NEJM (December 22, 2016) contains two articles on ocrelizumab in PPMS--one on ocrelizumab vs. placebo, the other on ocrelizumab vs. interferon beta-1a:
Ocrelizumab versus Placebo in Primary Progressive Multiple Sclerosis
Xavier Montalban, M.D., Stephen L. Hauser, M.D., Ludwig Kappos, M.D., Douglas L. Arnold, M.D., Amit Bar-Or, M.D., Giancarlo Comi, M.D., Jérôme de Seze, M.D., Gavin Giovannoni, M.D., Hans-Peter Hartung, M.D., Bernhard Hemmer, M.D., Fred Lublin, M.D., Kottil W. Rammohan, M.D., Krzysztof Selmaj, M.D., Anthony Traboulsee, M.D., Annette Sauter, Ph.D., Donna Masterman, M.D., Paulo Fontoura, M.D., Ph.D., Shibeshih Belachew, M.D., Ph.D., Hideki Garren, M.D., Ph.D., Nicole Mairon, M.D., Peter Chin, M.D., and Jerry S. Wolinsky, M.D., for the ORATORIO Clinical Investigators
BACKGROUND
An evolving understanding of the immunopathogenesis of multiple sclerosis suggests that depleting B cells could be useful for treatment. We studied ocrelizumab, a humanized monoclonal antibody that selectively depletes CD20-expressing B cells, in the primary progressive form of the disease.
METHODS
In this phase 3 trial, we randomly assigned 732 patients with primary progressive multiple sclerosis in a 2:1 ratio to receive intravenous ocrelizumab (600 mg) or placebo every 24 weeks for at least 120 weeks and until a prespecified number of confirmed disability progression events had occurred. The primary end point was the percentage of patients with disability progression confirmed at 12 weeks in a time-to-event analysis.
B cells contribute to the pathogenesis of multiple sclerosis, including the primary progressive form.Although the mechanisms of tissue injury in multiple sclerosis are uncertain, B cells may influence pathogenesis through antigen presentation,6 autoantibody production,or cytokine secretion.6 B cells are present in meningeal inflammation, which is characteristic of chronic multiple sclerosis and may cause adjacent cortical demyelinating and neurodegenerative pathologic features.CD20 is a cell-surface antigen found on pre-B cells and mature and memory B cells but not on the earliest B-cell precursors or on plasma cells.Ocrelizumab is a humanized monoclonal antibody that selectively depletes CD20-expressing B cells while preserving the capacity for B-cell reconstitution and preexisting humoral immunity.
A previous phase 2–3 trial of the chimeric monoclonal anti-CD20 antibody rituximab (OLYMPUS trial) in primary progressive multiple sclerosis did not meet its primary efficacy end point, but a subgroup analysis showed delayed progression of disability in younger patients (<51 years of age) with evidence of increased inflammatory disease activity.3 Those results provided the rationale and in part informed the trial design for this investigation of ocrelizumab in patients with primary progressive multiple sclerosis. Here, we report results from a phase 3, randomized, parallel-group, double-blind, placebo-controlled trial (ORATORIO) that investigated the efficacy and safety of ocrelizumab in patients with primary progressive multiple sclerosis.
RESULTS
The percentage of patients with 12-week confirmed disability progression was 32.9% with ocrelizumab versus 39.3% with placebo (hazard ratio, 0.76; 95% confidence interval [CI], 0.59 to 0.98; P=0.03). The percentage of patients with 24-week confirmed disability progression was 29.6% with ocrelizumab versus 35.7% with placebo (hazard ratio, 0.75; 95% CI, 0.58 to 0.98; P=0.04). By week 120, performance on the timed 25-foot walk worsened by 38.9% with ocrelizumab versus 55.1% with placebo (P=0.04); the total volume of brain lesions on T2-weighted magnetic resonance imaging (MRI) decreased by 3.4% with ocrelizumab and increased by 7.4% with placebo (P<0.001); and the percentage of brain-volume loss was 0.90% with ocrelizumab versus 1.09% with placebo (P=0.02). There was no significant difference in the change in the Physical Component Summary score of the 36-Item Short-Form Health Survey.
Infusion-related reactions, upper respiratory tract infections, and oral herpes infections were more frequent with ocrelizumab than with placebo.
Neoplasms occurred in 2.3% of patients who received ocrelizumab and in 0.8% of patients who received placebo; there was no clinically significant difference between groups in the rates of serious adverse events and serious infections.
CONCLUSIONS
Among patients with primary progressive multiple sclerosis, ocrelizumab was associated with lower rates of clinical and MRI progression than placebo. Extended observation is required to determine the long-term safety and efficacy of ocrelizumab. (Funded by F. Hoffmann–La Roche; ORATORIO ClinicalTrials.gov number, NCT01194570.)
For discussion, see
http://www.nejm.org/doi/full/10.1056/NEJMoa1606468?query=TOC#t=articleDiscussion.
The entire article can be seen
here.
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Ocrelizumab versus Interferon Beta-1a in Relapsing Multiple Sclerosis
Stephen L. Hauser, M.D., Amit Bar-Or, M.D., Giancarlo Comi, M.D., Gavin Giovannoni, M.D., Hans-Peter Hartung, M.D., Bernhard Hemmer, M.D., Fred Lublin, M.D., Xavier Montalban, M.D., Kottil W. Rammohan, M.D., Krzysztof Selmaj, M.D., Anthony Traboulsee, M.D., Jerry S. Wolinsky, M.D., Douglas L. Arnold, M.D., Gaelle Klingelschmitt, Ph.D., Donna Masterman, M.D., Paulo Fontoura, M.D., Ph.D., Shibeshih Belachew, M.D., Ph.D., Peter Chin, M.D., Nicole Mairon, M.D., Hideki Garren, M.D., Ph.D., and Ludwig Kappos, M.D., for the OPERA I and OPERA II Clinical Investigators
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.)
The entire article can be seen
here.