Sarilumab patients had less disease activity and pain, greater response rates.
Nearly one third of patients with rheumatoid arthritis (RA) use biologic agents alone, either because they cannot tolerate methotrexate or it is contraindicated. Biologics that target different inflammatory cytokines have expanded treatment options for these patients. Whereas adalimumab (Humira/AbbVie) targets tumor necrosis factor α (TNF-α), sarilumab (Kevzara/Sanofi and Regeneron) targets interleukin 6 (IL-6). However, as new biologics like sarilumab are introduced, comparative data are needed to determine which agent to select.
To meet this need, the phase III MONARCH trial compared the efficacy and safety of sarilumab and adalimumab when used as monotherapy for 6 months in patients with active RA who could not continue taking methotrexate because of intolerance or inadequate response. This active-controlled, double-blind, double-dummy superiority trial was done in 86 centers worldwide and enrolled patients from February 11, 2015, though January 20, 2016. Gerd Burmester, MD (pictured), professor of medicine and director of the Department of Rheumatology and Clinical Immunology at Charité-University Medicine Berlin in Berlin, Germany, led the study team.
MONARCH’s intent-to-treat population consisted of 369 patients. The study team randomly assigned 184 of them to receive sarilumab, 200 mg, every 2 weeks, and 185 to receive adalimumab, 40 mg, every 2 weeks.
The primary study endpoint was change from baseline in 28-joint disease activity score based on erythrocyte sedimentation rate. At study end, the investigators found that sarilumab reduced this score significantly more than adalimumab did (−3.28 vs. −2.20, P < 0.0001) and that the chances of reaching a remission-equivalent score were nearly 5 times greater with sarilumab than with adalimumab (odds ratio, 4.88; 95% confidence interval, 2.54—9.39; P < 0.0001).
In addition, more sarilumab patients than adalimumab patients achieved remission (7% vs 3%, P = 0.0468) and low disease activity (42% vs. 25%, P = 0.0005) as measured by the Clinical Disease Activity Index. According to the study team, these findings are particularly notable because this index is “a measure of clinical response independent of acute-phase reactants that may favor IL-6 inhibition.”
Differences in several other secondary study endpoints also favored sarilumab. For example, response rates were significantly greater in the sarilumab group than in the adalimumab group (P ≤ 0.0074). The sarilumab group also had significantly less pain and disability and more improvement in health status than the adalimumab group did. And the investigators noted a trend toward less fatigue in the sarilumab group.
Adverse events occurred in a similar proportion of patients in each treatment group (64%). The most common adverse events were headache and worsening of RA in the adalimumab group and injection site reactions and neutropenia in the sarilumab group. However, in both groups, incidence of infection by category were similar: 1% for serious infections, and 28% for nonserious ones. As a result, the MONARCH team concluded that the safety profiles of both agents were consistent with the effects anticipated for their drug class.
“Collectively, these data demonstrate that sarilumab improves signs and symptoms and functional disability of RA” in patients who cannot continue taking methotrexate, they summarized. What’s more, they characterized sarilumab as “an appropriate, effective, and superior monotherapy compared with TNF-α inhibition” in such patients.
However, the U.S. Food and Drug Administration (FDA) has not approved sarilumab for any indication. In October, 2016, the FDA notified Sanofi and Regeneron that it would not approve sarilumab because of deficiencies identified during inspection of Sanofi’s fill and finish facility in Le Trait, France.
In January, 2017, Health Canada approved sarilumab for adults with moderately to severely active RA who have an inadequate response or intolerance to one or more disease-modifying antirheumatic drugs. As a result, Sanofi and Regeneron announced plans to resubmit their application to market sarilumab in the United States to the FDA in the first quarter of 2017. The planned resubmission was subject to a successful FDA re-inspection of Sanofi's Le Trait facility, and the firms anticipated an FDA approval decision in the second quarter of 2017.
Adalimumab monotherapy is FDA-approved for moderately to severely active RA.
The final report on the study, “Efficacy and safety of sarilumab monotherapy versus adalimumab monotherapy for the treatment of patients with active rheumatoid arthritis (MONARCH): a randomised, double-blind, parallel-group phase III trial,” appears in the May 2017 issue of the Annals of the Rheumatic Diseases.