By Jai S. Perumal, MD
Synopsis: Nine-year follow-up data from open-label extension of the Phase III clinical trials of ocrelizumab show that, although the efficacy of ocrelizumab was maintained throughout the duration of the study, patients who were treated with ocrelizumab from the beginning of the Phase III trials did better than the patients who were on subcutaneous (SC) interferon β-1a initially and were switched to ocrelizumab at the onset of the open-label extension period.
Source: Cerqueira JJ, Berthele A, Cree BAC, et al. Long- term treatment with ocrelizumab in patients with early-stage relapsing MS: Nine-year data from the OPERA studies open-label extension. Neurology. 2025;104(4):e210142.
Ocrelizumab is a high-efficacy therapy for the treatment of relapsing-remitting multiple sclerosis (RRMS). Regarding treatment approaches to multiple sclerosis, there is a growing body of evidence that suggests that early optimal treatment confers the greatest benefits on long-term disability outcomes. The conventional algorithms, which use an escalation strategy whereby patients are started on a relatively lower efficacy medication and switched to a higher efficacy medication if the disease is refractory to treatment, might result in these patients never “catching up” to patients who were on high-efficacy treatment from the onset. The authors of this study examined patients in the open-label extension of ocrelizumab clinical trials with these concepts in mind.
Two Phase III clinical trials (OPERA I and OPERA II) were undertaken to evaluate the efficacy and safety of ocrelizumab in RRMS. Ocrelizumab treatment was compared to interferon β-1a given subcutaneously three times per week. A total of 1,656 patients from these two trials were randomized in a 1:1 manner to receive ocrelizumab 600 mg intravenously every 24 weeks or interferon β-1a, 44 mcg three times per week. The duration of the trial was 96 weeks.
A total of 757 patients among those who were in the Phase III trials agreed to participate in the open-label extension study. Of these, 505 patients completed a nine-year follow-up. At the start of the open-label extension phase, patients who had been taking ocrelizumab during the double-blind period continued ocrelizumab, and patients who had been taking interferon β-1a were switched to ocrelizumab. For this subgroup analysis, patients who had been diagnosed within two years of enrollment in the original Phase III clinical trials and were treatment-naïve alone were selected. There were 382 patients in the interferon-ocrelizumab group and 375 patients in the ocrelizumab-ocrelizumab group. Outcomes assessed included NEDA-3 (no evidence of disease activity, i.e., no relapses, no disability progression, no new or enlarging T2 lesion or T1 gadolinium enhancing lesion on magnetic resonance imaging [MRI]), 25-week confirmed disability progression, new lesions on MRI, and changes in brain volume.
NEDA-3 analysis showed that at 336 weeks (nine years), 48.2% of the ocrelizumab-ocrelizumab patients maintained stable NEDA status while 25.7% of the interferon-ocrelizumab patients maintained stability. After interferon patients were switched to ocrelizumab during the open-label extension phase, the relapse rate, MRI activity, and disability accumulation between the two groups were similar, but the interferon-ocrelizumab group never regained the disability accrual or volume loss that occurred during the double-blind phase when they were taking interferon. Therefore, the overall disability and brain volume loss was worse than what was observed in the ocrelizumab-ocrelizumab patients.
Confirmed disability progression during the double-blind phase showed statistically significant differences between the interferon and ocrelizumab groups. There was a 30% lower risk of reaching 24-week confirmed disability in the ocrelizumab group. During the open-label extension, although the progression rates were similar, the initial advantage for the ocrelizumab group over the interferon group remained persistent. Regarding brain volume, this difference seemed even more significant. As was seen with disability, during the double-blind phase the interferon group showed greater brain volume loss. Even after the interferon group was switched to ocrelizumab at the onset of the open-label phase, the rate of brain volume loss remained higher for the duration of follow-up. The more severe progression of both disability and brain volume loss highlighted the significance of optimizing multiple sclerosis treatment from the onset of diagnosis.
Commentary
The results of this long-term follow-up study of ocrelizumab in RRMS demonstrates high sustained efficacy. In keeping with emerging evidence, early effective treatment had the greatest effect, not just on immediate disease control but, more importantly, on long-term disability. In comparison to interferon β-treated patients, those taking ocrelizumab demonstrated superior efficacy as manifested by the reduced relapse rate, less disability, and fewer brain MRI lesions during the double-blind phase.
After the interferon β group was switched to ocrelizumab during the open-label extension, they also showed improved disease control after the switch. However, the patients who were switched from interferon to ocrelizumab never caught up on the disability progression or brain volume loss that occurred during the double-blind phase.
This study specifically included patients with a recent onset of RRMS (within two years of diagnosis; patients were treatment-naïve) and, thus, the findings make one reflect that there may be an early therapeutic window of opportunity to delay or prevent long-term disability in multiple sclerosis.
Jai S. Perumal, MD, is Assistant Professor of Neurology, Weill Cornell Medical College.