Genzyme/Sanofi, Novartis, Receptos, and TG Therapeutics. GN has received speaker honoraria from Bayer, Biogen, Celgene, Merck, Novartis, and Roche. NB, AK, WC-B, and MV are employees of and may hold stock and/or stock options in Biogen. TK was an employee of Biogen at the time of these analyses and may hold stock and/or stock options in Biogen., (© The Author(s), 2024.)

Background: Diroximel fumarate (DRF) is approved for adults with relapsing-remitting multiple sclerosis (RRMS) in Europe and for relapsing forms of MS in the United States. DRF and dimethyl fumarate (DMF) yield bioequivalent exposure of the active metabolite monomethyl fumarate. Prior studies indicated fewer gastrointestinal (GI)-related adverse events (AEs) with DRF compared with DMF., Objective: To report final outcomes from EVOLVE-MS-1., Methods: EVOLVE-MS-1 was an open-label, 96-week, phase 3 study assessing DRF safety, tolerability, and efficacy in patients with RRMS. The primary endpoint was safety and tolerability; efficacy endpoints were exploratory., Results: Overall, 75.7% (800/1057) of patients completed the study; median exposure was 1.8 (range: 0.0-2.0) years. AEs occurred in 938 (88.7%) patients, mostly of mild (28.9%) or moderate (50.3%) severity. DRF was discontinued due to AEs in 85 (8.0%) patients, with < 2% discontinuing due to GI or flushing/flushing-related AEs. At Week 96, mean number of gadolinium-enhancing lesions was significantly reduced from baseline (72.7%; p < 0.0001); adjusted annualized relapse rate was 0.13 (95% confidence interval: 0.11-0.15)., Conclusion: DRF was generally well tolerated over 2 years, with few discontinuations due to AEs; radiological measures indicated decreased disease activity from baseline. These outcomes support DRF as a treatment option in patients with RRMS., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: BAS: research grant support from AbbVie, Biogen, Bristol Myers Squibb, Greenwich Biosciences, Novartis, and Sanofi and consulting and/or speaking fees from Alexion, Biogen, Bristol Myers Squibb, Cigna, Cycle, EMD Serono, Genentech, Horizon, Janssen, Novartis, Octave Bioscience, Roche, Sanofi, and TG Therapeutics.DLA: consulting fees from Albert Charitable Trust, Alexion Pharma, Biogen, Celgene, Frequency Therapeutics, Genentech, Med-Ex Learning, Merck, Novartis, Population Council, Receptos, Roche, and Sanofi-Aventis; grants from Biogen, Immunotec, and Novartis; and equity interest in NeuroRx.JD: advisory boards for Amicus, Biogen, Janssen, Medis, Merck, Novartis, Roche, Sanofi-Genzyme, and Teva; speaker bureaus for Biogen, Bayer, Hemofarm, Janssen, Medis, Medtronic, Merck, Novartis, Roche, Sanofi-Genzyme, Teva, and Zentiva; and research grant from Roche.MSF: research/educational grants from Sanofi-Genzyme; honoraria/consultation fees from Alexion/AstraZeneca, BMS (Celgene), EMD Serono, Hoffman La-Roche, Actelion/Janssen (J&J), Novartis, Quanterix, Sanofi-Genzyme, and Teva Canada Innovation; advisory boards/boards of directors for Alexion/AstraZeneca, Atara Biotherapeutics, Bayer Healthcare, Celestra Health, Hoffman La-Roche, Actelion/Janssen (J&J), EMD Serono/Merck Serono, Novartis, and Sanofi-Genzyme; and participated in speakers bureau for Sanofi-Genzyme and EMD Serono.RG: research support and speaker’s honoraria from Bayer-Schering, Biogen Idec, BMS, Chugai, Eisai, Genesis, Janssen, Merck Serono, Nikkiso Pharma, Novartis, Roche, Sanofi-Genzyme, Sandoz, and Teva; consulting honoraria from ZLB Behring, Baxter, Roche, and Talecris; and personal stock options in Bayer, Merck, and Roche.MG: consulting fees from Biogen, EMD Serono, Novartis, and Sanofi-Genzyme; research support from Alkermes; and speaker bureaus for Biogen, EMD Serono, Genentech-Roche, and Sanofi-Genzyme.EJ: advisory boards for Biogen and speaker fees from Biogen, Novartis, Roche, and Sanofi.CLG: consultant/advisory boards/speaker bureaus for Biogen, Bristol Myers Squibb, EMD Serono, Genentech, Janssen, Novartis, Sanofi-Genzyme, and TG Therapeutics.RTN: consultant for Abata Therapeutics, Banner Life Sciences, BeiGene, Biogen, Bristol Myers Squibb, Genentech, Genzyme, GW Therapeutics, Janssen, Horizon Therapeutics, Lundbeck, NervGen, and TG Therapeutics.DN: research support from and consultant/advisory boards/speaker bureaus for Adamas, Alkermes, Alexion, Bayer, Biogen, Celgene/BMS, EMD Serono, Janssen, Novartis, Roche-Genentech, and Sanofi-Genzyme.JO: research support from Biogen Idec, EMD Serono, and Roche and personal compensation for consulting/speaking from Biogen Idec, BMS, EMD Serono, Eli Lilly, Roche, Sanofi-Genzyme, and Novartis.MAHP: consultant/advisory boards/speaker bureaus for Biogen, Bristol Myers Squibb, EMD Serono, Genentech, Janssen, Novartis, Sanofi-Genzyme, and TG Therapeutics.KS: research support from Merck; advisory boards for Biogen, Celgene/BMS, Merck, Novartis, Roche, Sanofi, and TG Therapeutics.FTB: research support and travel grants, through his institution, from the German Science Fund (DFG), German Federal Ministry of Education and Science (BMBF), Bayer-Schering, Merck, Novartis, Pfizer, Roche, Sanofi, and Teva and speaker fees from and advisory boards for Actelion, Alexion, Bayer, Biogen, CSL Behring, Fresenius, Horizon, Merck, Novartis, Roche, Sanofi-Genzyme, and Teva.AW: adviser fees from AbbVie and research support from AbbVie, Alkermes, and Biogen.TZ: personal compensation for consulting services and speaker honoraria from Bayer, Biogen Idec, Novartis, Sanofi, Synthon, and Teva and financial support for research activities from Bayer, Biogen Idec, Novartis, Sanofi-Aventis, and Teva.WC-B, HC, SL, MS, SLS, and TW: employees of and hold stock/stock options in Biogen.SW: consulting fees from and advisory boards for Biogen, Celgene, and EMD Serono; speaker bureaus for Biogen, Celgene, EMD Serono, Roche-Genentech, and Sanofi-Genzyme; and research support from Biogen, Celgene, EMD Serono, Novartis, Receptos, Roche-Genentech, Sanofi-Genzyme, and TG.