Higher Ocrelizumab Doses Reduce Disability Progression Risk in Relapsing MS

Long-term, high exposure to ocrelizumab better reduces the risk for disability progression among people with relapsing multiple sclerosis (MS), without increasing serious infection risk, according to study results presented at the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2025, held in West Palm Beach, Florida from February 27 to March 1.

The OPERA I/II trials (ClinicalTrials.gov Identifier: NCT01247324/NCT01412333) found that higher doses of ocrelizumab led to deeper B-cell depletion and a greater reduction in disability progression without an increase in adverse events. However, the long-term safety of higher dose ocrelizumab has yet to be examined.

For the current study, researchers evaluated the safety and efficacy of ocrelizumab after 10 years of treatment. Patients (N=784) who were assigned to receive ocrelizumab in the OPERA I/II trials were evaluated for the rates of serious infections and the proportion of patients with serum immunoglobulin (IgG) levels below the lower limit of normal (LLN) on the basis of quintile of mean ocrelizumab serum concentration (C_mean) during the 2-year double-blind trial period.

Serious infections at year 1 of ocrelizumab treatment (range, 1.40-1.98 per 100 patient-years) and year 10 (range, 1.89-2.67 per 100 patient-years) were similar and stable across ocrelizumab exposure levels.

The average depletion in IgG levels over 10 years was similar across ocrelizumab quartiles, however, the researchers noted that individuals with the highest ocrelizumab C_mean had lower IgG levels at baseline (mean, 10.15 vs 11.12 g/L) and year 10 (mean, 7.23 vs 8.18 g/L), resulting in a higher rate of IgG below the LLN in quartile 4 compared with quartile 1 (11.3% vs 9.6%), respectively.

Patients with relapsing MS free from 48-week confirmed disability progression over the 10-year treatment period was 84.5% vs 73.9% for those with the highest ocrelizumab C_mean compared with those with the lowest C_mean. Compared with lower ocrelizumab concentration, higher ocrelizumab concentration tended to decrease risk for confirmed disability progression (hazard ratio [HR], 0.63; 95% CI, 0.37-1.07; P =.09).

The reduction in relapse activity was similar across ocrelizumab quartiles at year 10 (annualized relapse rate [ARR] range, 0.02-0.05 per year). Whole brain volume loss from week 24 to year 10 was also similar across quartiles and were comparable with normal aging (mean difference [MD] range, -3.10% to -2.81%).

“Over a 10-year period, higher ocrelizumab exposure remained associated with greater reduction in risk of disability progression, while risk of [serious infections] did not increase with additional exposure, suggesting an improved benefit-risk profile for higher ocrelizumab doses,” the researchers wrote. They added, “confirmatory trials (MUSETTE [ClinicalTrials.gov Identifier: NCT04544436] and GAVOTTE [ClinicalTrials.gov Identifier: NCT04548999]) evaluating the efficacy and safety of higher dose ocrelizumab are ongoing.”

Disclosure: This research was supported by Genentech, Inc. Please see the original reference for a full list of disclosures