FDA advisory committee rejects approval for sirukumab, voices safety concerns

The FDA Arthritis Advisory Committee voted 1-12 in a move against recommending approval of the biologics license application for sirukumab injection for the treatment of moderately to severely active rheumatoid arthritis among patients who have had an inadequate response or are intolerant to one or more disease modifying anti-rheumatic drugs.

The meeting focused on one phase 2 dose ranging study and three phase 3 studies which assessed the efficacy and safety of sirukumab, an interleukin-6 (IL-6) inhibitor with the proposed trade name Plivensia (Janssen Biotech Inc.). The results showed sirukumab at doses of 50 mg every 4 weeks and 100 mg every 2 weeks effectively reduced the symptoms, delayed the progression of structural damage and improved patient reported outcomes of rheumatoid arthritis (RA), and had a similar safety profile to other biologics used in the management of RA. Janssen Biotech proposed sirukumab 50 mg every 4 weeks as the only dose for the treatment of patients with RA based on the efficacy and safety data.

Mortality not an option

The main concern among committee members was the safety profile, which ended in a vote of 1-12 that sirukumab was not safe in the treatment of moderately to severely active RA in adult patients. Committee members voiced concerns surrounding the uncertainty of the safety signals, that sirukumab had too broad of an indication and the imbalance in the all-cause mortality.

“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 sort of a nondescript way for all people who have failed second line drugs,” David Felson, MD, MPH, said.

While most of the mortality found in the study was due to cardiovascular risk, Mara L. Becker, MD, MSCE, said the risk-benefit ratio was too high, even with a risk that should be easily identifiable.

“My fear was someone may be going early in the course and that risk-benefit ratio being outweighed and mortality is final,” she said. “Even though much of that mortality is cardiovascular risk and we hope we would be able to identify that and recognize those people who are at risk, it is too final for me at this point.”

However, James Katz, MD, director of the Rheumatology Fellowship and Training Branch at the National Institute of Arthritis and Musculoskeletal Diseases, was the only committee member who voted yes, noting that he felt the same about sirukumab as he does all biologics.

“[Sirukumab] does not scare me any more than all the other drugs that I use,” Katz said. “I am scared by all the biological agents and this is no different.”

More data needed

When looking at the data overall, Daniel H. Solomon, MD, MPH, noted that he found the trial design and analysis to be inconclusive, and more long-term outcomes and comparative data is needed.

“While this could be a play of chance, the mortality issues were concerning and the intermediate endpoints on the way toward mortality, serious infection, [cardiovascular] CV risk, GI perforation are obviously concerning,” Solomon said. “There would need to be some way of having a fair comparison. Again, whether that is related to an active comparator or placebo I think is a longer conversation.”

Sirukumab is efficacious

Beyond the concerns of safety, the committee voted 13-0 that the data provide substantial evidence that sirukumab was effective in the treatment of moderately to severely active RA in adult patients. Despite the unanimous vote, Steven B. Meisel, PharmD, said he would like to see additional comparison data.

“I would like to see some additional data though at some point and that is comparing the efficacy of [sirukumab] to the other IL-6 agents,” Meisel said.

In a company press release, Newman Yeilding, MD, head of Immunology Development for Janssen Research & Development, said company officials were disappointed and disagree with the committee’s interpretation of the sirukumab benefit-to-risk profile.

“We remain confident in the data accumulated to date supporting sirukumab in the treatment of moderately to severely active RA. We look to continue discussions with the FDA in their review of the application, as we believe sirukumab represents an important therapeutic option for patients with RA,” he said. – by Casey Tingle

References:

Arthritis Advisory Committee Meeting. Wed., Aug. 2, 2017. https://www.fda.gov/AdvisoryCommittees/Calendar/ucm564731.htm

http://www.janssen.com/fda-advisory-committee-does-not-recommend-approval-sirukumab-treatment-moderately-severely-active

Disclosures: The researchers report no relevant financial disclosures.

