The New England Journal of Medicine Neurology's article (January 19, 2017) on Ocrevus for PPMS is one of the 10 articles of 2017 that the journal considers most significant. This is a review of the article as it appeared in NEJM Neurology on January 27, 2017. It was nearly a year ago but it sums up the thinking on Ocrevus:
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January 27, 2017
Positive Clinical Trial Results for Ocrelizumab in Primary Progressive Multiple Sclerosis
Robert T. Naismith, MD reviewing Montalban X et al. N Engl J Med 2017 Jan 19.
This B-cell depleting therapy reduced worsening disability by 24%.
Effective treatments for primary progressive multiple sclerosis (PPMS) have remained a major unmet need. A phase II study of rituximab in PPMS was overall negative, but subgroup analyses suggested possible benefit in younger and less disabled patients. Similar to rituximab, the investigational drug ocrelizumab depletes B cells via binding by CD20. For this multicenter, randomized, double-blind, placebo-controlled, manufacturer-sponsored phase 3 study, investigators recruited 732 patients with PPMS (age range, 18–55; Expanded Disability Status Scale score 3.0– 6.5 [i.e., mild disability through walker dependent]; disease duration <15 years) who met diagnostic criteria plus the presence of abnormal cerebrospinal fluid. Ocrelizumab or placebo was administered as two 300-mg doses separated by 2 weeks, repeated every 6 months.
Disability worsening confirmed at 3 months (the primary outcome) occurred for 33% on ocrelizumab versus 39% on placebo, a 24% relative risk reduction. The 25-foot timed walk worsened from baseline by 39% on treatment versus 55% on placebo. Ocrelizumab also had favorable effects on T2 lesion volume and change in brain volume. Mild infusion reactions occurred in 40% on ocrelizumab and led to discontinuation in 0.4%. Common infections were slightly increased with ocrelizumab. Neoplasms were identified in 2.3% on ocrelizumab versus 0.8% on placebo.
COMMENT
The MS field welcomes favorable study results for PPMS. Ocrelizumab is reasonably well tolerated, and the infrequent dosing is convenient. One third of patients still progressed while taking ocrelizumab, so clinicians should balance optimism with expectations when discussing this treatment with patients. Patients who are older than 55, wheelchair bound, and with disease duration >15 years were not studied; benefits in that population remain unknown. To assess the risk for neoplasms and infectious complications, long-term evaluation of data from clinical trial populations and postmarketing investigations will be needed. For patients with PPMS who fit study criteria, treatment at this time seems recommendable, pending FDA approval.
Dr. Naismith has received honoraria for consulting with Genentech, manufacturer of ocrelizumab.
EDITOR DISCLOSURES AT TIME OF PUBLICATION
Disclosures for Robert T. Naismith, MD at time of publication
Consultant / Advisory board Alkermes; Acorda Therapeutics; Bayer HealthCare; Biogen Idec; EMD Serono; Genzyme Corp./Sanofi; Genentech; Malinckrodt Pharmaceuticals; Pfizer; Novartis
Speaker’s bureau Acorda Therapeutics; Biogen Idec; Genzyme Corp./Sanofi
Grant / Research support National Multiple Sclerosis Society; National Institutes of Health
Positive Clinical Trial Results for Ocrelizumab in Primary Progressive Multiple Sclerosis
Robert T. Naismith, MD reviewing Montalban X et al. N Engl J Med 2017 Jan 19.
This B-cell depleting therapy reduced worsening disability by 24%.
Effective treatments for primary progressive multiple sclerosis (PPMS) have remained a major unmet need. A phase II study of rituximab in PPMS was overall negative, but subgroup analyses suggested possible benefit in younger and less disabled patients. Similar to rituximab, the investigational drug ocrelizumab depletes B cells via binding by CD20. For this multicenter, randomized, double-blind, placebo-controlled, manufacturer-sponsored phase 3 study, investigators recruited 732 patients with PPMS (age range, 18–55; Expanded Disability Status Scale score 3.0– 6.5 [i.e., mild disability through walker dependent]; disease duration <15 years) who met diagnostic criteria plus the presence of abnormal cerebrospinal fluid. Ocrelizumab or placebo was administered as two 300-mg doses separated by 2 weeks, repeated every 6 months.
Disability worsening confirmed at 3 months (the primary outcome) occurred for 33% on ocrelizumab versus 39% on placebo, a 24% relative risk reduction. The 25-foot timed walk worsened from baseline by 39% on treatment versus 55% on placebo. Ocrelizumab also had favorable effects on T2 lesion volume and change in brain volume. Mild infusion reactions occurred in 40% on ocrelizumab and led to discontinuation in 0.4%. Common infections were slightly increased with ocrelizumab. Neoplasms were identified in 2.3% on ocrelizumab versus 0.8% on placebo.
COMMENT
The MS field welcomes favorable study results for PPMS. Ocrelizumab is reasonably well tolerated, and the infrequent dosing is convenient. One third of patients still progressed while taking ocrelizumab, so clinicians should balance optimism with expectations when discussing this treatment with patients. Patients who are older than 55, wheelchair bound, and with disease duration >15 years were not studied; benefits in that population remain unknown. To assess the risk for neoplasms and infectious complications, long-term evaluation of data from clinical trial populations and postmarketing investigations will be needed. For patients with PPMS who fit study criteria, treatment at this time seems recommendable, pending FDA approval.
Dr. Naismith has received honoraria for consulting with Genentech, manufacturer of ocrelizumab.
EDITOR DISCLOSURES AT TIME OF PUBLICATION
Disclosures for Robert T. Naismith, MD at time of publication
Consultant / Advisory board Alkermes; Acorda Therapeutics; Bayer HealthCare; Biogen Idec; EMD Serono; Genzyme Corp./Sanofi; Genentech; Malinckrodt Pharmaceuticals; Pfizer; Novartis
Speaker’s bureau Acorda Therapeutics; Biogen Idec; Genzyme Corp./Sanofi
Grant / Research support National Multiple Sclerosis Society; National Institutes of Health
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