Understanding Ocrelizumab’s Impact on Advanced Progressive MS: Insights From Dr. Gavin Giovannoni

At the 2025 European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) Congress, held September 24-26, in Barcelona, Spain, investigators presented intruiging late-breaking data from ORATORIO-HAND, a phase 3b trial (NCT04035005) testing ocrelizumab (Ocrevus; Genentech) in more advanced patients with progressivemultiple sclerosis (MS). Otherwise known as O-HAND, the double-blind, placebo-controlled trial included 1013 patients with primary progressive MS with an Expanded Disability Status Scale (EDSS) score of 3.0-8.0 who were followed for 144 weeks or until at least 340 progression events were observed.

All told, ocrelizumab outperformed placebo on the primary end point, a composite of time to onset of 12-week confirmed disability progression (12W-CDP), in 9-Hole Peg Test (CDP-9HPT) or EDSS (CDP-EDSS). Overall, results showed that The percentage of ocrelizumab and placebo patients with 12W-CDP on the composite endpoint was 32.7% vs 40.4% (hazard ratio, 0.70 [95% CI, 0.57-0.86]; risk reduction [RR], 30%; P = 0.0007), 16.7% vs 24.9% on 9HPT (RR, 41%; P = 0.0002) and 23.0% vs 30.8% on EDSS (RR, 33%; P = 0.0013).

To better understand the significance of the data, NeurologyLive® reached out to lead investigator Gavin Giovannoni, MBBCh, PhD, FCP, FRCP, FRCPath, a professor of neurology at Barts and London School of Medicine and Dentistry. In the discussion, Giovannoni explained how the trial’s inclusive structure–featuring older, nonambulatory patients and an upper-limb-focused outcome–was developed in collaboration with regulators to address major gaps in progressive MS research. Furthermore, he shared insights on how these design innovations could reshape future MS trials, and what the results may mean for continuing therapy beyond traditional disability cutoffs.

NeurologyLive: For our clinical audience of neurologists, can you provide an overview of the design of the phase 3b ORATORIO-HAND study and some of its main goals?

Gavin Giovannoni, MD, PhD: We have to go back to the original ORATORIO trial, which was a study of ocrelizumab in primary progressive MS. It was conducted in a fairly early, well-defined population, and it was a positive trial, mainly driven by patients who had what we call “active” scans—those with gadolinium-enhancing lesions at baseline. That meant the benefit was strongest in the subgroup of active PPMS.

When the European Medicines Agency (EMA) reviewed the data, they weren’t entirely convinced. They felt the population may have been enriched with relapsing patients since about a quarter of participants had MRI activity. So, as part of approving the drug, the EMA essentially required that Roche reproduce the ORATORIO findings.

Hidden in that original study was something quite interesting. We noticed that the therapy was nearly twice as effective in delaying upper-limb worsening, as measured by the Nine-Hole Peg Test (9HPT), compared with lower-limb measures like the EDSS or the Timed 25-Foot Walk. That led me to lobby Roche and Genentech to expand on the original concept. I suggested we look beyond the traditional population and include people who were already wheelchair users, shifting our focus to upper-limb function as the main outcome. Once someone is in a wheelchair, the EDSS isn’t a particularly sensitive measure anymore.

The idea was to reproduce the original ORATORIO study but broaden it to include more advanced PPMS while centering upper-limb function as the primary measure. So, O-HAND became a study of ocrelizumab’s effectiveness in a more advanced population, going beyond what the EMA initially requested.

That mattered because once people become wheelchair users, they are often excluded from trials, and in many health systems, they must stop therapy once they reach EDSS 7. Yet, if you talk to these patients, they’ll tell you that hand and arm function becomes everything—it’s what allows them to stay independent. As many say, “your arms become your legs.” There was, and still is, a major unmet need.

The process of getting the study approved was not straightforward. Some within the company were hesitant because of the cost, complexity, and perceived risk. But we pushed forward and got the EMA’s support for a trial that would include older and more disabled patients—those up to 65 years old and with up to 20 years of disease duration.

It was a very challenging trial to run. Once you start including wheelchair users, logistics become more complex facilities need accessibility modifications, and assessments take longer. Then COVID-19 hit, making recruitment extremely difficult. There were also major sites in Ukraine, and the war created serious disruptions. On top of that, ocrelizumab was already approved for PPMS while this was a placebo-controlled study, so there were ethical concerns around equipoise. Despite all that, we got the study done, and the results, in my view, are very impressive.

Looking at the results, what stood out to you from an efficacy standpoint?

