Dr Howard ThomHoward Thom, PhD, MSc
Using a number of network meta-analyses (NMAs), a systematic review has shown that ocrelizumab (Ocrevus, Genentech) is superior, or at least comparable, to more than 10 currently available disease-modifying therapies (DMTs) for relapsing multiple sclerosis (MS).1

As well, the safety profile of the humanized anti-CD20 monoclonal antibody was found to be similar to each of the DMTs included in the analysis.

Conducted by Howard Thom, PhD, MSc, a lecturer in health economics at the University of Bristol, and colleagues, the review consisted of data from MEDLINE, Embase, the Cochrane Library, trial registers, relevant conferences websites, and health technology assessment agency websites. In total, 33 randomized clinical trials were included, with the key efficacy outcomes that were assessed consisting of 12-week confirmed disability progression (CDP) and annualized relapse rate (ARR).

The group compared ocrelizumab’s 600-mg dose to 12-mg alemtuzumab, 300-mg natalizumab, 3.5-mg/kg and 5.25-mg/kg cladribine, 150-mg daclizumab, 0.5-mg fingolimod, 240-mg dimethyl fumarate, 44-µg and 250-µg subcutaneous interferon ß-1a, 125-µg pegylated interferon ß-1a, 40-mg and 20-mg glatiramer acetate, 14-mg and 7-mg teriflunomide, and placebo.

Thom and colleagues wrote that the findings support that ocrelizumab “offers a complete and valuable package for the treatment of patients with RMS.” They ranked the treatments by using surface under the cumulative ranking curve (SUCRA) values, finding that 600-mg ocrelizumab ranked in the top 3 for ARR (third; 88.9%), 12-week CDP (first; 95.5%), and serious adverse events (second; 78.7%). For discontinuation for due to adverse events, it ranked seventh (60%).

For 24-week CDP, ocrelizumab was found to be more effective than placebo, interferon β-1a 44 μg, and teriflunomide 7 mg, based on the 95% credible intervals.

The only treatments more effective than ocrelizumab for ARR were alemtuzumab 12 mg, and natalizumab 300 mg, while interferon ß-1a 250 µg was the only higher-ranking treatment for serious adverse events. The researchers noted that this can be  attributed to 2 things: the rarity of 24-week CDP compared to 12-week CDP, and the greater interconnectedness and fewer jumps between ocrelizumab and the other treatments in 12-week CDP, “which decreases the uncertainty in the NMA.”

“These models and the SUCRA ranking values calculated from them suggest that ocrelizumab has an efficacy and safety profile that is superior to or comparable with other available DMTs across all outcomes, except natalizumab and alemtuzumab for one safety outcome: all-cause discontinuation,” Thom and colleagues remarked.

The limitations of using NMAs included the lack of randomized clinical trials with statistical power to analyze safety, and that both serious adverse events and adverse events were only recorded during trial periods. As well, Thom et al. acknowledged that 12-week results obtained from the clinical trials may not be relevant for long-term outcomes, and the lack of clarity regarding how an induction treatment can be discontinued, which in turn impacts the discontinuation due to AEs and all-cause discontinuation networks used.

Additionally, the research team noted that while these findings were similar to that found by the Institute for Clinical and Economic Review’s (ICER) 2017 report on the effectiveness and value of disease-modifying treatments,2 the methodology differed.

ICER, they noted, did not analyze the proportion of relapse-free patients, only comparing absolute safety outcomes, with the group writing that “despite ICER's emphasis of the benefit-risk profiles, ratings seem biased towards efficacy and analysis of safety was limited.” As well ICER used event counts for the combined CDP network, while the new analysis used all available data by combining hazard ratio and count data. The ICER report also included data for rituximab when used off-label for treatment of relapsing MS, though there was no approved dose included, and the report excluded cladribine.

“In the absence of head-to-head trials against other DMTs for the treatment of patients with [relapsing MS], this NMA provides important evidence on the relative efficacy and safety of ocrelizumab compared with other approved treatments for [relapsing MS],” Thom and colleagues concluded.

A version of this article first appeared on MDMag.com.
REFERENCES
1. McCoool R, Wilson K, Arber M, et al. Systematic review and network meta-analysis comparing ocrelizumab with other treatments for relapsing multiple sclerosis. Mult Scler Relat Dis. Published online January 2, 2019. msard-journal.com/article/S2211-0348(18)30580-7/fulltext. Accessed January 18, 2019.
2. ICER. Disease-Modifying Therapies for Relapsing-Remitting and Primary-Progressive Multiple Sclerosis: Effectiveness and Value. Published March 6, 2017. icer-review.org/wp-content/uploads/2016/08/CTAF_MS_Final_Report_030617.pdf. Accessed January 18, 2019.