BARCELONA, Spain — In a noninferiority trial in pediatric-onset multiple sclerosis (POMS), ocrelizumab met its primary endpoint compared with fingolimod, demonstrating better tolerability and greater reductions in disease activity on brain imaging.

The study’s noninferiority design does not permit claims of superior efficacy, but the findings suggest that if approved, ocrelizumab “has the potential to be a highly effective and well-tolerated treatment for POMS,” said principal investigator Brenda Banwell, MD, Johns Hopkins University, Baltimore.

Banwell presented the findings at Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) 2025.

Beyond Fingolimod

POMS is a rare but serious condition, with limited treatment options. Fingolimod is currently the only disease-modifying therapy approved for pediatric use in the US, though several other options are available in Europe.

Fingolimod reduces circulating T cells by binding to sphingosine-1-phosphate receptors. In 2018, it was approved for use in children aged 10 years or older.

In 2017, ocrelizumab was approved for adults with primary progressive MS, secondary progressive MS, and relapsing remitting MS (RRMS). It is effective, has a favorable safety profile, and works by depleting B cells by binding to the CD20 receptor. However, its efficacy in POMS has not been fully studied.

The OPERETTA 2 trial was designed to evaluate whether ocrelizumab could provide a safe and effective alternative to fingolimod for children with RRMS.

The multinational phase 3 study included 187 children aged 10-17 years. Participants were randomized 1:1 to receive either 600 mg of intravenous ocrelizumab every 24 weeks or 0.5 mg of oral fingolimod daily, with both groups receiving a matching placebo for the alternative.

For the primary noninferiority endpoint, ocrelizumab reduced the annualized relapse rate (ARR) by 48% (0.07 vs 0.14) relative to fingolimod after a median follow-up of more than 132 weeks.

Relapse Reduction

Relapse events increased gradually and at a similar rate early on. However, unlike fingolimod, ocrelizumab achieved near-complete suppression of relapses beginning around week 24 and continuing through the end of follow-up.

In addition to the lower rate of relapses on an annualized basis, Banwell reported that 31.2% of the relapses in the fingolimod group were judged to be severe vs none in the ocrelizumab group.

All 10 patients in the ocrelizumab group who experienced a relapse fully recovered compared with 13 of 16 (81.5%) in the fingolimod group. Of the remaining three patients on fingolimod, two did not recover and one recovered with sequelae.

The trial’s primary noninferiority endpoint had to be met before secondary endpoints could be assessed, with superiority testing permitted once noninferiority was established. Safety outcomes and laboratory changes were also evaluated.

Ocrelizumab was superior to fingolimod in preventing new or enlarging T2 lesions and new T1 gadolinium-enhancing (Gd+) lesions — secondary endpoints that Banwell described as “key.”

Ocrelizumab was also associated with a 48% relative reduction in annualized T2 lesions compared with fingolimod (3.83 vs 7.28; P < .001). At week 24, fewer patients on ocrelizumab had new T2 lesions (6.5% vs. 42.5%), and by week 96 the rate was 0% vs 41.4%.

At week 12, the proportion of patients with at least one T1 Gd+ lesion was 87% lower with ocrelizumab than with fingolimod (4.3% vs 15.9%; P = .001).

Safety Data Validated

Consistent with findings from the earlier OPERETTA 1 trial of ocrelizumab in POMS, which is not yet published, OPERETTA 2 associated ocrelizumab with an adverse-event profile comparable with placebo over 96 weeks.

Overall, ocrelizumab demonstrated a modest numerical safety advantage over fingolimod for several outcomes, including fewer patients experiencing a serious adverse event (6.5% vs 8.5%) and fewer discontinuing treatment due to an adverse event (0% vs 3.3%).

Although a higher proportion of patients in the ocrelizumab group experienced an infection (73.1% vs 58.7%), Banwell noted that the annual number of infections was only modestly higher with ocrelizumab (1.5 vs 1.2) after adjusting for time on treatment. The rate of serious infections was nearly identical between the two groups (3.2% vs 3.3%).

Surprisingly, infusion-related reactions (IRRs) were more than twice as common in the ocrelizumab group compared with fingolimod group (48.4% vs 23.9%). However, Banwell noted that rates in both groups were substantially higher than expected from previous studies. She added that she could not explain why the placebo group experienced an IRR rate exceeding 20%.

The open-label extension of OPERETTA 2 is already underway, with a planned follow-up of at least 144 weeks. Patients transitioning from fingolimod to ocrelizumab will undergo a brief washout period.

The phase 3 OPERETTA 2 results align with earlier real-world experience: a small of 29 children with RRMS treated with ocrelizumab reported no serious side effects, a 97% reduction in annualized relapse rate, and stable Expanded Disability Status Scale (EDSS) scores.

Supports ‘Real World’ Data

The phase 3 OPERETTA 2 results align with earlier real-world experience. In a small retrospective analysis of 29 children with RRMS treated with ocrelizumab, led by senior author Anu Jacob, MD, DM, staff physician in the Neurology Department of the Cleveland Clinic’s Neurological Institute in Abu Dhabi, United Arab Emirates, the ARR was reduced by 97% from baseline. On the basis of EDSS scores, no progression was observed over 15 months of follow-up.

Medscape Medical News contacted Jacob for comment who said that his experience was consistent with case reports that have led clinicians to use this agent off label for POMS, particularly in challenging cases.

“The results of the trial are as expected,” he said. OPERETTA 2 “provides the added level of confidence required for physicians, patients, and families.”

However, he said not all questions have been answered about long-term exposure, indicating that he will be following the long-term extension.

“I do worry about the risk of hypogammaglobulinemia that comes with long-term treatment. This may be a problem especially with young children who will be on it for much longer than adults.”

This study was funded by Hoffmann-LaRoche. Banwell reported financial relationships with Hoffmann-LaRoche as well as Novartis and UCB. Jacob reported no relevant financial conflicts of interest.