The US Food and Drug Administration’s (FDA) Arthritis Advisory Committee voted overwhelmingly (12 no, 1 yes) not to recommend sirukumab (proposed name Plivensia, Janssen Biotech, Inc) for the treatment of adults with moderately to severely active rheumatoid arthritis (RA) who have responded inadequately to or are unable to tolerate one or more disease-modifying antirheumatic drugs (DMARDs) such as methotrexate.
While the 13-member committee voted unanimously that the data do provide substantial evidence of the efficacy of sirukumab for the treatment of these patients, they voted overwhelmingly (12 no, 1 yes) that the safety profile is not adequate to support approval for sirukumab.
Sirukumab is a human monoclonal antibody that inhibits the cytokine interleukin 6 (IL-6). The suggested dose is 50 mg subcutaneously every 4 weeks.
The FDA previously approved two other monoclonal antibody products that disrupt the IL-6 signaling pathway, sarilumab and tocilizumab, for the same indication on May 23, 2017, and January 11, 2010, respectively. However, while sirukumab targets IL-6, tocilizumab and sarilumab target the IL-6 receptor.
Clinical Trials
The votes followed discussion of a 52-week phase 2 dose-ranging, placebo-controlled radiographic study (ARA3002) and three pivotal phase 3 trials.
The phase 2 study included approximately 30 patients in each treatment group.
Two of the phase 3 trials compared sirukumab 100 mg every 2 weeks and 50 mg every 4 weeks with placebo. Patients in all treatment groups also received background conventional DMARD (cDMARD) treatment, which typically consisted of methotrexate. The other phase 3 trial compared monotherapy with the same sirukumab doses against adalimumab monotherapy.
One phase 3 trial assessed radiographic progression; that trial used a comparison group treated with placebo for 52 weeks and provided early (week 18) and late (week 40) escapes on the basis of less than 20% improvement from baseline in both swollen and tender joint counts.
Both sirukumab doses (100 mg every 2 weeks and 50 mg every 4 weeks) in the phase 3 trials reduced signs and symptoms of RA on the basis of proportion of patients who achieved American College of Rheumatology response criteria and reduction in Disease Activity Score 28-C-reactive protein, for improvement of physical function as assessed by the Health Assessment Questionnaire-Disability Index, and for structural progression reduction as measured by the van der Heijde modified Sharp score.
Both sirukumab doses were similarly effective over placebo and were not superior to adalimumab.
Safety Profile Gives Panel Members Pause
The primary adverse events were related to immunosuppression, consistent with those found with other DMARDS; however, there was a trend of increased overall mortality with sirukumab compared with placebo. Of 35 deaths that occurred in study patients, 34 occurred in those taking sirukumab.
Common causes of death were major cardiac adverse events, infection, and malignancy. Rates of increased mortality were comparable with both sirukumab doses. Sirukumab was also linked to increased risk for serious infection, and opportunistic infection and tuberculosis were both reported.
“While these immunosuppression-related adverse events and laboratory parameter changes were in qualitative terms similar to other products targeting the IL-6 pathway, the observation of the trend of increased overall mortality seen within the controlled time period of registration studies seems unique for the sirukumab program,” the FDA explains it its background document.
“I voted no due to the imbalance in the all-cause mortality and the broad indication,” said voting member Mara L. Becker, MD, MSCE, director, division of pediatric rheumatology, and associate chair, department of pediatrics, Children’s Mercy Kansas City; and associate professor of pediatrics, University of Missouri–Kansas City, all in Missouri.
Both doses of sirukumab were also associated with laboratory abnormalities that included decreased neutrophil counts and increased liver function test values; and increased low-density lipoprotein, high-density lipoprotein, and triglyceride parameters.
“I voted ‘no’ because of the too broad an indication and the uncertainty of the safety signal,” said temporary voting member Michael H. Weisman, MD, Endowed Chair in Rheumatology and director, division of rheumatology, Cedars–Sinai Medical Center, Los Angeles; and Distinguished Professor of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California.
The company had proposed sirukumab 50 mg every 4 weeks as the only dose for use in patients with RA on the basis of the efficacy and safety data.
“I think the safety data is a little too uncertain to lump this with all the other biologics that we have, and it makes me uncomfortable voting in favor of approving its use in a nondescript way for all people who fail second-line drugs; I think that’s a step a little too far, given the data that we currently have,” said temporary voting committee member David T. Felson, MD, director, Clinical Epidemiology Research and Training Unit, and professor of medicine and public health, Boston University School of Medicine, Massachusetts.
“[It was a] close call for me. I am sympathetic to the fact that I think there’s a real possibility that the difference we’re seeing in mortality is a bias; the efficacy results are strong in terms of what they needed to show, and I just cannot completely shake the uncertainty about the mortality,” said temporary voting member Erica Brittain, PhD, mathematical statistician and deputy branch chief, biostatistics research branch, division of clinical research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.
“I voted no also because of safety concerns…I would have been more enthusiastic if this was a completely novel mechanism of action, but in view of the existing IL-6 receptor antagonists, I was less enthusiastic about this drug,” said Maria E. Suarez-Almazor, MD, PhD, Barnts Family Distinguished Professor; deputy department chair (research); and chief, section of rheumatology and section of clinical research and education, department of general medicine, division of internal medicine, University of Texas MD Anderson Cancer Center, Houston.
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