Ocrelizumab shows promise in primary progressive and relapsing–remitting MS
medwireNews: Phase 3 trial results have shown the benefits of ocrelizumab for reducing disability progression in patients with primary progressive multiple sclerosis (MS) and disease activity in patients with the relapsing–remitting disease subtype.
The positive findings for ocrelizumab, a humanized monoclonal antibody that selectively depletes CD20-expressing B cells, have been reported in three separate trials in The New England Journal of Medicine.
In one of the three trials – ORATORIO – ocrelizumab treatment in patients with primary progressive MS was associated with a significant 25% reduction in the risk of disease progression, defined as a sustained increase on the Expanded Disability Status Scale (EDSS) score of at least 1.0 point (baseline score ≤5.5 points) or 0.5 points (baseline score >5.5 points), compared with placebo.
Among 488 patients randomly assigned to receive 600 mg of the drug intravenously every 24 weeks for at least 120 weeks, 32.9% had disease progression at 12 weeks compared with 39.3% of 244 patients given placebo. At 24 weeks the rates were 29.6% versus 35.7%, respectively.
“The efficacy of ocrelizumab in our trial indicates that B cells contribute to the pathogenesis of primary progressive multiple sclerosis and that B-cell–mediated inflammation has a direct or indirect role in neurodegeneration,” report researcher Jerry Wolinsky (University of Texas Health Science Center at Houston, USA) and colleagues.
Peter Calabresi, from Johns Hopkins University School of Medicine in Baltimore, Maryland, USA, calls the trial a “landmark study in the field” in a related editorial. He adds: “This is the first drug to show a significant effect in slowing disability progression in a phase 3 trial in primary progressive multiple sclerosis.”
Ocrelizumab also showed superiority in the primary outcome of the other two trials – OPERA I and OPERA II – in which the drug was compared with interferon beta-1a in a total of 1656 patients with relapsing–remitting MS. The annualized relapse rates during a 96-week treatment period were a significant 46% and 47% lower with ocrelizumab in OPERA I and II, respectively.
Although conducted independently, the two trials were exactly the same in design, with ocrelizumab 600 mg every 24 weeks randomly assigned to 410 and 417 patients in OPERA I and II, respectively, and subcutaneous interferon beta-1a 44 µg three times a week to 411 and 418 patients.
Among the secondary endpoints, the risk of disability progression was found to be significantly reduced by 40% at 12 and 24 weeks with ocrelizumab versus interferon beta-1a in a pooled analysis of OPERA I and OPERA II, while the chances of disability improvement at 12 weeks were increased by 33%.
In the ORATORIO trial, significantly fewer patients treated with ocrelizumab than placebo experienced a worsening in timed 25-foot walk performance at week 120 compared with baseline, at 38.9% versus 55.1%.
But ocrelizumab was only associated with significantly superior improvements in patient outcome measures for general health and quality of life in the OPERA 2 trial.
Magnetic resonance imaging (MRI) results supported the efficacy findings in all three trials. Ocrelizumab was associated with significantly greater reductions in total brain lesion volume and greater suppression of brain volume loss in primary progressive MS patients compared with placebo, and fewer new or newly enlarged lesions in relapsing–remitting MS patients compared with interferon beta-1a.
But Stephen Hauser (University of California, San Francisco, USA) and fellow authors of the OPERA trials note that further study will be needed to determine whether their MRI outcomes, including nearly complete cessation of new plaque formation with ocrelizumab in patients with relapsing–remitting MS, “translate into enhanced protection against accrual of disability over the long term.”
Infusion-related reactions and infections, including upper respiratory tract and herpes virus-associated infections, were the most common adverse events and these tended to be more frequent with ocrelizumab than either placebo or interferon beta-1a.
There were also numerically more patients with neoplasms in the ocrelizumab-treatment groups in the ORATORIO and OPERA I trials compared with their comparison groups, which the researchers say warrants ongoing evaluation.
Calabresi cautions that until the extent of such risk factors is known, clinicians need to “carefully consider” which patients are likely to benefit most from ocrelizumab, and “stay vigilant with regard to monitoring for side effects that could be managed effectively if detected early.”
By Lucy Piper
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