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ULTIMATE I/II Extension

Five Years of Ublituximab in Multiple Sclerosis: ULTIMATE I and II Open-Label Extension Study

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Year of Publication: 2026

Authors: Cree BAC, Fox E, Hartung HP, ..., Steinman L

Journal: JAMA Neurology

Citation: JAMA Neurol. 2026;83(4):348-358. doi:10.1001/jamaneurol.2026.0007

Link: https://doi.org/10.1001/jamaneurol.2026.0007

Clinical Question

Does continuous ublituximab treatment over 5 years sustain clinical benefits and maintain a favorable safety profile in relapsing multiple sclerosis?

Bottom Line

Five years of ublituximab in relapsing MS yields sustained, low disease activity (year-5 ARR equivalent to ~1 relapse per 50 participant-years), with 92% of continuously treated participants free from 24-week confirmed disability progression and no new safety signals — supporting early initiation of high-efficacy anti-CD20 therapy.

Major Points

  • TER-UBL participants achieved a 58.4% ARR reduction in the first year after switching (0.182 vs 0.076; RR 0.42; 95% CI 0.29-0.60; P<.001).
  • ARR continued to decrease over OLE: UBL-UBL 0.053, 0.032, 0.020 in years 3, 4, 5; TER-UBL 0.076, 0.048, 0.045.
  • At year 5, only 1 relapse occurred per 50 participant-years of continuous ublituximab.
  • CDP24 at year 5: 8.0% UBL-UBL vs 14.3% TER-UBL (P=.01) — 92% of continuously treated patients free from confirmed disability progression.
  • CDI24 at year 5: 17.0% UBL-UBL vs 12.2% TER-UBL (P=.02), favoring early initiation.
  • Safety consistent with pivotal trials; no new signals. Serious infection EAIR/100 PY 2.10 (UBL-UBL) and 2.58 (TER-UBL), excluding COVID events.
  • Mean immunoglobulin levels remained above lower limit of normal, and serious infection rates did not differ by Ig level.

Design

Study Type: Open-label extension of two identical phase 3, multicenter, randomized, double-blind, active-controlled trials

Randomization:

Blinding: Open-label (extension); double-blind during the prior 96-week core period

Allocation: Non-randomized in OLE; all participants received ublituximab

Enrollment Period: DBP September 2017 to November 2020; OLE enrollment began November 2019; data cutoff January 1, 2024

Follow-up Duration: Up to 5 years of ublituximab exposure (2-year DBP + up to 3-year OLE)

Centers: 104

Countries:

Sample Size: 985

Analyzed: 851

Analysis: Modified intention-to-treat (mITT) for efficacy; safety population included all participants receiving ≥1 ublituximab dose. ARR analyzed by negative binomial regression GEE with treatment, region, baseline EDSS strata, year, and treatment × year as covariates and log(years of treatment) as offset. CDP24 and CDI24 estimated by Kaplan-Meier; HRs from Cox regression. OLE analyses were post hoc.

Registration: NCT04130997

Inclusion Criteria

  • Adults with relapsing multiple sclerosis (RMS)
  • Completion of the ULTIMATE I or ULTIMATE II 96-week double-blind period
  • Election to enroll in the ULTIMATE open-label extension

Baseline Characteristics

CharacteristicUBL-UBLTER-UBLOverall
N entered OLE422429
No Gd+ T1 lesions at OLE baseline (%)98.682
EDSS ≤3.5 at OLE baseline (%)90.183.4
Mean age (years)38.5
Female (n, %)532 (62.5%)
Male (n, %)319 (37.5%)

Arms

FieldUBL-UBL (continued ublituximab)Control
N422429
InterventionUblituximab 150 mg IV on day 1, 450 mg IV at week 3, then 450 mg IV every 24 weeks (continuation from DBP)Teriflunomide during DBP, then switched to ublituximab 150 mg IV day 1, 450 mg IV week 3, then 450 mg IV every 24 weeks in OLE
DurationUp to 5 years total (2-year DBP + up to 3-year OLE)Up to 3 years of ublituximab in OLE after 2-year teriflunomide DBP

Outcomes

OutcomeTypeControlInterventionHR / OR / RRP-value
Annualized relapse rate (ARR) — relapse adjudication panel–confirmed relapses per participant-yearPrimaryTER-UBL year 5 ARR 0.045 (post-switch year 1 ARR 0.076; pre-switch 0.182)UBL-UBL year 5 ARR 0.020 (years 3, 4, 5: 0.053, 0.032, 0.020)0.42<.001 (TER-UBL pre vs post-switch)
SecondaryTER-UBL 14.3%UBL-UBL 8.0%.01
SecondaryTER-UBL 12.2%UBL-UBL 17.0%.02
Secondary92%
Safety
SafetyOn average remained above the lower limit of normal; no significant differences in serious infection rates by Ig level
SafetyConsistent with established pivotal trial profile; no new safety signals with prolonged treatment
COVID-19 and COVID-19 pneumonia terms excluded from analysis due to pandemic-related biasAdverse
125 did not complete year 5 (36 active, 26 withdrew, 23 COVID-19 reason, 21 AE, 2 investigator/sponsor decision, 2 lost to follow-up, 2 noncompliance, 1 lack of efficacy, 1 malignancy, 1 pregnancy, 1 death, 9 other)Adverse
102 did not complete year 5 (40 withdrew, 29 active, 13 AE, 8 COVID-19 reason, 4 lost to follow-up, 3 lack of efficacy, 2 pregnancy, 1 investigator/sponsor decision, 1 malignancy, 1 other)Adverse

Subgroup Analysis

No significant differences in serious infection rates observed regardless of immunoglobulin level.

Criticisms

  • Open-label extension design with no concurrent comparator after year 2
  • OLE analyses were post hoc and not prespecified
  • Radiographic (MRI) outcomes not collected for most OLE participants due to COVID-19 pandemic deprioritization of study MRIs
  • Exclusion of COVID-19 and COVID-19 pneumonia AEs limits comparability of infection rates during pandemic period
  • Selection bias: only ~85% of DBP completers entered OLE and ~70% remained at year 5, potentially enriching for tolerators/responders
  • Imbalanced OLE baseline characteristics (more Gd+ lesion-free and lower EDSS in UBL-UBL) reflect carry-over effects from DBP and may bias between-arm comparisons in OLE

Based on: ULTIMATE I/II Extension (JAMA Neurology, 2026)

Authors: Cree BAC, Fox E, Hartung HP, ..., Steinman L

Citation: JAMA Neurol. 2026;83(4):348-358. doi:10.1001/jamaneurol.2026.0007

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