By Jai S. Perumal, MD
Assistant Professor of Neurology, Weill Cornell Medical College
Dr. Perumal reports she receives grant/research support from Genzyme Corp., and is on the speakers bureau for Biogen Idec, Genzyme Corp., Acorda Therapeutics, and Teva Pharmaceuticals.
SYNOPSIS: A Phase III trial of ocrelizumab in primary-progressive multiple sclerosis and two Phase III trials of ocrelizumab in relapsing-remitting multiple sclerosis have demonstrated efficacy with treatment.
SOURCES: Montalban X, Hauser SL, Kappos L, et al.; for the ORATORIO Clinical Investigators. Ocrelizumab versus placebo in primary progressive multiple sclerosis. N Engl J Med 2017;376:209-220.
Hauser SL, Bar-Or A, Comi G, et al.; for the OPERA I and OPERA II Clinical Investigators. Ocrelizumab versus interferon beta-1a in relapsing multiple sclerosis. N Engl J Med 2017;376:221-234.
Efficacy of Ocrelizumab in Primary-progressive Multiple Sclerosis. No disease-modifying therapy currently is approved for the treatment of primary-progressive multiple sclerosis (PPMS). Several therapies currently approved for relapsing-remitting multiple sclerosis (RRMS) were tested in PPMS, but failed to meet the primary endpoint. Based on emerging data that B cells may play a major role in the pathogenesis of MS and may have a significant role in progressive MS, the authors undertook this study of ocrelizumab for PPMS. Seven hundred thirty-two patients were randomized in a 2:1 distribution to either ocrelizumab or placebo. The dose of ocrelizumab was 600 mg every six months, administered as 300 mg infusions two weeks apart. The primary outcome was 12-week confirmed disability progression. Trial duration was at least 120 weeks of treatment until the occurrences in the trial cohort of 253 instances of disability progression. Disability was defined as a 1-point increase in EDSS for those with EDSS ≤ 5.5 and 0.5-point increase if the baseline EDSS was > 5.5. Key inclusion criteria were patients with PPMS between the ages of 18 and 55 years, EDSS between 3 and 6.5, and presence of either elevated immunoglobulin index or positive oligoclonal bands in CSF.
The primary endpoint was met, with the percentage of patients on ocrelizumab who had disability progression = 32.9% and those on placebo = 39.3% (hazard ratio, 0.76; 95% confidence interval, 0.59-0.98; relative risk reduction, 24%; P = 0.03). The secondary endpoints at 24 weeks, confirmed disability and performance on timed 25-foot walk, also were met.
Efficacy of Ocrelizumab in RRMS. Two Phase III clinical trials (OPERA I and OPERA II) were undertaken to evaluate the efficacy and safety of ocrelizumab in RRMS. Ocrelizumab treatment was compared to interferon beta-1a given subcutaneously three times a week. A total of 1,656 patients from these two trials were randomized in a 1:1 manner to receive ocrelizumab 600 mg IV every 24 weeks or interferon beta 1a 44 micrograms three times per week. The duration of the trial was 96 weeks. Key inclusion criteria were MS patients between the ages of 18 and 55 years with EDSS between 0 and 5.5 and at least two clinical relapses within the previous two years or one relapse within the preceding year.
The primary endpoint was annualized relapse rate at 96 weeks. In both OPERA I and OPERA II, it was 0.16 in the ocrelizumab group and 0.29 in the interferon beta group, which indicated a 46% lower rate of relapse (P < 0.001). With regard to disability progression, the percentage of patients with disability progression was 9.1% in the ocrelizumab group and 13.6% in the interferon beta group, which represents a 40% lower risk for the ocrelizumab group (P < 0.001). Secondary endpoints included MRI outcomes of gadolinium-enhancing lesions and new or enlarging T2 lesions, also in favor of ocrelizumab over interferon beta treatment (P < 0.003).
Adverse Events Associated with Ocrelizumab. ORATORIO Trial. The most frequently reported adverse event was infusion-associated reactions, which were seen in about 40% of patients. Most were not severe and only two patients in the trial withdrew because of infusion reactions. Upper respiratory tract infections were more common in the ocrelizumab group vs. placebo, 10.9% and 5.9%, respectively. Oral herpes also was more common in the ocrelizumab group, 2.3% vs. 0.4%. There was no case of progressive multifocal leukoencephalopathy (PML). During the Phase III trial, 11/486 (2.3%) patients who received ocrelizumab developed malignancies — four patients with breast carcinoma, three patients with basal cell carcinoma, and one each of endometrial carcinoma, anaplastic large cell lymphoma, malignant fibrous histiocytoma, and pancreatic carcinoma. Additionally, one case of basal cell carcinoma and a case of squamous cell carcinoma were reported during the open-label extension phase. In the placebo group, there were two malignancies (0.4%), cervical adenocarcinoma and basal cell carcinoma. There were four deaths in the ocrelizumab group, one each due to pulmonary embolism, pneumonia, pancreatic carcinoma, and aspiration pneumonia.
OPERA I and OPERA II trials. The most common adverse events were infusion-related reactions similar to that reported in the ORATORIO trial. Overall infection rates generally were similar between the ocrelizumab and interferon groups. Herpes infections were more frequent in the ocrelizumab group (5.9% vs. 3.4%). There were no cases of opportunistic infections, including PML. During the trial, there were four malignancies reported (0.5%), and during the open-label extension, there were five more cases. In total, they included four cases of breast carcinoma, two basal cell carcinoma, two malignant melanoma, and one renal cell carcinoma. The interferon group had two reports of malignancy — one mantle cell lymphoma and one squamous cell carcinoma.
For the first time, a treatment trial for PPMS has had positive results, which is very encouraging for the treatment of primary progressive MS. A prior trial of rituximab, a chimeric anti-CD-20 molecule with a mechanism of action similar to the humanized anti-CD-20 antibody ocrelizumab, did not meet its primary endpoint of efficacy in disability progression. However, a sub-analysis showed that younger patients with gadolinium-enhancing lesions suggestive of active inflammation did show benefit on disability with rituximab treatment. FDA approval of ocrelizumab would be the first approval of a drug for the treatment of PPMS and, hopefully, would make a meaningful difference for patients with PPMS, especially younger patients in delaying disability.
The results of ocrelizumab in RRMS demonstrates high efficacy, making it one of the treatment options for patients with highly active disease. It also offers convenience of administration and less difficulty with compliance, as it will be administered in infrequent infusions every six months.
With regard to adverse events, infusion reactions were common in the ocrelizumab group but were mostly mild or moderate, except for one incidence of bronchospasm. The frequency of infections, including UTIs and respiratory tract infections, did not appear significantly different between the different treatment groups. However, there were two infection-related deaths, one due to community-acquired pneumonia and one due to aspiration pneumonia, in the ocrelizumab-treated patients in the PPMS trial. No opportunistic infections, including PML, were seen. There were more malignancies reported with ocrelizumab than the other groups, predominantly breast carcinoma. This is a concern that will need further evaluation and close monitoring. An FDA decision regarding approval is expected in March 2017.