BARCELONA, Spain — A new phase 3 trial of ocrelizumab in primary progressive multiple sclerosis (PPMS) showed meaningful benefit in older patients and those with advanced disease — a first for this patient population.

“I hope these data change how we think about MS,” reported the principal investigator, Gavin Giovannoni, MBBCh, PhD, professor of neurology of the Institute of Neurology at University College London, London, England. The message, he added, is “don’t give up on treatment of MS for people in a wheelchair.”

Giovannoni, presented the results at late-breaking session on September 26 at Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) 2025.

Older, More Disabled Population

The impact of ocrelizumab in older and more disabled people with PPMS is not fully understood, particularly in preventing worsening of hand function — a critical aspect of self-care and independence — highlighting the need for a dedicated study in this population.

To address the unknown effects of ocrelizumab in older and more disabled patients with PPMS — particularly on hand function — this phase 3b, randomized, placebo-controlled trial assigned participants to receive either ocrelizumab or placebo.

The multinational trial, known as ORATORIO-HAND, randomly assigned 1013 patients with PPMS to receive ocrelizumab 600 mg or placebo every 6 months for up to 144 weeks to evaluate its efficacy and safety.

Median follow-up is approaching 3 years, with approximately 85% of patients receiving ocrelizumab and 79% of patients receiving placebo still enrolled at the most recent data assessment.

The study’s primary endpoint was a composite of 12-week confirmed disability progression (CDP), measured either by worsening on the Nine-Hole Peg Test (9-HPT) (≥ 20% from baseline) or by the Expanded Disability Status Scale (EDSS).

Relative to placebo, ocrelizumab showed protection from advancing disease across the primary and multiple secondary endpoints.

Less Disability Progression

For the composite primary endpoint, ocrelizumab reduced the risk for 12-week confirmed disability progression by 30% compared with placebo (hazard ratio [HR], 0.70; P = .0007).

Broken down by components, risk reductions were 41% for CDP-9HPT (HR, 0.59; P = .0002) and 33% for CDP-EDSS (HR, 0.67; P = .0013). When assessed as progression on either 9HPT or EDSS, the overall risk reduction was 55% (HR, 0.45; P < .0001).

Interestingly, the relative benefit was greater among those enrolled in the trial with an EDSS score ≥ 6.5 (HR, 0.47) relative to a lower score (HR, 0.77), a finding that emphasizes the opportunity for a clinical impact in those with advanced disease, said Giovannoni.

However, he noted that an age stratification showed less benefit in those older than 55 years (HR, 0.89) than in those aged 55 or younger (HR, 0.65). In this group, the relatively modest numerical advantage did not reach statistical significance.

Following the pivotal ORATORIO trial, which led to ocrelizumab’s approval for PPMS worldwide in 2017, ORATORIO-HAND is only the second positive phase 3 trial in this disease, said Giovannoni.

Compared with the first trial, ORATORIO-HAND was designed to include older patients and those with more advanced disease. It enrolled patients with a higher median EDSS score (6.0 vs 4.5), longer time since symptom onset (9.0 vs 5.9 years), and greater prior exposure to disease-modifying therapies (8.1% vs 6.1%), Giovannoni noted.

Because ORATORIO excluded patients older than 55 years, virtually no participants in the first trial (0.7%) were older than 55 years compared with roughly 27% of those enrolled in ORATORIO-HAND, which allowed enrollment up to age 65.

Reassuring Safety Profile

Brain volume was monitored throughout the trial, but there was no difference in the rate of decline between patients receiving active therapy and those on placebo. The study showed the same placebo-like safety profile observed in ORATORIO, but the data were even more reassuring, said Giovannoni.

While ORATORIO could not rule out a risk for malignancy or serious infections, the current trial showed no signal of malignancy, and rates of serious infections — including COVID — were comparable between groups.

The greatest numerical difference in adverse events involved patients with infusion-related reactions, which were more common in the ocrelizumab group (20.8% vs 4.3%).

Following the presentation, Giovannoni was asked specifically if he would consider ocrelizumab in patients older than 65 years even though they were excluded from this trial. Although he acknowledged that benefits are likely to be relatively reduced with age, he replied that he would not use age 65 as a ceiling.

Similarly, he said he would not withhold ocrelizumab from patients with secondary PMS, for which the therapy is already approved in most countries.

“I am among those who consider primary and secondary MS to be essentially the same disease, so I would expect very similar results in this group,” he said.

Cautious Optimism

Commenting on the research, Peter Calabresi, MD, director of the Multiple Sclerosis Center at Johns Hopkins Medicine, Baltimore, said Giovannoni’s message is appropriate, but he was more cautious about the extent to which clinical practice should change based on the ORATORIO-HAND results.

For example, because ocrelizumab’s benefits are largely or entirely driven by its anti-inflammatory effects, he suggested it is reasonable to consider that these benefits may diminish in older patients. One interpretation is that patients with PPMS with less active inflammation are likely to derive less benefit.

“We will need to see the published manuscript and hear more details,” he said.

Calabresi acknowledged that the study was highly positive, reinforcing the value of ocrelizumab in the treatment of PPMS. He also expressed appreciation for Giovannoni’s point that clinicians should not give up trying to modify progression even in patients who are wheelchair-bound.

However, he is waiting for more data before weighing in on the premise that this study should immediately produce a profound change in the perception of PPMS prognosis.

This study was funded by Hoffmann-LaRoche. Giovannoni reported financial relationships with that company as well as AbbVie, Aslan, Atara, Biogen, Bristol-Myers Squibb-Celgene, GlaxoSmithKline, GW Pharma, Janssen, Jazz, Johnson & Johnson, LIFNano, Merck, Moderno, Novartis, Sanofi-Genzyme, Serono, and Teva. Calabresi reported financial relationships with Biogen, Lilly, Genentech, and Novartis.