Ocrelizumab may reduce disability progression in adults with primary progressive multiple sclerosis
EBM Focus - Volume 12, Issue 2
- Most treatments have been shown to be ineffective for primary progressive multiple sclerosis (MS), but there is some evidence that anti-CD20 antibodies targeting B lymphocytes might delay progression in adults < 51 years old.
- The ORATORIO trial randomized over 700 adults ≤ 55 years old with primary progressive MS to ocrelizumab 600 mg IV infusion vs. placebo every 24 weeks for at least 120 weeks.
- Ocrelizumab modestly reduced the risk of sustained disability progression (in 32.9% with ocrelizumab compared to 39.3% with placebo, hazard ratio 0.76 [95% CI 0.59-0.98]), providing a treatment option for patients with primary progressive MS and evidence that targeting B-cell-mediated inflammation may be a fruitful avenue for future research.
Disease modifying therapies may reduce relapse rates and progression of relapsing-remitting MS (PLoS One 2015;10(12):e0144538), but most treatments have been shown to be ineffective for primary progressive MS (Lancet 2016 Mar 12;387(10023):1075, Cochrane Database Syst Rev 2010 May 12;(5):CD004678, Lancet Neurol 2013 Sep;12(9):857). However, a subgroup analysis of the OLYMPUS trial (Ann Neurol 2009 Oct;66(4):460) found that the anti-CD20 monoclonoal antibody rituximab, which targets B lymphocytes, may delay progression in patients with primary progressive MS who are < 51 years old. To further assess if targeting B cells may reduce progression, the ORATORIO trial investigated the anti-CD20 antibody ocrelizumab. In the trial, 732 adults ≤ 55 years old with primary progressive MS were randomized to ocrelizumab 600 mg IV infusion vs. placebo every 24 weeks for at least 120 weeks (median 148 weeks). All patients had Expanded Disability Status Scale (EDSS) score 3-6.5 (where 10 indicates severe disability) and elevated immunoglobulin G (IgG) index or ≥ 1 IgG oligoclonal band detected in cerebrospinal fluid. Patients were excluded for prior use of immunosuppressive drugs. The primary outcome was progression of disability—an increase in EDSS score ≥ 1 point from baseline if baseline EDSS score ≤ 5.5, otherwise a ≥ 0.5 point increase—lasting for at least 12 weeks.
Disability progression lasting at least 12 weeks occurred less frequently with ocrelizumab, with progression in 32.9% with ocrelizumab compared to 39.3% with placebo (hazard ratio 0.76 [95% CI 0.59-0.98], p = 0.03, NNT 20 over first 120 weeks of treatment [estimated from survival curves]). A similar effect was seen for disability progression lasting at least 24 weeks, occurring in 29.6% vs. 35.7% (p = 0.04). Also, mean decline in performance on a timed 25-foot walk was less with ocrelizumab (time to walk increased by 38.9% vs. 55.1% from baseline to 120 weeks [p = 0.04]). Regarding adverse events, infusion-related reactions occurred in 39.9% with ocrelizumab and 25.5% with placebo (mild in 26.5% vs. 15.9%, none life-threatening or fatal); infections occurred in 71.4% vs. 69.9% (with upper respiratory tract infections in 10.9% vs. 5.9%); and neoplasms were found in 2.3% vs. 0.8% (statistical comparisons were not reported).
This trial shows that the anti-CD20 antibody ocrelizumab may reduce disability progression in adults younger than 55 years old with primary progressive MS. The reduction is significant, but not dramatic, and the 95% confidence interval includes differences that may not be clinically meaningful. Nonetheless, this trial is important because it, along with an earlier subgroup analysis of the OLYMPUS trial (with the anti-CD20 antibody rituximab), provide the only evidence to date demonstrating some reduction in disability progression with disease modifying therapies. The results of the two trials also suggest that targeting B-cell-mediated inflammation may be useful as an avenue for future research in treating primary progressive MS. The increased rate of neoplasms with ocrelizumab warrants some concern and longer-term evaluation. Thus, the results of the ORATORIO trial are encouraging (as are the results of a related study showing improvement with ocrelizumab compared to interferon beta-1a in patients with relapsing MS), but further research is needed to better determine efficacy and safety of ocrelizumab for treating MS.
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