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) in older patients and 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 9-Hole Peg Test (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 patients who are more disabled, ORATORIO-HAND allowed enrolment of older participants (≤65 years of age) with EDSS scores of 3.0–8.0. Immunosuppressive treatment was permitted except for anti-CD20 medication, 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-HPT (CDP-9HPT) or worsening on the EDSS (CDP-EDSS). Secondary endpoints included time to 12-week and 24-week CDP in 9HPT and EDSS, as well as the annual rate of change in T2 lesion volume or total brain volume.

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

Ocrelizumab was associated with a 30% relative risk reduction (RRR) in the composite 12-week CDP, as measured by EDSS or 9HPT. Event rates were 32.7% in the ocrelizumab group and 40.4% in the placebo group (see Figure). Significant reductions were also observed in the individual components of composite CDP: 16.7% versus 24.9% for 12-week 9HPT (RRR 41%; P=0.0002) and 23.0% versus 30.8% for EDSS (RRR 33%; P=0.0013). Results were similar for 24-week 9HPT and EDSS. Prof. Giovannoni suggested that the 9HPT may be a more sensitive outcome measure than the EDSS in this patient population. 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 participants, a reduced risk of disability progression was observed. T2 lesion volume decreased in ocrelizumab-treated participants, but no difference in brain volume change was observed in the placebo group.

Figure: Risk of reaching the primary composite endpoint of CDP [1]



CDP, confirmed disability progression.

The safety profile was comparable between groups. Prof. Giovannoni reported no clear malignancy signal with ocrelizumab. ORATORIO-HAND is the first positive randomised MS trial 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):209–20.

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Posted on 25 November 202525 November 2025