Rethinking Progressive MS Studies to Better Include Advanced Patients: Gavin Giovannoni, MBBCh, PhD, FCP, FRCP, FRCPath

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"ORATORIO-HAND changes how we design progressive MS trials—event-driven, composite endpoints, and more inclusive of advanced patients who’ve too often been left out of research."

There were several notable late-breaking presentations at the 2025 European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) Congress, including findings from the phase 3b ORATORIO-HAND trial (NCT04035005) of ocrelizumab (Ocrevus; Genentech). Led by Gavin Giovannoni, MBBCh, PhD, FCP, FRCP, FRCPath, the trial comprised a wide net of patients with primary progressive multiple sclerosis (PPMS), including those with more advanced MS, defined as Expanded Disability Status Scale (EDSS) scores of 7.0-8.0.

All told, ocrelizumab met its primary end point, with 32.7% of patients experiencing confirmed disability progression (CDP) at 12 weeks compared with 40.4% of those on placebo (HR, 0.70; 95% CI, 0.57–0.86; RR, 30%; P = .0007). In addition, 16.7% of ocrelizumab-treated patients had confirmed progression in hand function on the 9-Hole Peg Test (RR, 41%; P = .0002), an end point Giovannoni believes should be used more frequently. Above all, the ORATORIO-HAND trial confirmed findings from the previously completed ORATORIO study (NCT01194570), and provided new evidence of benefit in an older, more disabled patient population.

Giovannoni, a professor of neurology at Barts and London School of Medicine and Dentistry, sat down with NeurologyLive® to discuss the key lessons from ORATORIO-HAND and their implications for future MS trial design. He explained how the trial, which uniquely enrolled patients with advanced primary progressive MS, introduced an event-driven model and emphasized upper-limb function—measured by the Nine-Hole Peg Test—over traditional EDSS endpoints that are less sensitive in late-stage disease. Giovannoni noted that this approach allows for smaller, shorter, and more ethically efficient trials while including patients who have historically been excluded due to high disability scores.

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REFERENCE
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.