Improvements in no evidence of disease activity with ublituximab vs. teriflunomide in the ULTIMATE phase 3 studies in relapsing multiple sclerosis.

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.
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