Lancet
Ocrelizumab: first drug to slow advanced progressive MS
Clinical takeaway: Ocrelizumab is FDA-approved for primary progressive MS, and these results support its use in older and more disabled patients. Treatment benefit was weakest without MRI evidence of disease activity.
Primary progressive MS affects 10% to 15% of people with the condition, and treatment options have long been limited. Whether patients who are further along in the disease still benefit from treatment had been an open question, in part because earlier trials capped enrollment at age 55 and at moderate disability. ORATORIO-HAND was built to test treatment in exactly the patients those trials left out.
Ocrelizumab reduced the risk of confirmed disability progression by 30% versus placebo. The effect was stronger on hand and arm function than on walking: a 41% reduction in 9-Hole Peg Test progression compared with 33% on the standard disability scale. That distinction matters because patients with worsening MS rank hand function above mobility, citing independence in grooming and toileting.
Among those with MRI activity at baseline, ocrelizumab cut progression risk by 55%. In the most disabled patients at enrollment, it cut risk by 49%. Among patients still ambulatory at baseline, treatment reduced the risk of needing a wheelchair by 52%.
The prespecified analysis showed no significant benefit in patients without MRI activity, though a post-hoc analysis using a narrower definition suggested benefit there as well. And unlike the original ORATORIO trial, this study found no significant effect on brain volume loss, a difference the authors could not fully explain.
ORATORIO-HAND is a phase 3b, double-blind, randomized trial of 1,013 patients with PPMS across 138 sites in 22 countries, enrolled between August 2019 and December 2024. Patients aged 18 to 65 with disability scores spanning early to advanced disease received ocrelizumab 600 mg or placebo every 6 months for up to 144 weeks. Roughly 27% were 55 or older and about 15% had advanced disability, a population with disease duration about 44% longer than in the original ORATORIO trial.
Nearly a third of treated patients still progressed at 12 weeks, though fewer did under longer confirmation windows that better capture irreversible decline. Several subgroup analyses were underpowered, and long-term data in older and more disabled patients are not yet available.
"These findings are important because they show that treatment can make a meaningful difference to people with more advanced forms of MS and can help preserve hand and arm function," said Gavin Giovannoni, MD, lead author and professor of neurology at Queen Mary University of London. "Our study suggests we should think differently about what successful treatment looks like in advanced MS and that we shouldn't assume a lack of benefit in certain groups."
Source: Giovannoni G. Lancet. 2026 May 28. Efficacy and safety of ocrelizumab in primary progressive multiple sclerosis, including older patients and those with more advanced disease (ORATORIO-HAND): a multicentre, double-blind, randomised, placebo-controlled, phase 3b study