Treatment with ocrelizumab helps delay progression of disability, especially of the upper limb, in a broad population of patients with primary progressive multiple sclerosis (PPMS), including those who are older and have more advanced disease, according to the phase 3b ORATORIO-HAND trial.
Compared with placebo, ocrelizumab was associated with a 30-percent reduction in the risk of 12-week composite confirmed disability progression—the primary endpoint (hazard ratio [HR], 0.70, 95 percent confidence interval [CI], 0.57–0.86; p=0.0007). The corresponding number needed to treat was 13. [Lancet 2026;407:2195-2207]
The reduced risk of disability progression with ocrelizumab vs placebo was consistently observed whether progression was measured by Nine-Hole Peg Test (9HPT) scores (HR, 0.59; p=0.0002) or by Expanded Disability Status Scale (EDSS) scores (HR, 0.67; p=0.0013).
“Although multiple observational studies have shown clinical benefits with ocrelizumab for patients with PPMS and an EDSS score of more than 6.5, this study provides the first randomized, controlled evidence of a disease-modifying therapy in patients with advanced PPMS, with benefits extending to delaying and even preventing worsening of hand function,” according to the investigators led by Prof Gavin Giovannoni from Queen Mary University of London, London, UK.
“[This] is crucial for maintaining independence and quality of life and might be of relevance to clinical decision making, subject to patient and clinician goals,” Giovannoni and colleagues added.
Patient population
The findings are in line with those reported in the pivotal ORATORIO trial, with ocrelizumab treatment resulting in a significant reduction in overall disability progression and worsening of the upper limb function. [N Engl J Med 2017;376:209-220; Mult Scler 2018;24:1862-1870]
“ORATORIO-HAND was designed to prospectively address the key eligibility gaps of the ORATORIO trial, which excluded patients older than 55 years or with an EDSS score of more than 6.5,” the investigators said.
Key eligibility criteria in ORATORIO-HAND included age 18–65 years, a diagnosis of PPMS as specified in the 2017 McDonald criteria, documented history or presence at screening of elevated IgG index or one or more IgG oligoclonal bands, an EDSS score of at least 3–8, and the ability to complete the 9HPT in more than 25 s (mean of the two hands) and within 240 s with each hand. The disease duration had to be <20 years for those with an EDSS score of 7–8, <15 years with an EDSS score of 5.5–6.5, and <10 years with an EDSS score of ≤5.
A total of 1,013 patients (56 percent female, 93 percent White) met the eligibility criteria, of which 27 percent were age ≥55 years and 16 percent had an EDSS score of >6.5. These patients were randomly assigned to receive treatment with either intravenous ocrelizumab 600 mg (n=505) or placebo (n=508) every 6 months for 144 weeks or until a prespecified number of progression events occurred.
“Compared with the ORATORIO population, [the ORATORIO-HAND] population had a 44-percent longer median disease duration and greater hand function impairment, taking a mean of 7 s longer to do the 9HPT,” according to Giovannoni and colleagues.
Benefit across subgroups
Among patients with MRI activity at baseline, the risk of 12-week composite confirmed disability progression was lower by 55 percent with ocrelizumab vs placebo (HR, 0.45, 95 percent CI, 0.31–0.64; p<0.0001).
Ocrelizumab was also associated with a significant risk reduction in 12-week composite confirmed disability progression among patients with an EDSS score >6.5 (HR, 0.51) and those aged ≤55 years (HR, 0.65).
“Although a significant treatment benefit was not observed in patients older than 55 years, those with an EDSS score of more than 6.5 showed a highly robust treatment effect. In this subgroup, approximately 25 percent were aged 55 years or older,” the investigators said. “These results challenge notions of a rigid therapeutic ceiling based on age or disease stage.”
Safety profile
The adverse event profile was balanced between ocrelizumab and placebo and consistent with the known safety profile for ocrelizumab, Giovannoni and colleagues noted.
Infusion-related reactions were more common in the ocrelizumab group than in the placebo group (21 percent vs 4 percent), but these were mostly mild or moderate in severity and were resolved. Serious adverse events (AEs) occurred in 13 percent of patients each in the ocrelizumab and placebo groups. AEs led to treatment discontinuation in 3 percent and 2 percent of patients in the respective groups.
In each treatment group, malignancies were documented in 1 percent of patients and deaths occurred in 2 percent.
Clinical implications
“The demonstration of ocrelizumab’s efficacy in ORATORIO-HAND solidifies the therapeutic rationale for treating PPMS, extending the window of opportunity to patients with advanced disease,” according to the investigators.
“These findings are of great importance for the multiple sclerosis community, as they extend the window of opportunity for treatment in patients of older age and with advanced disease, and potentially across the entire spectrum of overlapping multiple sclerosis phenotypes,” they added.