The FDA Arthritis Advisory Committee voted 1-12 in a move against recommending approval of the biologics license application for sirukumab injection for the treatment of moderately to severely active rheumatoid arthritis among patients who have had an inadequate response or are intolerant to one or more disease modifying anti-rheumatic drugs.

The meeting focused on one phase 2 dose ranging study and three phase 3 studies which assessed the efficacy and safety of sirukumab, an interleukin-6 (IL-6) inhibitor with the proposed trade name Plivensia (Janssen Biotech Inc.). The results showed sirukumab at doses of 50 mg every 4 weeks and 100 mg every 2 weeks effectively reduced the symptoms, delayed the progression of structural damage and improved patient reported outcomes of rheumatoid arthritis (RA), and had a similar safety profile to other biologics used in the management of RA. Janssen Biotech proposed sirukumab 50 mg every 4 weeks as the only dose for the treatment of patients with RA based on the efficacy and safety data.

Mortality not an option

The main concern among committee members was the safety profile, which ended in a vote of 1-12 that sirukumab was not safe in the treatment of moderately to severely active RA in adult patients. Committee members voiced concerns surrounding the uncertainty of the safety signals, that sirukumab had too broad of an indication and the imbalance in the all-cause mortality.

“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 sort of a nondescript way for all people who have failed second line drugs,” David Felson, MD, MPH, said.

While most of the mortality found in the study was due to cardiovascular risk, Mara L. Becker, MD, MSCE, said the risk-benefit ratio was too high, even with a risk that should be easily identifiable.

“My fear was someone may be going early in the course and that risk-benefit ratio being outweighed and mortality is final,” she said. “Even though much of that mortality is cardiovascular risk and we hope we would be able to identify that and recognize those people who are at risk, it is too final for me at this point.”

However, James Katz, MD, director of the Rheumatology Fellowship and Training Branch at the National Institute of Arthritis and Musculoskeletal Diseases, was the only committee member who voted yes, noting that he felt the same about sirukumab as he does all biologics.

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“[Sirukumab] does not scare me any more than all the other drugs that I use,” Katz said. “I am scared by all the biological agents and this is no different.”

More data needed

When looking at the data overall, Daniel H. Solomon, MD, MPH, noted that he found the trial design and analysis to be inconclusive, and more long-term outcomes and comparative data is needed.

“While this could be a play of chance, the mortality issues were concerning and the intermediate endpoints on the way toward mortality, serious infection, [cardiovascular] CV risk, GI perforation are obviously concerning,” Solomon said. “There would need to be some way of having a fair comparison. Again, whether that is related to an active comparator or placebo I think is a longer conversation.”

Sirukumab is efficacious

Beyond the concerns of safety, the committee voted 13-0 that the data provide substantial evidence that sirukumab was effective in the treatment of moderately to severely active RA in adult patients. Despite the unanimous vote, Steven B. Meisel, PharmD, said he would like to see additional comparison data.

“I would like to see some additional data though at some point and that is comparing the efficacy of [sirukumab] to the other IL-6 agents,” Meisel said.

In a company press release, Newman Yeilding, MD, head of Immunology Development for Janssen Research & Development, said company officials were disappointed and disagree with the committee’s interpretation of the sirukumab benefit-to-risk profile.

“We remain confident in the data accumulated to date supporting sirukumab in the treatment of moderately to severely active RA. We look to continue discussions with the FDA in their review of the application, as we believe sirukumab represents an important therapeutic option for patients with RA,” he said. – by Casey Tingle

References:

Arthritis Advisory Committee Meeting. Wed., Aug. 2, 2017. https://www.fda.gov/AdvisoryCommittees/Calendar/ucm564731.htm

http://www.janssen.com/fda-advisory-committee-does-not-recommend-approval-sirukumab-treatment-moderately-severely-active

Disclosures: The researchers report no relevant financial disclosures.