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Ocrelizumab Reduces Disability Progression by 30% in Broader PPMS Population
In a large phase 3b randomised controlled trial, ocrelizumab reduced the risk of 12-week composite confirmed disability progression by approximately 30% compared with placebo in patients with primary progressive multiple sclerosis, including older individuals and those with more advanced disease (HR 0.70, 95% CI 0.57–0.86; p=0.0007). The treatment effect was substantially stronger in the MRI-active subgroup, where a 55% risk reduction was observed (p<0.0001).
What Was Studied
The ORATORIO-HAND trial investigated whether ocrelizumab could delay disability progression in a deliberately broad population of PPMS patients — specifically those who are older or have more advanced neurological impairment — groups that had been underrepresented in earlier pivotal trials. The primary endpoint was time to onset of 12-week composite confirmed disability progression (12W-cCDP), capturing deterioration in either upper limb function via the 9-Hole Peg Test or overall disability via the Expanded Disability Status Scale (EDSS), evaluated both across the full trial population and within an MRI-active subgroup.
How It Was Studied
ORATORIO-HAND was a multicentre, double-blind, randomised, placebo-controlled phase 3b study conducted across 138 sites in 22 countries. Adults aged 18–65 years with confirmed PPMS and an EDSS score ranging from 3.0 to 8.0 — a range encompassing moderate to severe disability — were enrolled, with 1,013 participants randomly assigned in a 1:1 ratio to receive either intravenous ocrelizumab 600 mg or matched placebo every six months for up to 144 weeks. Rigorous blinding was maintained by separating efficacy and safety assessment responsibilities between investigators, using centrally masked MRI reading, and concealing laboratory values that might reveal treatment allocation from site personnel until the primary analysis was complete.
What Was Observed
- Overall disability progression was significantly reduced with ocrelizumab. Confirmed composite disability progression at 12 weeks occurred in 33% of patients on ocrelizumab compared with 40% on placebo — approximately a 30% lower relative risk of reaching this milestone (HR 0.70, 95% CI 0.57–0.86; p=0.0007). This effect was statistically robust and consistent with a clinically meaningful delay in disease worsening.
- Patients with MRI activity at baseline showed a markedly larger treatment benefit. In the prespecified MRI-active subgroup, the relative risk reduction reached 55% (p<0.0001), suggesting that detectable inflammatory disease activity at baseline identifies individuals who derive a particularly strong response to ocrelizumab even in the context of progressive disease.
- Overall infection rates were marginally higher with ocrelizumab but largely attributable to COVID-19. Infections were reported in 48% of ocrelizumab-treated patients versus 45% on placebo; however, after excluding COVID-19 infections, rates were virtually identical between groups (38% vs 37%), indicating no meaningful excess infectious burden from the drug itself under contemporary conditions.
- Serious adverse events and serious infections occurred at comparable rates across both treatment arms. The overall safety profile was described as manageable and broadly consistent between groups, with no new safety signals identified in this broader, more vulnerable PPMS population.
Why This Matters
The original ORATORIO trial established ocrelizumab’s efficacy in PPMS, but enrolled a relatively restricted patient population. ORATORIO-HAND specifically targeted older patients and those with higher disability scores — populations who represent a substantial proportion of people living with PPMS but for whom treatment evidence was limited. Demonstrating that ocrelizumab delays disability progression, with particular strength in hand function outcomes, in patients with EDSS scores up to 8.0 substantially widens the evidence base for treatment decision-making in advanced disease stages.
How to Read This Result
This is a well-designed, large, multinational phase 3b trial with a robust and statistically significant primary result; however, the study remains ongoing and data beyond the 144-week treatment window — including open-label extension outcomes and longer-term safety — have not yet been reported.
Limitations
The abstract does not explicitly report study limitations.