By William Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco. Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco
Drs. Elliott and Chan report no financial relationships relevant to this field of study.
The FDA has approved the first drug for the treatment of primary progressive multiple sclerosis (PPMS) in addition to relapsing forms of multiple sclerosis (RMS). Ocrelizumab is a glycosylated humanized monoclonal antibody directed against CD20-expressing B-cells. Its action is similar to that of rituximab, a chimeric anti-CD20 antibody, which depletes CD20-expressing B cells. The FDA granted ocrelizumab breakthrough designation, fast-track designation, and priority review. Ocrelizumab is marketed as Ocrevus.
INDICATIONS
Ocrelizumab is indicated for the treatment of patients suffering from RMS or PPMS.1
DOSAGE
The recommended dose is 300 mg by IV infusion initially, followed by 300 mg two weeks later.1 Subsequent doses are 600 mg every six months. Premedication with methylprednisone (or equivalent) and an antihistamine (e.g., diphenhydramine) is recommended prior to each infusion. Ocrelizumab is available as 300 mg (30 mg/mL) single-dose vials.
POTENTIAL ADVANTAGES
Ocrelizumab is the first drug approved for PPMS, and has been shown to be more effective than interferon beta-1a in RMS.2,3
POTENTIAL DISADVANTAGES
Infusion reaction is the most common adverse event. Even with premedication, the frequency is 34-40% and is most likely with the first infusion. Less than 1% were serious, requiring hospitalization. Ocrelizumab is contraindicated in patients with active hepatitis B infection. In clinical trials, there was a higher proportion of subjects experiencing upper respiratory tract infections compared to interferon beta-1a (40% vs. 33%). It may increase the risk of malignancies. The frequencies of breast cancer were 0.8% (6/781) vs. 0% (0/668) in controlled trials. Long-term effectiveness, safety, and tolerability remain to be established.
COMMENTS
Historically, MS therapies have targeted primarily T cells. However, recent evidence suggests that B cells, B cell-derived plasma cells, and antibodies play a key role in the pathogenesis of MS.4 The encouraging results with the chimeric anti-CD20 monoclonal antibody rituximab, formed the basis for the investigation of a humanized, less immunogenic, anti-CD20 antibody, ocrelizumab.5,6 This agent targets CD20 expressed on cell surfaces of pre-B-cells, mature B cells, and memory B cells. The approval for ocrelizumab was based on two randomized, double-blind, double-dummy, active-controlled studies in patients with RMS (96 weeks) and a placebo-controlled study in patients with PPMS (up to 120 weeks).1-3 In the comparative studies, subjects with RMS were randomized to ocrelizumab (410 in the first study, 417 in the second study) or interferon beta-1a (44 mcg SQ three times per week; 411 and 418, respectively).1,2 These subjects exhibited mean Expanded Disability Status Scale scores of approximately 2.8 (moderate disability) and at least two documented clinical relapses within the previous two years or one relapse within the past year before screening. The primary efficacy endpoint was the annualized relapse rate. Secondary endpoints included proportion of patients with 12-week confirmed disability progression, mean number of T1 gadolinium (Gd)-enhancing lesions per MRI, and mean number of new and/or enlarged T2 hyperintense lesions. There was a relative reduction in ARR of 46% in the first study (0.156 vs. 0.292) and 47% in the second study (0.155 vs. 0.290). The proportion of patients who were relapse-free was 83% vs. 71% and 82% vs. 72%. In the pooled analysis, there was a 40% risk reduction (hazard ratio [HR], 0.60) in the proportion with 12-week confirmed disability progression (9.8% vs. 15.2%). For MRI endpoints, there were 94-95% relative reduction in T1 Gd-enhancing lesions and 77-83% relative reduction in mean number of new and/or enlarged lesions. In the study involving PPMS (n = 488 on ocrelizumab and 244 on placebo), there was a 24% risk reduction (HR, 0.76) in the proportion of patients with 12-week confirmed disability (32.9% vs. 39.3%; P = 0.032). In addition, there was significant mean change in volume of T2 lesion from baseline to week 120 (-0.39 vs. 0.79; P < 0.0001).
CLINICAL IMPLICATIONS
MS is a chronic, immune-mediated disorder of the central nervous system. Relapsing remitting is the most common form of MS, affecting about 85% of patients. Primary progressive represents about 10%. Ocrelizumab, with a different mechanism of action, is more effective than a common standard of care for RMS and is the first approved for PPMS. There are 13 products approved for treating MS, mainly RMS. Ocrelizumab appears to provide a significant addition for the treatment of MS. Ocrelizumab is expected to cost $65,000 per year.
REFERENCES
- Ocrevus Prescribing Information. Genentech, Inc. March 2017.
- Hauser SL, Bar-Or A, Comi G, et al. Ocrelizumab versus interferon beta-1a in relapsing multiple sclerosis. N Engl J Med 2017;376:221-234.
- Montalban X, Hauser SL, Kappos L, et al. Ocrelizumab versus placebo in primary progressive multiple sclerosis. N Engl J Med 2017;376:209-220.
- Kinzel S, Weber MS. B cell-directed therapeutics in multiple sclerosis: Rationale and clinical evidence. CNS Drugs 2016;30:1137-1148.
- Castillo-Trivino T, Braithwaite D, Bacchetti P, Waubant E. Rituximab in relapsing and progressive forms of multiple sclerosis: A systematic review. PLoS One 2013;8(7):e66308. doi: 10.1371.
- Menge T, Dubey D, Warnke C, et al. Ocrelizumab for the treatment of relapsing-remitting multiple sclerosis. Expert Rev Neurother 2016;16:1131-1139.
Ocrelizumab is indicated for the treatment of patients suffering from relapsing multiple sclerosis or primary progressive multiple sclerosis.
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