MUSETTE & GAVOTTE
(2026)Objective
To assess whether a bodyweight-adjusted higher dose of ocrelizumab (1200 mg or 1800 mg) is superior to the approved 600 mg dose for controlling disability progression in relapsing (MUSETTE) and primary progressive (GAVOTTE) multiple sclerosis.
Study Summary
• GAVOTTE (PPMS): 12-week cCDP occurred in 47% (235/500) with high-dose vs 49% (124/253) with 600 mg ocrelizumab (HR 0.95, 95% CI 0.76–1.18; p=0.64)
• High-dose ocrelizumab did NOT further improve disability progression control in either RMS or PPMS
• Safety profiles were comparable between high-dose and 600 mg arms; no new safety concerns identified
• MUSETTE showed the lowest annualised relapse rate ever observed in a controlled phase 3 RMS trial
Intervention
High-dose ocrelizumab (1200 mg if baseline body weight <75 kg, or 1800 mg if ≥75 kg) by IV infusion every 24 weeks, compared with the approved 600 mg dose every 24 weeks.
Inclusion Criteria
Age 18–55 years; diagnosis of RMS (MUSETTE: RRMS or active SPMS, EDSS 0.0–5.5, ≥2 relapses in prior 2 years or 1 relapse in prior year) or PPMS (GAVOTTE: per 2017 McDonald criteria, EDSS 3.0–6.5).
Study Design
Arms: MUSETTE: High-dose ocrelizumab (n=577) vs 600 mg ocrelizumab (n=283); GAVOTTE: High-dose ocrelizumab (n=500) vs 600 mg ocrelizumab (n=253)
Patients per Arm: MUSETTE: 577 vs 283; GAVOTTE: 500 vs 253
Outcome
• GAVOTTE 12-week cCDP: 47% (high-dose) vs 49% (600 mg), HR 0.95 (95% CI 0.76–1.18), p=0.64 — NOT significant
• MUSETTE adverse events: 96% (high-dose) vs 94% (600 mg); serious AEs 13% vs 12%; fatalities 1% vs <1%
• GAVOTTE adverse events: 90% (high-dose) vs 91% (600 mg); serious AEs 12% vs 11%; fatalities <1% vs 1%
• Findings confirm favourable benefit–risk profile of approved 600 mg ocrelizumab dose
Bottom Line
In both RMS (MUSETTE) and PPMS (GAVOTTE), bodyweight-adjusted high-dose ocrelizumab (1200/1800 mg) did NOT further improve control of disability progression compared with the approved 600 mg dose, despite greater peripheral B-cell depletion. Safety was comparable. The standard 600 mg dose remains the appropriate choice for both RMS and PPMS.
Major Points
- Neither MUSETTE (RMS) nor GAVOTTE (PPMS) met its primary endpoint of superiority over the 600 mg dose
- MUSETTE 12-week cCDP: 34% vs 37% (HR 0.93, 95% CI 0.73–1.18; p=0.53)
- GAVOTTE 12-week cCDP: 47% vs 49% (HR 0.95, 95% CI 0.76–1.18; p=0.64)
- Greater peripheral B-cell depletion with the high dose did NOT translate into improved clinical outcomes
- Safety profiles were similar between dose groups; no new safety concerns identified
- MUSETTE showed the lowest annualised relapse rate ever observed in a controlled phase 3 RMS trial
- Findings suggest disability accumulation is driven largely by progression independent of relapse activity (PIRA) and may require targeting CNS-compartmentalised B cells or non-B-cell mechanisms
- Circulating B-cell concentration alone may be an insufficient measure to guide ocrelizumab treatment decisions
Study Design
- Study Type
- Phase 3b, multicentre, randomised, double-blind, parallel-group, active-controlled superiority trials
- Randomization
- Yes
- Blinding
- Double-blind (patients, investigators, and sponsor blinded to treatment allocation)
- Sample Size
- 1613
- Follow-up
- MUSETTE: median 184.4 weeks; GAVOTTE: median 174.1 weeks (event-driven, minimum 120 weeks)
- Centers
- 271
- Countries
- MUSETTE: 21 countries, GAVOTTE: 22 countries
Primary Outcome
Definition: Time to onset of 12-week composite confirmed disability progression (cCDP), defined as first occurrence of: increase in EDSS ≥1.0 point from baseline (if baseline ≤5.5) or ≥0.5 points (if baseline >5.5); OR ≥20% increase in T25FWT from baseline; OR ≥20% increase in 9HPT from baseline
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| MUSETTE: 37% (104/283) with 600 mg; GAVOTTE: 49% (124/253) with 600 mg | MUSETTE: 34% (198/577) with high-dose; GAVOTTE: 47% (235/500) with high-dose | 0.93 (MUSETTE: 0.73–1.18; GAVOTTE: 0.76–1.18) | MUSETTE p=0.53; GAVOTTE p=0.64 |
Limitations & Criticisms
- Despite achieving greater peripheral B-cell depletion, the high dose did not translate to improved clinical outcomes — suggesting circulating B-cell levels alone may not be an adequate biomarker for treatment optimization
- Pre-existing favourable control of disease activity with the 600 mg dose may have limited the ceiling for incremental benefit (lowest ARR ever observed in a phase 3 RMS trial)
- Protocol deviations were notable: 19% of MUSETTE and 24% of GAVOTTE participants had major protocol deviations, though balanced between arms
- Trials cannot address whether targeting CNS-compartmentalised B cells (which may not be reflected by peripheral B-cell depletion) would yield benefit
Citation
Lancet 2026; 407: 2180–94