The FDA's Arthritis Advisory Committee (AAC) gave the agency a lot to chew on Wednesday as it voted 12-1 against recommending approval of Janssen Biotech Inc.'s sirukumab as a new tool in the rheumatoid arthritis (RA) armamentarium.

Panelists agreed that the monoclonal antibody (MAb) that inhibits interleukin (IL)-6 showed efficacy in treating RA, but they were concerned about the safety data coupled with the broadness of the proposed indication that would allow sirukumab to be used to treat adults with moderately to severely active RA who had an inadequate response or are intolerant to at least one disease-modifying anti-rheumatic drug (DMARD).

Given the number of small molecule and biologic DMARDs that have been approved, as well as the need for more options, several AAC members said they would be more comfortable with approving sirukumab if the indication were restricted to patients who had failed on several other DMARDs.

The safety concerns focused on an imbalance in deaths during clinical development of the drug. Out of 35 deaths reported during the trials, only one occurred in the placebo arm. Janssen, part of New Brunswick, N.J.-based Johnson & Johnson, attributed the imbalance to patients on placebo being able to "escape" after week 18 and a crossover to sirukumab for all patients at week 24. But despite Janssen's analyses of the differences, "we're still seeing the imbalances we're all wrestling with," the FDA's Greg Levine told the AAC.

The FDA's Badrul Chowdhury agreed. "This was really a challenge," he said, adding that even though crossover designs have been accepted in the past, the agency may need to rethink their use in the future.

Adding to the uncertainty about the safety signal was that it didn't seem to be dose-related, as there were no differences in mortality rates between two dosage arms – one at 100 mg every two weeks and the other at 50 mg every four weeks.

Interpreting the data

"We're all struggling with how to interpret this safety data, and I'm not sure there's an easy way to cope with that struggle," said panelist David Felson, a professor and director of the clinical epidemiology research and training unit at Boston University School of Medicine. The question for him was whether the efficacy, which was not superior to what's already available, is worth the uncertain safety concerns.

Echoing several other panelists, Michael Weisman said, "This is really a dilemma, isn't it?" The director of the Division of Rheumatology at Cedars-Sinai Medical Center and a professor at the David Geffen School of Medicine at the University of California, Los Angeles, Weisman said given what he knows about sirukumab and the need to monitor patients, he would feel comfortable enough with the data to prescribe the drug. But he questioned the safety if the drug were advertised to "every Tom, Dick and Harry that sees these patients in the community."

Noting that two other IL-6 drugs have been approved for the same indication, Maria Suarez-Almazor, a professor and section chief for rheumatology and clinical research/education in the internal medicine division at the University of Texas M.D. Anderson Cancer Center, said she would be more supportive of sirukumab if it had a novel mechanism of action.

While the molecule falls in the IL-6 bucket, its target differs from that of the other IL-6 drugs. Sirukumab aims at IL-6 itself, but Roche Holding AG's Actemra (tocilizumab) and the recently approved Kevzara (sarilumab), partnered by Sanofi SA and Regeneron Pharmaceuticals Inc., target the IL-6 receptor.

The lone vote to recommend approval was cast by James Katz, director of the Rheumatology Fellowship and Training Branch at the National Institute of Arthritis and Musculoskeletal Diseases. "I'm very scared by all the biological agents," he said, adding that sirukumab scares him no more than the others.

Questioning use of placebo

The discussion of the safety data led to concerns about placebo-controlled RA trials, especially long-term ones. Mara Becker, director of the pediatric rheumatology division at Children's Mercy Kansas City and an associate professor at the University of Missouri-Kansas City, questioned the ethics of a placebo-controlled trial – the FDA's gold standard – when so many drugs have been approved for RA.

She said she wouldn't want to keep patients with RA on placebo for very long, because even if they seemed to be doing well, they could still be incurring joint damage. She and others commended Janssen for not putting patients in harm's way by allowing the 18-week escape in its 52-week placebo-controlled trial, but she noted the patients still may have suffered damage.

Several other panelists agreed that, in the future, the FDA needs to limit the time patients are on placebo in RA trials. They also stressed that a crossover design, as used in Janssen's study, muddies the safety data.

The alternative would be noninferiority trials comparing the proposed drug to one that's already been approved. At that suggestion, the FDA's Greg Levine whipped out a chart that showed sample size calculations for adequate power of a noninferiority trial. Using an active comparator quickly blows up into large trials with thousands of patients at a cost of hundreds of millions of dollars.

While observational studies could shed some light on safety data, the committee and FDA officials recognized the difficulty in comparing data across a range of trial protocols. Levine said the FDA's statistical group that covers rheumatology is discussing trial design for RA.

What lies ahead for sirukumab depends on whether the FDA follows the AAC vote, asks for further analysis of existing data, or wants a noninferiority trial that would compare the molecule with one of the approved IL-6 drugs. Suarez-Almazor noted that Janssen could face difficulty in recruiting for such a trial, given the uncertainty about the mortality imbalance.

The AAC vote was the second blow delivered to sirukumab in the space of a week. Last week, Glaxosmithkline plc announced it was stepping away from its sirukumab partnership with Janssen so it could prioritize its strongest assets by shifting resources away from those that offer more limited opportunities. (See BioWorld Today, Aug. 2, 2017.)