Ublituximab Reduces Relapses Compared With Teriflunomide in Multiple Sclerosis


In a phase 3 trial, ULTIMATE I and II, ublituximab resulted in lower annualized relapse rates and fewer brain lesions on MRI than teriflunomide among participants with relapsing multiple sclerosis.

Lawrence Steinman, MD, Zimmerman Professor of Neurology & Neurological Sciences, and Pediatrics, Stanford University

Lawrence Steinman, MD

Data from ULTIMATE I and II (NCT03277261 and NCT03277248), a recent pair of phase 3 trials, showed that ublituximab, in investigational treatment developed by TG Therapeutics, resulted in lower annualized relapse rates (ARRs) and fewer brain lesions on MRI than teriflunomide (Aubagio; Sanofi) for patients with relapsing multiple sclerosis (MS) over the duration of 96 weeks.1

The ARR was 0.08 with ublituximab and 0.19 with teriflunomide from the ULTIMATE I trial, (rate ratio, 0.41; 95% CI, 0.27-0.62; P <.001), while the ARR was 0.09 and 0.18 in the ULTIMATE II trial (rate ratio, 0.51; 95% CI, 0.33-0.78; P =.002). Ublituximab produces B-cell depletion and enhances antibody-dependent cellular cytolysis, which could be beneficial treatment for patients with relapsing MS.

Lawrence Steinman, MD, Zimmerman Professor of Neurology & Neurological Sciences, and Pediatrics, Stanford University, and colleagues wrote, “Although no opportunistic infections occurred in either group in either of the trials, a higher frequency of infections, including serious infections, was observed with ublituximab than with teriflunomide.” In the ublituximab group, infusion-related reactions occurred in 47.7% of the participants. Notably, serious infections occurred in 5.0% in the ublituximab group compared with 2.9% in the teriflunomide group.

The findings additionally showed a significantly lower risk of worsened disability with ublituximab treatment. Although, the investigational therapy was also associated with infusion-related reactions, which occurred in 47.7% of the participants in the ublituximab group.

The ULTIMATE I trial (n = 549), and the ULTIMATE II trial (n = 545) had a median follow-up of 95 weeks. Participants with relapsing MS were randomly assigned in a ratio of 1:1 and received intravenous ublituximab, 150 mg on day 1, followed by 450 mg on day 15 and at weeks 24, 48, and 72. The other participants received the oral placebo or oral teriflunomide, 14 mg once daily and the intravenous placebo. The ARR was the primary end point. The number of gadolinium-enhancing lesions on MRI by 96 weeks and worsening of the disability were the secondary end points.

Ofatumumab Outperforms Teriflunomide in Newly Diagnosed, Treatment-Naïve Multiple Sclerosis

Consistent with the overall population, newly diagnosed, treatment-naïve patients with MS showed better relapse rates, all-cause disability worsening—including progression independent of relapse activity—with ofatumumab over teriflunomide.

A pooled analysis was performed on the 2 trials and showed that 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, 0.50-1.41; P = .51). The ublituximab group had the mean number of gadolinium-enhancing lesions as 0.02 and 0.49 was the mean in the teriflunomide group (rate ratio, 0.03; 95% CI, 0.02-0.06; P <.001) in the ULTIMATE I trial. While in the ULTIMATE II trial the mean number of gadolinium-enhancing lesions was 0.01 for ublituximab group and 0.25 for the teriflunomide group (rate ratio, 0.04; 95% CI, 0.02-0.06; P <.001).

Teriflunomide was associated with a numerically lower rate of worsening of disability in both trails than reported in previous studies with this drug, though the authors noted no conclusions could be drawn from this.2,3 “The low annualized relapse rate in both groups in each of the current trials may have led to a lower rate of worsening of disability associated with relapse,” Steinman and colleagues noted.

One of the limitations of conducting the trials is that no inferences were able to be made regarding the efficacy of ublituximab in comparison with other therapies for MS that are more potent than teriflunomide. The participants were consistent with previous anti-CD20 trials in relapsing MS, except participants from Eastern Europe as they were overrepresented, for the baseline characteristics.

Steinman et al wrote, “Long-term assessment of ublituximab is required to determine whether progressive multifocal leukoencephalopathy would occur with continued treatment.” Future trials are needed to determine the efficacy and safety of ublituximab for patients with relapsing MS compared with other disease-modifying treatments.

1. Steinman L, Fox E, Hartung HP, et al. Ublituximab versus Teriflunomide in Relapsing Multiple Sclerosis. N Engl J Med. 2022;387(8):704-714. doi:10.1056/NEJMoa2201904
2. Hauser SL, Bar-Or A, Cohen JA, et al. Ofatumumab versus Teriflunomide in Multiple Sclerosis. N Engl J Med. 2020;383(6):546-557. doi:10.1056/NEJMoa1917246
3. O'Connor P, Wolinsky JS, Confavreux C, et al. Randomized trial of oral teriflunomide for relapsing multiple sclerosis. N Engl J Med. 2011;365(14):1293-1303. doi:10.1056/NEJMoa1014656
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