• Lawrence Steinman, Edward Fox, Hans-Peter Hartung, Enrique Alvarez, Peiqing Qian, Sibyl Wray, Derrick Robertson, DeRen Huang, Krzysztof Selmaj, Daniel Wynn, Gary Cutter, Koby Mok, Yanzhi Hsu, Yihuan Xu, Michael S Weiss, Jenna A Bosco, Sean A Power, Lily Lee, Hari P Miskin, CreeBruce A CBACFrom the Beckman Center for Molecular Medicine, Stanford University, Stanford (L.S.), and the Weill Institute for Neurosciences, University of California, San Francisco, San Francisco (B.A.C.C.) - both in California; Central Texas Neurolog, and ULTIMATE I and ULTIMATE II Investigators.
• From the Beckman Center for Molecular Medicine, Stanford University, Stanford (L.S.), and the Weill Institute for Neurosciences, University of California, San Francisco, San Francisco (B.A.C.C.) - both in California; Central Texas Neurology Consultants, Round Rock (E.F.); Heinrich Heine University Medical School, Düsseldorf, Germany (H.-P.H.); the Brain and Mind Centre, University of Sydney, Sydney (H.-P.H.); Medical University of Vienna, Vienna (H.-P.H.); Palacký University Olomouc, Olomouc, Czech Republic (H.-P.H.); University of Colorado, Aurora (E.A.); Swedish Medical Center, Seattle (P.Q.); Hope Neurology, Knoxville, TN (S.W.); University of South Florida, Tampa (D.R.); Columbus Neuroscience, Westerville, OH (D.H.); the Department of Neurology, University of Warmia and Mazury, Olsztyn, and Center of Neurology, Lodz - both in Poland (K.S.); Consultants in Neurology, Northbrook, IL (D.W.); and TG Therapeutics, New York (G.C., K.M., Y.H., Y.X., M.S.W., J.A.B., S.A.P., L.L., H.P.M.).
• N. Engl. J. Med. 2022 Aug 25; 387 (8): 704-714.

BackgroundThe monoclonal antibody ublituximab enhances antibody-dependent cellular cytolysis and produces B-cell depletion. Ublituximab is being evaluated for the treatment of relapsing multiple sclerosis.MethodsIn two identical, phase 3, double-blind, double-dummy trials (ULTIMATE I and II), participants with relapsing multiple sclerosis were randomly assigned in a 1:1 ratio to receive intravenous ublituximab (150 mg on day 1, followed by 450 mg on day 15 and at weeks 24, 48, and 72) and oral placebo or oral teriflunomide (14 mg once daily) and intravenous placebo. The primary end point was the annualized relapse rate. Secondary end points included the number of gadolinium-enhancing lesions on magnetic resonance imaging (MRI) by 96 weeks and worsening of disability.ResultsA total of 549 participants were enrolled in the ULTIMATE I trial, and 545 were enrolled in the ULTIMATE II trial; the median follow-up was 95 weeks. In the ULTIMATE I trial, the annualized relapse rate was 0.08 with ublituximab and 0.19 with teriflunomide (rate ratio, 0.41; 95% confidence interval [CI], 0.27 to 0.62; P<0.001); in the ULTIMATE II trial, the annualized relapse rate was 0.09 and 0.18, respectively (rate ratio, 0.51; 95% CI, 0.33 to 0.78; P = 0.002). The mean number of gadolinium-enhancing lesions was 0.02 in the ublituximab group and 0.49 in the teriflunomide group (rate ratio, 0.03; 95% CI, 0.02 to 0.06; P<0.001) in the ULTIMATE I trial and 0.01 and 0.25, respectively (rate ratio, 0.04; 95% CI, 0.02 to 0.06; P<0.001), in the ULTIMATE II trial. In the pooled analysis of the two trials, 5.2% of the participants in the ublituximab group and 5.9% in the teriflunomide group had worsening of disability at 12 weeks (hazard ratio, 0.84; 95% CI, 0.50 to 1.41; P = 0.51). Infusion-related reactions occurred in 47.7% of the participants in the ublituximab group. Serious infections occurred in 5.0% in the ublituximab group and in 2.9% in the teriflunomide group.ConclusionsAmong participants with relapsing multiple sclerosis, ublituximab resulted in lower annualized relapse rates and fewer brain lesions on MRI than teriflunomide over a period of 96 weeks but did not result in a significantly lower risk of worsening of disability. Ublituximab was associated with infusion-related reactions. (Funded by TG Therapeutics; ULTIMATE I and II ClinicalTrials.gov numbers, NCT03277261 and NCT03277248.).Copyright © 2022 Massachusetts Medical Society.

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