Ocrelizumab Demonstrates Efficacy Over Placebo in Phase 3b ORATORIO-HAND Trial of Primary Progressive MS

New late-breaking findings from the phase 3b ORATORIO-HAND trial (NCT04035005) of ocrelizumab (Ocrevus; Genentech) showed that the treatment significantly delayed overall disability progression and worsening of upper limb function in patients with primary progressive multiple sclerosis (PPMS), including those with more advanced stages of the disease.¹

Among 1013 participants (ocrelizumab, n = 505; placebo, n = 508), 32.7% of patients treated with ocrelizumab experienced confirmed disability progression (CDP) at 12 weeks, the primary end point, compared with 40.4% in the placebo group (HR, 0.70; 95% CI, 0.57–0.86; RR, 30%; P = .0007). In individual measures of the composite end point, 16.7% of ocrelizumab recipients versus 24.9% of placebo recipients had confirmed progression in hand function on the 9-Hole Peg Test (9HPT; RR, 41%; P = .0002), and 23.0% versus 30.8% experienced worsening on the Expanded Disability Status Scale (EDSS; RR, 33%; P = .0013).

ORATORIO-HAND trial was a multicenter, randomized, double-blind, placebo-controlled phase 3b study assessing the efficacy and safety of ocrelizumab compared with placebo in patients with PPMS. Eligible patients aged 18 to 65 years with EDSS scores between 3.0 and 8.0 were randomly assigned in a 1:1 ratio to receive either 600 mg of intravenous ocrelizumab or placebo every 6 months for up to 144 weeks, or until at least 340 progression events occurred. The median age was 48 years among patients in the treatment group and 47 years for those in the placebo group. In addition, the median baseline EDSS was 6.0, and the median treatment duration was about 144 weeks for both groups.

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These findings were presented at the 2025 European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) Congress, held September 24-26, in Barcelona, Spain, by lead author Gavin Giovannoni, MBBCh, PhD, FCP, FRCP, FRCPath, professor of neurology at Barts and London School of Medicine and Dentistry. Overall, the data from this study expanded on the original phase 3 ORATORIO trial (NCT01194570), which established ocrelizumab as the first therapy that demonstrated efficacy in PPMS, and provided new evidence of benefit in an older, more disabled patient population.²

Invesigators also conducted a prespecified analysis of the subset of participants with MRI activity at screening or baseline. In this subset group, 26.8% of patients treated with ocrelizumab experienced CDP on the composite end point compared with 45.9% receiving placebo (HR, 0.45; 95% CI, 0.31-0.64; RR, 55%; P <.000). Significant risk reductions of 62% for confirmed progression on 9HPT and 59% for confirmed progression on EDSS were also reported by researchers in this MRI-active subgroup.

Safety outcomes were consistent with the established profile of ocrelizumab. Overall adverse events (AEs) occurred in 74.9% of the ocrelizumab group and 71.1% of the placebo group. Serious AEs were reported in 12.8% and 13.2% of patients, respectively. Infusion-related reactions were more common with ocrelizumab (20.8% vs 4.3%), whereas malignancies occurred in 1.0% versus 0.6% of patients. Infections were reported in 48.4% of the ocrelizumab group and 44.7% of the placebo group, with serious infections in 6.3% and 5.3%. Discontinuation because of AEs was uncommon, occurring in 3.0% of ocrelizumab-treated patients and 2.4% of those receiving placebo.

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REFERENCES
1. Giovannoni G, Airas L, Bove R, et al. Ocrelizumab vs placebo in primary progressive MS: efficacy and safety results of the Phase IIIb ORATORIO-HAND study. Presented at ECTRIMS Congress; September 24-26, 2025; Barcelona, Spain. Late-Breaking Abstract O128.
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