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Five Years of Ublituximab Yields Progressively Lower Relapse Rates and Sustained Disability Stability in Relapsing MS
Continuous ublituximab treatment over five years reduced annualized relapse rate to just 0.020 by year 5, with 92% of continuously treated participants remaining free from 24-week confirmed disability progression. Participants who switched from teriflunomide to ublituximab also showed meaningful and sustained improvement, though disability outcomes at year 5 favored those who had started ublituximab earlier.
What Was Studied
This study examined whether the clinical benefits of ublituximab, an anti-CD20 monoclonal antibody that depletes B cells, are maintained and continue to improve over an extended treatment period of up to five years in adults with relapsing forms of multiple sclerosis (RMS). The primary focus was on long-term annualized relapse rate trajectory, confirmed disability progression, and the safety profile associated with sustained B-cell depletion.
How It Was Studied
This was an open-label extension (OLE) of the phase 3 ULTIMATE I and II randomized controlled trials, which had originally compared ublituximab to teriflunomide over a two-year double-blind period. Of 985 adults with RMS who completed the parent trials, 851 enrolled in the OLE, with data collected through January 1, 2024. Participants either continued ublituximab uninterrupted (UBL-UBL, n=422 at OLE entry) or switched from teriflunomide to ublituximab upon entering the OLE (TER-UBL, n=429 at OLE entry). By year 5, approximately 70% of enrolled participants in each group remained on treatment and were included in the analysis, representing a multicenter international cohort with a mean age of 38.5 years and 62.5% female.
What Was Observed
- Switching to ublituximab produced an immediate and sustained reduction in relapses. Among TER-UBL participants, the annualized relapse rate dropped by approximately 58% in the first year after switching (from 0.182 to 0.076; rate ratio 0.42, 95% CI 0.29–0.60; P < .001), and continued declining to 0.048 by year 4 and 0.045 by year 5, indicating persistent suppression of inflammatory disease activity.
- Continuous ublituximab treatment produced progressively lower relapse rates over time. UBL-UBL participants had ARRs of 0.053, 0.032, and 0.020 at years 3, 4, and 5 respectively — equivalent to roughly one relapse per 50 participant-years by the final year of follow-up, suggesting ongoing biological benefit with uninterrupted treatment.
- Early initiation of ublituximab was associated with better disability outcomes at five years. Confirmed disability progression at 24 weeks (CDP24) occurred in 8.0% of UBL-UBL participants versus 14.3% of TER-UBL participants (P = .01), while confirmed disability improvement at 24 weeks (CDI24) was achieved by 17.0% of UBL-UBL participants versus 12.2% of TER-UBL participants (P = .02), indicating a measurable advantage for those who started high-efficacy therapy sooner.
- The long-term safety profile remained consistent with what was observed in the pivotal trials. Serious infection rates (excluding COVID-19 events) were 2.10 per 100 participant-years in UBL-UBL participants and 2.58 in TER-UBL participants. Mean immunoglobulin levels stayed above the lower limit of normal throughout, and no significant increase in serious infections was detected in participants with lower immunoglobulin levels.
Why This Matters
These five-year data represent an extended longitudinal record for ublituximab in RMS, demonstrating that sustained B-cell depletion does not appear to plateau in its benefit — relapse rates continued to decline annually in continuously treated participants. The disability outcomes further suggest that the timing of treatment initiation carries long-term consequences, with earlier ublituximab exposure associated with lower rates of progression and higher rates of improvement at year 5.
How to Read This Result
While the findings are directionally strong and internally consistent, the open-label extension design, the absence of a placebo arm during the OLE phase, and attrition of roughly 30% by year 5 introduce the possibility that the remaining participants are a healthier or more treatment-responsive subset, which may lead to an optimistic picture of long-term efficacy.
Limitations
The open-label design of the extension phase removes blinding and introduces the potential for observational bias in outcome assessment. No placebo control was maintained during the OLE, making it impossible to isolate ublituximab’s effect from natural disease course or regression to the mean. Dropout of approximately 30% by year 5 raises concerns about selection bias, as participants who remained on treatment may not represent the full range of outcomes experienced by the original trial population. Additionally, the January 2024 data cutoff may not fully capture rare long-term safety events that could emerge with continued follow-up.