About halfway through the study, during the height of COVID, the sponsor decided to modify the primary endpoint. Originally, it was based solely on upper-limb function, but we changed it to a co-primary outcome: confirmed worsening on either EDSS or the Nine-Hole Peg Test. This allowed for a shorter study duration and fewer patients while maintaining statistical power since more events would be captured. Regulators approved this change.

The results were positive regardless. On the composite endpoint—confirmed progression at 12 weeks on either EDSS or 9HPT—there was roughly a 30% reduction in risk, which is consistent with the original ORATORIO findings. When you separate the measures, the treatment effect was stronger for upper limbs: about 33% on EDSS and 41% on 9HPT.

That finding supports a hypothesis we proposed years ago—that MS progression behaves like a length-dependent axonopathy. The longer a neuronal pathway, the more vulnerable it is to damage. The corticospinal tracts for lower limbs are about a meter long, while those for upper limbs are around 30 centimeters, meaning they have more reserve. That reserve gives you a better chance to see a treatment effect. This study reinforces that idea: in advanced MS, the upper limbs still have the capacity to respond.

The EMA also required that we reproduce ORATORIO’s MRI-active subgroup finding. In those with active baseline scans, ocrelizumab reduced progression risk by about 55%, again matching and extending what we saw before. What’s particularly exciting is that the treatment effect was as strong—if not stronger—in the wheelchair-using group compared with ambulatory patients. That was driven largely by the upper-limb results. So, even in advanced stages, we see meaningful benefit, and some patients even regained function rather than simply stabilizing.

You’ve been involved in many clinical trials over the years. What lessons from O-HAND can help shape future MS studies, particularly for progressive disease?

I think O-HAND changes the paradigm of how we design progressive MS trials. Historically, we treated PPMS as if it were relapsing MS—recruiting patients with high EDSS scores and using outcomes like EDSS alone, which aren’t sensitive enough in advanced disease. Many past studies failed not because the drugs didn’t work, but because the designs couldn’t detect the effect.

We learned several key lessons. First, make trials event-driven rather than fixed-duration so you have enough progression events to reach a meaningful result. Second, include both earlier and more advanced populations. Third, rely more on upper-limb measures like the Nine-Hole Peg Test, which is more responsive in progressive MS. Finally, composite outcomes—such as EDSS plus 9HPT—help capture multiple dimensions of progression, allowing for smaller, shorter, and more efficient studies.

My hope is that we’ll see this approach become standard, with regulatory support for trials that include nonambulatory patients and focus on functional outcomes that matter most to them. I also hope Roche and Genentech pursue a label extension for ocrelizumab up through EDSS 7 or 8, given the strength of these results.

Ocrelizumab remains the only FDA-approved therapy for progressive MS. How has our understanding of it evolved, and what do we still need to learn?

Anti-CD20 therapy with ocrelizumab is just the beginning of the story. The treatment effect in PPMS is smaller than in relapsing disease, likely because of timing—by the time someone is significantly disabled, much of the damage is already done. The goal should be to diagnose and treat PPMS as early as possible, which newer diagnostic criteria can help us achieve.

Even so, ocrelizumab isn’t a cure. Many patients continue to worsen with what we call progression independent of relapse activity, or “smoldering” MS. That’s why the next frontier involves drugs that penetrate the CNS more effectively to target inflammation within the brain itself. Large antibodies like ocrelizumab have limited CNS penetration.

The next wave—such as BTK inhibitors—is designed to address that. I see a future where ocrelizumab is used as an induction therapy, followed by a CNS-penetrant agent as maintenance or combination therapy. Trials will be needed to confirm that, but now we have a proven upper-limb outcome that can measure those effects more precisely.

Importantly, the safety data from O-HAND were reassuring. We didn’t see the malignancy signal observed in the original ORATORIO trial, suggesting that was likely a false positive. The treatment was effective in both men and women, with no unexpected infection patterns beyond what we’d expect in the context of COVID-19.

Interestingly, there’s an old lesson here. Back in the late 1980s, a trial of low-dose methotrexate in chronic progressive MS was labeled negative because it didn’t show EDSS improvement. Yet, that same study showed a large benefit in upper-limb measures like the Nine-Hole Peg and Box-and-Blocks tests—signals that were overlooked. If that trial had been designed like O-HAND, it might have been considered positive 35 years ago. Sometimes it just takes time for the right concepts to rise to the surface.

Transcript edited for clarity. Click here for more ECTRIMS 2025 coverage.