Ocrelizumab delays disability progression in older patients with PPMS

The ORATORIO-HAND study confirmed the significant efficacy of ocrelizumab in primary-progressive multiple sclerosis (PPMS), including in older patients with more advanced disease. Ocrelizumab was superior to placebo in delaying overall disability progression, as measured by the Expanded Disability Status Scale (EDSS), and in preventing worsening of upper limb function, as measured by the 9HPT.

ORATORIO-HAND (NCT04035005) is only the second positive phase 3 trial in PPMS [1], following its predecessor, ORATORIO [2]. To better assess the impact of ocrelizumab in more disabled patients, ORATORIO-HAND allowed enrolment of older patients (≤65 years) with EDSS scores of 3.0-8.0. Immunosuppressive treatment was permitted, provided a suitable washout period was observed. Prof. Gavin Giovannoni (Queen Mary University of London, UK) explained that participants were randomised 1:1 to receive ocrelizumab 600 mg or placebo every 6 months for 144 weeks, or until ≥340 progression events occurred. The primary endpoint was modified during the trial to a composite endpoint, allowing the study to be shortened by about 2 years. This endpoint was the time to onset of a 12-week confirmed disability progression (CDP) based on either a 20% worsening in the 9-Hole Peg Test (CDP-9HPT) or worsening on the EDSS (CDP-EDSS).

A total of 505 and 508 participants were randomised to ocrelizumab and placebo, respectively. Baseline characteristics were well-balanced: median age 48 (18-66) vs 47 (22-66) years, and median EDSS 6.0 (3.0-8.0) vs 6.0 (2.5-8.0). Median treatment duration was 144 weeks.

Ocrelizumab was associated with a 30% relative risk reduction (RRR) in the composite CDP on EDSS or 9HPT (P=0.0007). Event rates were 32.7% in the ocrelizumab group and 40.4% in the placebo group (HR 0.70; 95% CI 0.57-0.86). Significant reductions were also observed in the individual components: 16.7% vs 24.9% for 9HPT (RRR 41%; P=0.0002) and 23.0% vs 30.8% for EDSS (RRR 33%; P=0.0013). In the MRI-active subgroup (n=368), ocrelizumab achieved a 55% reduction in the primary endpoint (26.8% vs 45.9%; HR 0.45; 95% CI 0.31-0.64). Importantly, even in older and more disabled patients, a reduced risk of disability progression was observed.

The safety profile was comparable between groups. Prof. Giovannoni reported no clear malignancy signal with ocrelizumab. He suggested that the 9HPT may be a more sensitive outcome measure than the EDSS in this patient population. ORATORIO-HAND is the first positive randomised MS trial in MS to employ a composite endpoint.

1. Giovannoni G, et al. Ocrelizumab vs placebo in primary progressive MS: efficacy and safety results of the Phase IIIb ORATORIO-HAND study. O128, ECTRIMS 2025 Congress, 24-26 September 2025, Barcelona, Spain.
2. Montalban X, et al. N Engl J Med. 2017;376(3):209-220.

Medical writing support was provided by Michiel Tent.

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Posted on 29 September 202529 September 2025