clinical study insights
Questions Surrounding Early Use of Ocrelizumab in Patients With Relapsing Multiple Sclerosis
Clinical Study Title:
Ocrelizumab versus Interferon Beta-1a in Relapsing Multiple Sclerosis
Clinical Study Abstract:
BACKGROUND: B cells influence the pathogenesis of multiple sclerosis. Ocrelizumab is a humanized monoclonal antibody that selectively depletes CD20+ B cells.
METHODS: In two identical phase 3 trials, we randomly assigned 821 and 835 patients with relapsing multiple sclerosis to receive intravenous ocrelizumab at a dose of 600 mg every 24 weeks or subcutaneous interferon beta-1a at a dose of 44 μg three times weekly for 96 weeks. The primary end point was the annualized relapse rate.
RESULTS: The annualized relapse rate was lower with ocrelizumab than with interferon beta-1a in trial 1 (0.16 vs. 0.29; 46% lower rate with ocrelizumab; P<0.001) and in trial 2 (0.16 vs. 0.29; 47% lower rate; P<0.001). In prespecified pooled analyses, the percentage of patients with disability progression confirmed at 12 weeks was significantly lower with ocrelizumab than with interferon beta-1a (9.1% vs. 13.6%; hazard ratio, 0.60; 95% confidence interval [CI], 0.45 to 0.81; P<0.001), as was the percentage of patients with disability progression confirmed at 24 weeks (6.9% vs. 10.5%; hazard ratio, 0.60; 95% CI, 0.43 to 0.84; P=0.003). The mean number of gadolinium-enhancing lesions per T1-weighted magnetic resonance scan was 0.02 with ocrelizumab versus 0.29 with interferon beta-1a in trial 1 (94% lower number of lesions with ocrelizumab, P<0.001) and 0.02 versus 0.42 in trial 2 (95% lower number of lesions, P<0.001). The change in the Multiple Sclerosis Functional Composite score (a composite measure of walking speed, upper-limb movements, and cognition; for this z score, negative values indicate worsening and positive values indicate improvement) significantly favored ocrelizumab over interferon beta-1a in trial 2 (0.28 vs.0.17, P=0.004) but not in trial 1 (0.21 vs. 0.17, P=0.33). Infusion-related reactions occurred in 34.3% of the patients treated with ocrelizumab. Serious infection occurred in 1.3% of the patients treated with ocrelizumab and in 2.9% of those treated with interferon beta-1a. Neoplasms occurred in 0.5% of the patients treated with ocrelizumab and in 0.2% of those treated with interferon beta-1a.
CONCLUSIONS: Among patients with relapsing multiple sclerosis, ocrelizumab was associated with lower rates of disease activity and progression than interferon beta-1a over a period of 96 weeks. Larger and longer studies of the safety of ocrelizumab are required. (Funded by F. Hoffmann–La Roche; OPERA I and II ClinicalTrials.gov numbers, NCT01247324 and NCT01412333, respectively.)
Hauser SL, Bar-Or A, Comi G, et al; OPERA I and OPERA II Clinical Investigators. Ocrelizumab versus interferon beta-1a in relapsing multiple sclerosis. N Engl J Med. 2017;376(3):221-234.
If we treat early, using the best immunosuppressants available, will we stop the disease from entering the progressive phase where patients experience disability?
Chairman, Department of Neurology
What we have learned from rheumatoid arthritis, where we can see the initial event, is that if you go in hard with the biological anti–tumor necrosis factor alpha very early on, you can basically stop the disease and reset the immune system. The idea of allowing inflammation to occur in the central nervous system and allowing for potential permanent neurologic disability by using less-effective drugs does not make sense. The critical question in multiple sclerosis (MS) is, if we treat patients early, before there are clinical symptoms, and continue treatment for 2 or 3 years, can we stop the disease? If we treat early, using the best immunosuppressants available, will we stop the disease from entering the progressive phase where patients experience disability? Our approach at Yale is to recommend ocrelizumab for patients with a clear MS diagnosis. To better understand what the drugs are actually doing, we need new biomarkers based on single-cell RNA sequencing on the cerebrospinal fluid and blood. We need to know that, if we treat a patient very early with a particular drug for a specified length of time, will we stop the disease. That is the direction we are trying to move toward now.