Phase 3b GAVOTTE Trial Reveals No Added Benefit With Higher-Dose Ocrelizumab in Primary Progressive MS

Late-breaking data presented at the 2025 European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) Congress, held September 24-26, in Barcelona, Spain, from the ongoing phase 3b GAVOTTE study (NCT04548999) showed that a higher body-weight–adjusted dose of ocrelizumab (Ocrevus; Genentech) did not did not further slow disease progression compared with the FDA-approved 600-mg intravenous (IV) regimen in patients with primary progressive multiple sclerosis (PPMS).¹

Among 753 patients with PPMS (high dose ocrelizumab, n = 500; ocrelizumab 600-mg n = 253), primary findings revealed that control of disability progression did not improve by increasing the dose above the approved dose of ocrelizumab (HR, 0.95; 95% CI 0.76-1.18; P = .64). Presented by lead author Stephen Hauser, MD, professor of neurology and director of the Weill Institute for Neurosciences at UCSF, results showed that a higher dose of ocrelizumab produced greater depletion of blood CD19+ B cells than the 600-mg dose, with B-cell counts less than or equal to 0.4 cells/µL in 30.8% versus 20.0% of patients, respectively.

The phase 3b, multicenter, randomized, double-blind GAVOTTE study enrolled adults aged 18 to 55 years with PPMS, diagnosed according to the 2017 revised McDonald criteria, who had an Expanded Disability Status Scale (EDSS) score between 3 and 6.5. Participants were randomized 2:1 to receive either a high dose of ocrelizumab—1200 mg for those weighing under 75 kg or 1800 mg for those 75 kg or more—or the approved 600-mg dose, administered every 24 weeks for at least 120 weeks. The primary end point of the trial was time to onset of composite CDP (cCDP), defined as a 12-week confirmed increase in EDSS, at least a 20% decline from baseline on the Timed 25-Foot Walk Test, or at least a 20% decline from baseline on the 9-Hole Peg Test.

Coming into the trial, patients with PPMS received at least 1 infusion of ocrelizumab, and 84.5% had not received prior treatment with any MS disease-modifying therapy. Authors noted that the mean age at baseline was 41.8 years (SD, 9.0); 53.1% were women and 87.5% were White. In addition, the mean baseline EDSS score was 4.7 (SD, 1.2), and the mean time since MS symptom onset and diagnosis were 6.2 (SD, 3.8) and 3.2 (SD, 3.6) years, respectively. These baseline characteristics were consistent with those observed in the prior phase 3 ORATORIO study (NCT01194570) of ocrelizumab.² Investigators also noted that high dose ocrelizumab did not demonstrate a greater benefit on secondary end points on measures of disability, cognition, brain volume, and neurofilament light chain.

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All told, the safety profile was consistent in both treatment arms with the known safety profile of ocrelizumab and had no new safety concerns identified. Rates of infusion-related reactions were similar, and all events resolved, with only 1 reaction occurring on Day 1 in the ocrelizumab 600-mg arm that led to treatment discontinuation. Authors also noted that immunoglobulin level decreases were comparable between the 2 treatment groups. Serious infection rates were similar as well, despite enrollment of the study being conducted during the COVID-19 pandemic from December 2020 to May 2023.

In the study, researchers did not observe any pattern of malignancies. In the high-dose ocrelizumab group (n = 4), reported cancers included basal cell carcinoma (n = 1), breast cancer (n = 1), glioblastoma (n = 1), and invasive ductal breast carcinoma (n = 1). In the 600-mg ocrelizumab group (n = 4), malignancies included pancreatic adenocarcinoma (n = 1), basal cell carcinoma (n = 1), malignant melanoma (n = 1), and prostate cancer (n = 1). Overall, the incidence of malignancies was consistent with real-world data reported in MS and with estimates in the general population.

Ocrelizumab is a recombinant, humanized anti-CD20 monoclonal antibody, approved by the FDA at 600-mg every 6 months for patients living with relapsing MS or PPMS. Authors noted that phase 3b GAVOTTE trial confirmed the favorable benefit-risk profile of the approved 600-mg dose of ocrelizumab for PPMS. Researchers underscored that both high-dose and ocrelizumab 600-mg resulted in control of disability progression similar to that observed in other ocrelizumab related studies such as ORATORIO, CONSONANCE (NCT03523858) and ORATORIO-HAND (NCT04035005).

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REFERENCES
1. Hauser S, Giovannoni G, Kappos L, et al. Efficacy and safety of rituximab versus cladribine in relapsing-remitting multiple sclerosis: Primary results from the NOR-MS randomized controlled phase 3 non-inferiority trial. Presented at ECTRIMS Congress; September 24-26, 2025; Barcelona, Spain. Late-Breaking Abstract O129.
2. Montalban X, Hauser SL, Kappos L, et al. Ocrelizumab versus Placebo in Primary Progressive Multiple Sclerosis. N Engl J Med. 2017;376(3):209-220. doi:10.1056/NEJMoa1606468