ORATORIO: Landmark trial shows reduced disability progression in primary progressive MS with ocrelizumab
Ocrelizumab, a humanized anti-CD20 monoclonal antibody, was associated with a reduced rate of disability progression in individuals with primary progressive multiple sclerosis (MS), based on findings of the phase III ORATORIO* trial.
“This is the first drug to show a significant effect in slowing disability progression in a phase III trial in primary progressive [MS], and therefore the trial represents a landmark study in the field,” said Professor Peter Calabresi, director of the Division of Neuroimmunology, Johns Hopkins University School of Medicine, Baltimore, Maryland, US, in a separate editorial. [N Engl J Med 2017;376:280-282]
Individuals with primary progressive MS on ocrelizumab were less likely to have disability progression at 12 weeks compared with individuals on placebo (32.9 percent vs 39.3 percent, hazard ratio [HR], 0.76, 95 percent confidence interval [CI], 0.59–0.98; p=0.03). Disability progression was still lower in the ocrelizumab arm compared with placebo at 24 weeks (29.6 percent vs 35.7 percent, HR, 0.75, 95 percent CI, 0.58–0.98; p=0.04). [N Engl J Med 2017;376:209-220]
Decreased performance on timed 25-foot walk was more evident in individuals on placebo compared with those on ocrelizumab (55.1 percent vs 38.9 percent; p=0.04) by week 120, while the total volume of hyperintense lesions on T2 weighted magnetic resonance images reduced by 3.4 percent in individuals on ocrelizumab and increased by 7.4 percent in individuals on placebo (p<0.001) between baseline and week 120.
Of the 725 study subjects (486 and 239 in the ocrelizumab and placebo arms, respectively), 20.4 percent of individuals on ocrelizumab experienced a severe adverse event compared with 22.2 percent of individuals on placebo, while 4.1 and 3.3 percent of individuals on ocrelizumab and placebo, respectively, experienced an adverse event that led to treatment discontinuation.
There was a higher incidence of upper respiratory tract infections in individuals on ocrelizumab compared with placebo (10.9 percent vs 5.9 percent), while nasopharyngitis and urinary tract infections were more common among those on placebo than ocrelizumab (27.2 percent vs 22.6 percent and 22.6 percent vs 19.8 percent, respectively). Mild-to-moderate oral herpes was more common among those on ocrelizumab than placebo (2.3 percent vs 0.4 percent).
Eleven patients on ocrelizumab (2.3 percent) reported neoplasms compared with two patients (0.8 percent) on placebo. The researchers recommended further study on the epidemiology of neoplasms as well as the long-term effects of ocrelizumab or other anti-CD20 agents on MS patients. Furthermore, the ongoing open-label phase of the study will enable the evaluation of ocrelizumab safety, they said.
Based on the hypothesis that the depletion of B cells may be an effective treatment strategy, researchers randomized 732 individuals (aged 18–55 years) with primary progressive MS to either intravenous ocrelizumab (600 mg in the form of two 300 mg infusions 14 days apart, n=488) or placebo (n=244) every 24 weeks for a minimum 120 weeks and until the occurrence of 253 disability progression events (determined as an increase of ≥1 point [for baseline ≤5.5 points] or ≥0.5 points [for baseline >5.5 points] from baseline on the Expanded Disability Status Scale [EDSS] confirmed for a minimum 12 weeks).
“The efficacy of ocrelizumab in our trial indicates that B cells contribute to the pathogenesis of primary progressive [MS] and that B-cell-mediated inflammation has a direct or indirect role in neurodegeneration,” said the researchers.
While ocrelizumab presents a much-needed treatment for primary progressive MS, the side effects of the drug must also be taken into account, said Calabresi. “[The] side effects will need to be studied in future trials and in phase IV monitoring in the community to understand the extent of the risk,” he said, urging clinicians to assess which patients would best benefit from ocrelizumab.