Five-Year Ublituximab Efficacy Sustained in Relapsing MS Trial
Key Clinical Summary
- In a 5-year analysis of 985 adults with relapsing multiple sclerosis (RMS), continuous ublituximab significantly reduced annualized relapse rate (ARR) and confirmed disability progression compared with delayed initiation.
- Participants switching from teriflunomide to ublituximab experienced a 58.4% ARR reduction within 1 year of transition.
- Long-term safety remained consistent, with no new safety signals and stable immunoglobulin levels.
Ublituximab provided sustained reductions in disease activity and disability progression over 5 years in adults with relapsing multiple sclerosis (RMS), according to findings published in JAMA Neurology. The data derive from the ongoing open-label extension (OLE) of the phase 3 ULTIMATE I and II trials and support early initiation of high-efficacy therapy in RMS.
Study Findings
The original 2-year ULTIMATE I and II randomized, double-blind trials demonstrated significant reductions in disease activity with ublituximab versus teriflunomide. Of 985 adults who completed the double-blind period, 851 entered the OLE. At year 5, more than 70% remained on ublituximab (mean age 38.5 years; 62.5% female).
Participants initially assigned to teriflunomide who switched to ublituximab (TER-UBL) experienced a 58.4% reduction in ARR at 1 year post-switch (0.182 vs 0.076; rate ratio 0.42; 95% CI, 0.29–0.60; P < .001). ARR continued to decline to 0.048 at year 4 and 0.045 at year 5.
Participants treated continuously with ublituximab (UBL-UBL) demonstrated further reductions in ARR beyond the double-blind period, reaching 0.053, 0.032, and 0.020 at years 3, 4, and 5, respectively. By year 5, ARR corresponded to approximately 1 relapse per 50 participant-years.
In the UBL-UBL group, 24-week confirmed disability progression (CDP24) occurred in 8.0% of participants compared with 14.3% of TER-UBL participants (P = .01). Confirmed disability improvement (CDI24) was observed in 17.0% and 12.2%, respectively (P = .02). At year 5, 92% of continuously treated participants remained free from CDP24.
Exposure-adjusted serious infection rates per 100 participant-years were 2.10 (UBL-UBL) and 2.58 (TER-UBL), excluding COVID-19 events. No significant differences in serious infection rates by immunoglobulin level were observed, and immunoglobulin levels remained above the lower limit of normal on average.
Clinical Implications
The magnitude of ARR reduction after switching from teriflunomide suggests that escalation to high-efficacy anti-CD20 therapy can rapidly attenuate inflammatory disease activity. However, participants who began ublituximab at trial outset experienced numerically better disability outcomes at 5 years, underscoring the potential advantage of early intervention.
The absence of new safety signals over prolonged exposure is also clinically relevant. Stable immunoglobulin levels and low serious infection rates provide reassurance regarding long-term B-cell–depleting therapy in appropriately monitored patients.
For clinicians managing RMS, these findings contribute to the growing evidence base supporting early use of high-efficacy therapies to optimize long-term neurologic outcomes.
Expert Commentary
“Studies demonstrating the long-term efficacy and safety of disease-modifying therapies (DMTs) are important given the lifelong and progressive nature of MS and the corresponding potential for long-term anti-CD20 monoclonal antibody treatment,” wrote Bruce A. C. Cree, MD, PhD, MAS, Weill Institute for Neurosciences, Department of Neurology, University of California, San Francisco, and study coauthors.
“Balancing the safety and efficacy of MS DMTs is valuable for long-term management of people with MS, and the results of the current interim analysis highlight the improved efficacy and safety of ublituximab over 5 years of treatment in participants with RMS,” they concluded.
