What question did this study set out to answer?

To assess the long-term efficacy and safety of ublituximab in individuals with relapsing forms of multiple sclerosis.

February 19, 2026Open Access

Five Years of Ublituximab in Multiple Sclerosis

BCBruce A. C. CreeUniversity of California, San Francisco EFEdward J. FoxEmory University HHHP HartungHeinrich Heine University Düsseldorf

Key Points

To assess the long-term efficacy and safety of ublituximab in individuals with relapsing forms of multiple sclerosis.
2-year, multicenter, randomized, active-controlled, double-blind design
Participants from ULTIMATE I and II continued or switched to ublituximab in the open-label extension study
Primary outcomes included annualized relapse rate, confirmed disability progression, and safety measures.
Over 70% of participants continued treatment with ublituximab at 5 years.
Annualized relapse rate decreased significantly over the years: 0.182 (year 1) to 0.045 (year 5) for switched participants.
Confirmed disability progression at year 5 was 8.0% in ublituximab participants vs 14.3% in switched participants.

Abstract

Importance In the 2-year Study to Assess the Efficacy and Safety of Ublituximab in Participants With Relapsing Forms of Multiple Sclerosis (ULTIMATE) I and II randomized clinical studies, disease activity was significantly reduced with ublituximab vs teriflunomide in participants with relapsing multiple sclerosis (RMS). Objective To evaluate long-term ublituximab clinical efficacy and safety. Design, Setting, and Participants The 2-year, multicenter, randomized, active-controlled, double-blind period (DBP) of the ULTIMATE I and II phase 3 studies occurred September 2017 to November 2020. Enrollment in the ongoing ULTIMATE open-label extension (OLE) study began November 2019; data cutoff for this analysis was January 1, 2024. Intervention ULTIMATE OLE participants continued ublituximab (UBL-UBL) or switched from teriflunomide to ublituximab (TER-UBL). Main Outcomes and Measures Efficacy (annualized relapse rate ARR, 24-week confirmed disability progression CDP24, and 24-week confirmed disability improvement CDI24) and safety were key outcomes. Results Of 985 adults with RMS who completed ULTIMATE I and II, 851 enrolled in the ULTIMATE OLE and were included in the analysis. On DBP completion, more than 85% of participants (UBL-UBL, 422 of 494; TER-UBL, 429 of 491) entered the OLE, of whom more than 70% (UBL-UBL, 297 of 422; TER-UBL, 327 of 429) continued taking ublituximab at year 5 (OLE year 3) at data cutoff, making up the analysis population (mean SD age, 38.5 9.7 years; 532 female 62.5%). TER-UBL participants experienced a 58.4% ARR reduction at 1 year after the switch (0.182 vs 0.076; rate ratio, 0.42; 95% CI, 0.29-0.60; P lt; .001), and ARR continued to decrease to 0.048 (year 4) and 0.045 (year 5). UBL-UBL participants had further ARR reductions after the DBP (0.053, 0.032, and 0.020 for years 3, 4, and 5, respectively). At year 5, CDP24 was 8.0% in UBL-UBL participants vs 14.3% in TER-UBL participants ( P = .01), and CDI24 was 17.0% in UBL-UBL participants vs 12.2% in TER-UBL participants ( P = .02). Adverse events were consistent with the established safety profile from pivotal trials, with exposure-adjusted incidence rates per 100 participant-years of serious infections (excluding COVID events) of 2.10 (UBL-UBL) and 2.58 (TER-UBL). On average, immunoglobulin levels remained above the lower limit of normal, and no significant differences in serious infection rates were observed regardless of immunoglobulin level. Conclusions and Relevance Results reveal that sustained clinical benefits were observed with 5 years of ublituximab treatment: ARR in year 5 showed 1 relapse per 50 participant-years of ublituximab treatment and 92% of UBL-UBL participants remained free from CDP24. Results confirm long-term ublituximab benefits and early initiation of high-efficacy treatment. Trial Registration ClinicalTrials.gov Identifier: NCT04130997

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