Citing safety concerns, the Food and Drug Administration’s Arthritis Advisory Committee voted overwhelmingly against recommending FDA approval of the interleukin-6 inhibitor sirukumab for refractory rheumatoid arthritis.

Janssen Biotech submitted a biologics license application (BLA) for the monoclonal antibody, seeking an indication for adults with moderately to severely active rheumatoid arthritis (RA) who had an inadequate response or intolerance to one or more prior disease-modifying antirheumatic drugs, but despite agreeing unanimously that the data presented by the applicant provided substantial evidence of efficacy for this indication, the committee voted 12-1 against approval at an Aug. 2 meeting.

All those who voted “no” expressed concerns about a possible increase in mortality risk among treated patients, and several stated that they felt the indication was too broad given the safety concerns.

“I’m not sure whether the safety signal is of concern or not. I don’t think there’s enough data here to know that. It’s concerning, and it may be just noise, but it may also be real and I’m not willing to ... be supportive of the notion that it’s safe enough to take its place along with other biologicals,” said temporary voting member David T. Felson, MD, professor of medicine and public health at Boston University.

Similarly, temporary voting member Erica Brittain, PhD, said the mortality concerns swayed her vote.

“It was a very close call for me. I do think there’s a real argument to be made about bias in the analysis that shows some possibility of a difference. On the other hand, I just couldn’t get past the uncertainty, and when we’re talking about mortality it’s hard to dismiss that,” said Dr. Brittain, a mathematical statistician and deputy chief of the Biostatistics Research Branch at the National Institute of Allergy and Infectious Diseases.

Michael H. Weisman, MD, also a temporary voting member and chair of rheumatology at Cedars-Sinai Medical Center in Los Angeles, said that if the indication had been narrowed – perhaps to those who showed a biologic response – he would have voted “yes.”

Temporary voting member James Katz, MD, was the only committee member to vote in favor of approval.

“I actually voted yes because this drug doesn’t scare me any more than all the other drugs I use. I’m very scared by all the biological agents, and this is no different,” said Dr. Katz, director of the Rheumatology Fellowship and Training Branch at the National Institute of Arthritis and Musculoskeletal Diseases.

Sirukumab differs from two other approved monoclonal antibodies that target the IL-6 pathway for the treatment of patients with RA – tocilizumab (Actemra) and sarilumab (Kevzara) – in that it targets IL-6, while the others target the IL-6 receptor. This slight difference could make a difference for some highly refractory patients who had failed to respond to prior treatments, according to applicant presentations at the meeting.

The efficacy and safety of the agent were assessed in a phase 2 dose-ranging study, as well in three pivotal phase 3 studies. Two of the phase 3 studies compared 100 mg twice weekly and 50 mg four times weekly doses of subcutaneous sirukumab to placebo – which were shown to have similar efficacy for reducing the signs and symptoms of RA – and a third compared those two doses against adalimumab (Humira) and showed that it was not superior to adalimumab for efficacy.

One phase 3 placebo-controlled study involving 878 refractory patients was published in February in The Lancet and showed that sirukumab was associated with rapid and sustained improvements in RA signs and symptoms, physical function, and health status, as well as improvement in physical and mental well-being.

However, a safety signal – a trend of increased overall mortality with sirukumab vs. placebo – emerged from the studies. The mortality was mainly associated with major adverse cardiovascular events, infection, and malignancy.

Three speakers, including RA patients or patient representatives, participated in the open public hearing portion of the committee meeting, and all spoke in favor of approval of sirukumab, but ultimately the committee agreed that the limited benefits of the agent – given that it does not involve an entirely new mechanism of action – did not outweigh the unknowns regarding safety.

Committee chairperson Daniel H. Solomon, MD, professor of medicine at Harvard Medical School and chief of the section of clinical sciences at Brigham and Women’s Hospital, both in Boston, said longer-term outcomes data with a clear comparator are needed.

The FDA will now consider the committee’s recommendations in making its final determination regarding the BLA.

All voting advisory committee members were screened and cleared with respect to potential conflicts of interest.

sworcester@frontlinemedcom.com

FDA committee rejects sirukumab approval on safety concerns