High-dose ocrelizumab 1200/1800 mg shows no significant difference in disability progression versus 600 mg in MS

This report details two phase 3b randomized controlled trials, MUSETTE and GAVOTTE, which evaluated a higher dose of ocrelizumab for multiple sclerosis. The studies were multicentre trials conducted in 21 and 22 countries, respectively. The population consisted of patients with relapsing or primary progressive multiple sclerosis aged 18 to 56 years. The MUSETTE trial enrolled 860 participants, and the GAVOTTE trial enrolled 753 participants. The intervention was high-dose ocrelizumab, defined as 1200 mg for patients with a baseline body weight less than 75 kg or 1800 mg for those with a baseline body weight of 75 kg or more. The comparator was the standard 600 mg dose of ocrelizumab. The primary outcome was the time to onset of 12-week composite confirmed disability progression (cCDP). The minimum follow-up was 120 weeks, with a median overall treatment duration of 184.4 weeks in MUSETTE and 174.1 weeks in GAVOTTE.

In the MUSETTE trial, the primary outcome occurred in 34% (198 of 577) of patients receiving high-dose ocrelizumab and in 37% (104 of 283) of those receiving 600 mg ocrelizumab. The hazard ratio was 0.93, with a 95% confidence interval of 0.73 to 1.18 and a p-value of 0.53, indicating no significant difference between the groups. In the GAVOTTE trial, the primary outcome occurred in 47% (235 of 500) of patients on high-dose ocrelizumab and in 49% (124 of 253) on the 600 mg dose. The hazard ratio was 0.95, with a 95% confidence interval of 0.76 to 1.18 and a p-value of 0.64, again showing no significant difference. These findings indicate that dose escalation did not further improve control of disability progression in either relapsing or primary progressive multiple sclerosis.

The trials did not report key secondary outcomes. Safety data showed that adverse events were common in both treatment groups. In MUSETTE, adverse events occurred in 552 (96%) of 577 patients on high-dose ocrelizumab and 267 (94%) of 283 on 600 mg ocrelizumab. In GAVOTTE, adverse events occurred in 447 (90%) of 499 patients on high-dose ocrelizumab and 230 (91%) of 254 on 600 mg ocrelizumab. Serious adverse events were reported in 77 (13%) of 577 and 34 (12%) of 283 in MUSETTE, and in 61 (12%) of 499 and 29 (11%) of 254 in GAVOTTE. The safety profiles were similar for high-dose and standard-dose ocrelizumab. Discontinuations due to adverse events were not reported.

These results can be compared to prior landmark studies of ocrelizumab in multiple sclerosis, such as the OPERA and ORATORIO trials, which established the efficacy of the 600 mg dose for reducing relapse rates and disability progression. The current trials suggest that increasing the dose beyond 600 mg does not provide additional benefit for the primary outcome of disability progression. This aligns with the practice relevance statement that high-dose ocrelizumab did not further improve control of disability progression.

Key methodological limitations include the lack of reported secondary outcomes, which limits a fuller understanding of the treatment effects. The trials were funded by F Hoffmann-La Roche, which may introduce potential bias, though this is common in pharmaceutical-sponsored research. The studies were conducted across multiple countries, which enhances generalizability but may introduce variability in care standards.

From a clinical perspective, these findings suggest that for patients with relapsing or primary progressive multiple sclerosis, the standard 600 mg dose of ocrelizumab remains appropriate, and dose escalation is not warranted based on disability progression outcomes. Clinicians should consider the safety profile, which was similar between doses, when making treatment decisions.

Several questions remain unanswered. The trials did not report secondary outcomes such as relapse rates or MRI measures, which are important in multiple sclerosis management. Long-term efficacy beyond the median follow-up of approximately 184 weeks is not known. The optimal dosing strategy for patients with different body weights or disease subtypes also requires further investigation.