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Ublituximab versus Teriflunomide in Relapsing Multiple Sclerosis

List of authors.
  • Lawrence Steinman, M.D.,
  • Edward Fox, M.D., Ph.D.,
  • Hans-Peter Hartung, M.D.,
  • Enrique Alvarez, M.D., Ph.D.,
  • Peiqing Qian, M.D.,
  • Sibyl Wray, M.D.,
  • Derrick Robertson, M.D.,
  • DeRen Huang, M.D., Ph.D.,
  • Krzysztof Selmaj, M.D., Ph.D.,
  • Daniel Wynn, M.D.,
  • Gary Cutter, Ph.D.,
  • Koby Mok, Ph.D.,
  • Yanzhi Hsu, Ph.D.,
  • Yihuan Xu, Ph.D.,
  • Michael S. Weiss, J.D.,
  • Jenna A. Bosco, B.S.,
  • Sean A. Power, B.S.,
  • Lily Lee, Ph.D.,
  • Hari P. Miskin, M.Sc.,
  • and Bruce A.C. Cree, M.D., Ph.D.
  • for the ULTIMATE I and ULTIMATE II Investigators*

Abstract

Background

The monoclonal antibody ublituximab enhances antibody-dependent cellular cytolysis and produces B-cell depletion. Ublituximab is being evaluated for the treatment of relapsing multiple sclerosis.

Methods

Download a PDF of the Research Summary.

In 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.

Results

A 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.

Conclusions

Among 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.)

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Funding and Disclosures

Supported by TG Therapeutics.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

This article was updated on August 25, 2022, at NEJM.org.

A data sharing statement provided by the authors is available with the full text of this article at NEJM.org.

We thank the participants and their families for their participation and commitment to these trials; the clinical trial team for the conduct of the trials; and Marina P. Gehring and Rachel Speer of Luminology Scientific Communications for medical writing assistance with an earlier version of the manuscript.

Author Affiliations

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.).

Dr. Steinman can be contacted at or at the Beckman Center for Molecular Medicine, Stanford University, 279 Campus Dr., Rm. B002, Stanford, CA 94305.

A complete list of investigators in the ULTIMATE trials is provided in the Supplementary Appendix, available at NEJM.org.

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