Genentech Reports High-Dose Ocrelizumab Fails to Show Additional Benefit in Relapsing MS

According to a new announcement, the phase 3 MUSETTE trial (NCT04544436) evaluating a higher dose of ocrelizumab (Ocrevus; Genentech) for relapsing multiple sclerosis (RMS) failed to show added benefit in slowing disability progression compared with the currently approved 600 mg dose. The MUSETTE trial, which followed patients for at least 120 weeks, demonstrated low and consistent rates of disability progression, aligning with previous pivotal studies of intravenous (IV) ocrelizumab 600 mg.¹

The study, a randomized, double-blind, controlled trial, assessed the efficacy and safety of a high-dose regimen (1200 mg or 1800 mg based on patient weight) against the standard 600 mg dose. The primary end point, a composite measure of confirmed disability progression at 12 weeks, was not met. However, predefined analyses on disease activity showed that the standard 600 mg dose achieved a historically low annualized relapse rate, reinforcing its effectiveness.

“Ocrevus is the first and only B-cell therapy approved for RMS and PPMS, and after more than ten years of treatment, the majority of people with RMS remain free from disease progression,” Levi Garraway, MD, PhD, chief medical officer and head of Global Product Development at Genentech, said in a statement.¹ He emphasized that the findings confirmed the current dosing regimen as optimal for slowing disability progression while also highlighting its impact on relapse rates.

Since its introduction, the company reported that ocrelizumab has become the most prescribed disease-modifying therapy for multiple sclerosis in the United States, with over 400,000 patients treated worldwide. The company has also expanded treatment options with a recently approved subcutaneous formulation of ocrelizumab (Ocrevus Zunovo) designed for patients in centers without IV infrastructure or with capacity limitations.² Additionally, Genentech noted that it is developing an on-body delivery system with a high-concentration formulation for enhanced convenience.

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The FDA’s decision to approve the new subcutaneous formulation was based on findings from the phase 3 OCARINA 2 trial (NCT05232825), a global, randomized study that compared the pharmacokinetics of subcutaneous ocrelizumab with its IV infusion. Overall, the study achieved its primary end point of demonstrating noninferiority of a 920-mg dose of subcutaneous therapy to the 600-mg IV dose.³

Presented at MSMilan 2023, the joint ECTRIMS-ACTRIMS meeting, data from OCARINA 2 showed that treatment with subcutaneous and IV administration led to similar exposure overall over the first 12 weeks of the study for the 116 patients who received each therapy in the study. Investigators recorded a geometric mean ratio comparing both arm’s area under the curve (AUC) of 1.29 (90% CI, 1.23-1.35; subcutaneous AUC weeks 1-12, 3500 µg/mL per day; IV AUC weeks 1-12, 2750 µg/mL per day). Regarding disease activity, 99% of patients experienced no relapses during the study period up to week 24, with 106 and 105 patients in the subcutaneous and IV groups, respectively, reporting none.

Overall, the most common location injection reactions—which occurred in 54 patients (45.8%)—were erythema (29.7%), pain (14.4%), swelling (8.5%), and pruritus (6.8%). Common systemic injection reactions, which occurred in 13 patients (11%), included headache (2.5%) and nausea (1.7%). Throughout OCARINA 2, none of the AEs led to withdrawal in either group.

The optimal dosage for subcutaneous ocrelizumab was identified in OCARINA 1, a phase 1b, dose-escalation, open-label trial. In the study, 131 patients received at least 1 dose of ocrelizumab 1200 mg or 920 mg. Originally, investigators selected 1200 mg as the candidate for subcutaneous dose based on all of the available data; however, 920 mg was subsequently chosen as the final subcutaneous dose. All told, the median overall ocrelizumab subcutaneous treatment duration was 2 years, with 95% of patients treated for at least 1 year with 3 doses of the therapy. Approximately 92.4% of patients were treated with subcutaneous ocrelizumab for 48 weeks.⁴

REFERENCES
1. Genentech Provides Update on Phase III Ocrevus High Dose Study in People With Relapsing Multiple Sclerosis. News Release. Published April 2, 2025. Accessed April 2, 2025. https://www.businesswire.com/news/home/20250402207576/en/Genentech-Provides-Update-on-Phase-III-Ocrevus-High-Dose-Study-in-People-With-Relapsing-Multiple-Sclerosis
2. FDA Approves Ocrevus Zunovo™ as the First and Only Twice-a-Year 10-Minute Subcutaneous Injection for People With Relapsing and Progressive Multiple Sclerosis. Genentech. September 13, 2024. Accessed September 13, 2024. https://finance.yahoo.com/news/fda-approves-ocrevus-zunovo-first-172300395.html
3. Newsome SD. Subcutaneous Ocrelizumab in Patients With Multiple Sclerosis: Results of the Phase III OCARINA II Study. Presented at: MSMilan; October 11-13, 2023; Milan, Italy. POSTER P370.
4. Newsome SD, Goldstick L, Townsend B, et al. Subcutaneous Ocrelizumab in Patients With Multiple Sclerosis: Results of the Phase Ib Dose-Finding OCARINA I Study. Presented at: 2023 MSMilan; October 11-12; Milan, Italy. Abstract P371.