FDA Approves Subcutaneous Formulation of Ocrelizumab for Relapsing and Progressive Multiple Sclerosis

The FDA has approved a new subcutaneous formulation of ocrelizumab (Ocrevus; Roche), a humanized monoclonal antibody designed to target CD20-positive B cells, as a treatment for relapsing forms of multiple sclerosis (MS) and primary progressive MS (PPMS), its original indication. Marketed as Zunovo, this expands on the administration options of ocrelizumab, which was originally approved in 2017 as an infusion.¹

The belief is that a subcutaneous administration of ocrelizumab will provide greater treatment flexibility and additional treatment options for patients and healthcare providers. This was the second approval for subcutaneous ocrelizumab, following the European Commission’s decision to do so in early July.

"Ocrevus Zunovo gives patients and providers another option for receiving Ocrevus, building on a decade of robust safety and efficacy data for Ocrevus in multiple sclerosis," Levi Garraway, MD, PhD, chief medical officer and head of Global Product Development at Genentech, said in a statement. "Today’s approval may offer greater flexibility for healthcare providers and people living with multiple sclerosis, based on their individual treatment needs."

According to the company, the belief is that the first time treatment with the new version could be as little as 55 minutes. Patients looking to go on the this subcutaneous formulation will need to take premedications at least 30 minutes prior to each dose. After the first dose, patients will be monitored by their healthcare provider for at least 60 minutes, with a 15-minute monitoring period following subsequent injections.

Similar to the EU, the FDA’s decision to approve this new 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 intravenous (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.²

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.

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In terms of safety, those on subcutaneous ocrelizumab reported more adverse events (AEs; 73.7%) than the IV group (45.8%). Between the 2 groups, serious AEs were comparable, with a reported rate of 2.5% (n = 3) in the subcutaneous group and 3.4% (n = 4) for the IV group. The difference in AE rates between the groups was primarily driven by nonserious mild and moderate injection reactions, which were deemed nontreatment limiting and resolved on their own, with only a few patients requiring treatmenting with analgesics and antihistamines.

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.

Additional efficacy data showed that both the subcutaneous and IV groups had a single patient report 1 relapse (0.9% of each group), for an unadjusted per year relapse rate of 0.02 for both groups. As for T1 gadolinium-enhancing lesions and T2 lesions, both groups reported similar baseline numbers—the subcutaneous group had 118 and 118, respectively, and the IV group had 118 and 118, respectively. By week 24, the T1 lesion counts were 49 for the subcutaneous group and 52 for the IV group, while T2 lesion counts were 61 and 65 for the 2 patient cohorts, respectively (week 8 adjusted lesion rate, 0.11 for subcutaneous, 0.12 for IV; week 24 adjusted lesion rate, 0.00 for both).

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.³

REFERENCES
1. 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
2. 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.
3. 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.