1. Two randomized clinical trials showed that intravenous ublituximab reduced relapse rate and the number of brain lesions in multiple sclerosis patients compared to oral teriflunomide.

2. Ublituximab treatment was associated with infusion-related reactions.

Evidence Rating Level: 1 (Excellent)

Study Rundown: B cell activity plays an important role in multiple sclerosis pathogenesis. B-cell antigen-specific monoclonal antibodies have demonstrated therapeutic effects for patients with multiple sclerosis. In a previous phase two trial, ublituximab, a novel B-cell antigen-specific monoclonal antibody, induced B-cell depletion and reduced relapse rate among patients with relapsing multiple sclerosis. Using data from two randomized clinical trial (ULTIMATE I and ULTIMATE II), the present study examined the efficacy and safety of intravenous ublituximab in patients with relapsing multiple sclerosis, compared to teriflunomide. Participants in the ublituximab group received intravenous ublituximab and oral placebo. Participants in the teriflunomide group received oral teriflunomide once daily and intravenous placebo on the same schedule as that in the ublituximab group. The annualized relapse rate was significantly lower in the ublituximab group compared to the teriflunomide group. The ublituximab also had a significantly lower number of gadolinium-enhancing lesions, a marker of active disease. However, close to half of the participants in the ublituximab group experienced infusion-related reactions. As a limitation, the results may not be generalizable to all populations, as participants were predominantly from Eastern Europe. The efficacy of ublituximab was also not compared to other multiple sclerosis therapies.

Click to read the study in NEJM

In-Depth [randomized control trial]: Results from two identical phase three randomized clinical trials were reported (ULTIMATE I (n=549) and ULTIMATE II (n=545)). Adults aged 18 to 55 with a diagnosis of relapsing multiple sclerosis were randomized in a 1:1 ratio to receive intravenous ublituximab and oral placebo or oral teriflunomide and intravenous placebo. Intravenous ublituximab was administered on days 1 and 15 and at weeks 24, 48, and 72. Oral teriflunomide was administered once daily. Participants were monitored for 96 weeks, followed by a 20-week monitoring period. The adjusted annual relapse rate over 96 weeks for the ublituximab and teriflunomide groups were 0.08 and 0.19 (rate ratio, 0.41; 95% Confidence Interval [CI], 0.27 to 0.62; p<0.001) in the ULTIMATE I trial and 0.09 and 0.18 (rate ratio, 0.51; 95% CI, 0.33 to 0.78; p=0.002) in the ULTIMATE II trial. The mean total number of gadolinium-enhancing lesions per MRI scan was significantly lower in the ublituximab group compared to the teriflunomide group for both ULTIMATE I (rate ratio, 0.03; 95% CI, 0.02 to 0.06; p<0.001) and ULTIMATE II (rate ratio, 0.04; 95% CI, 0.02 to 0.06; p<0.001) trials. By the end of the trial, CD19+ B cell counts were reduced by 97% in the ublituximab group compared to 18% in the teriflunomide group. Participant disability was pooled from both trials for analysis. There were no significant differences between groups in the proportion of participants with worsening disability at 12 or 24 weeks. Brain volume at six months was also not significantly different between groups. There were no significant differences between groups in the proportion of participants with infections or at least one adverse event. The most common adverse event in the ublituximab and teriflunomide groups were infusion-related reactions (47.7%) and headache (26.6%), respectively. While ublituximab is a promising treatment for reducing relapse for multiple sclerosis, larger and longer trials are necessary to understand the efficacy and safety of ublituximab compared to existing treatments.

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