An FDA advisory panel has concluded that the safety profile of the Johnson & Johnson (J&J)-sponsored rheumatoid arthritis (RA) candidate sirukumab did not support approval by the agency, even though the drug’s efficacy was found sufficient for authorization.
The FDA’s Arthritis Advisory Committee yesterday voted 12 to 1 against recommending approval based on the safety data, which showed that of the 35 patient deaths reported in sirukumab clinical trials, all but one (34) occurred in patients treated with sirukumab. A total of 2926 patients were treated with either 50-mg or 100-mg doses of sirukumab in five Phase III trials.
Thirty-one of the 35 deaths occurred within 16 weeks of last dose of study agent, the FDA disclosed in the staff-prepared Briefing Document on sirukumab submitted to the Committee.
The main causes of death, according to the Document, were cardiovascular events (13 patients), serious infections (8), malignancies (6), and other causes (9).
“The safety data submitted for sirukumab suggest it is associated with significant immunosuppression, as manifested by increased risks of serious infection, as well as important laboratory abnormalities, such as neutropenia and lipid parameter elevations,” the Document concluded. “Wide confidence intervals around treatment comparisons for serious rare events such as death, malignancy, and MACE [major adverse cardiac events] indicate that the imbalances could be due to chance but also that relatively large increases in risks on sirukumab cannot be ruled out based on the data alone. Such imbalances raise concern regarding these important safety risks.”
Also observed, according to the Document, were additional potential safety issues associated with sirukumab, related to events of gastrointestinal perforation and hypersensitivity.
Despite its concerns over sirukumab’s safety, the advisory committee voted 13 to 0 that the efficacy data submitted by J&J to the FDA supported its claim that the drug could treat RA.
The FDA usually, but not always, follows the recommendations of its advisory committees.
J&J has developed sirukumab through a partnership with GlaxoSmithKline (GSK) launched in 2011. GSK gained exclusive rights to commercialize sirukumab in North, Central, and South America, while Janssen retained commercialization rights in the rest of the world, including Europe.
J&J’s Janssen Biotech submitted the Biologics License Application for sirukumab in September 2016, based on data from the five Phase III trials comprising the SIRROUND clinical development program—SIRROUND-D, SIRROUND-T, SIRROUND-H, SIRROUND-M, and SIRROUND-LTE.
September 22 PDUFA Date
The FDA has set a September 22 target date for a decision under the Prescription Drug User Fee Act (PDUFA).
“We are disappointed and disagree with the group’s interpretation of the sirukumab benefit-to-risk profile,” Newman Yeilding, M.D., head of immunology development with J&J’s Janssen R&D, said yesterday in a company statement. “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.”
Sirukumab—which J&J plans to market under the name Plivensia™—is an anti-interleukin (IL)-6 human monoclonal antibody indicated for moderately to severely active RA in adults who have had an inadequate response or are intolerant to one or more disease-modifying antirheumatic drugs (DMARDs).
Sirukumab is designed to work by targeting IL-6, a naturally occurring protein believed to play a role in RA and other autoimmune conditions. According to J&J, sirukumab inhibits the IL-6 pathway differently than other IL-6 inhibitors currently approved for RA.
One advisory panel member expressed reluctance to recommend approval of sirukumab given recent FDA approvals for two other IL-6 targeting monoclonal antibodies. Sanofi and Regeneron Pharmaceuticals won the agency’s nod for RA-indicated Kevzara® (sarilumab) on May 22. That same day, the FDA okayed a new indication of giant cell arteritis for Roche’s Actemra®/RoActemra® (tocilizumab), an IL-6 inhibitor also approved for RA.
“If this was a new agent, I would probably be a little more enthusiastic. There is no reason to think that this new drug will act in a tremendously different way,” Maria Suarez-Almazor, M.D., Ph.D., rheumatology section chief at the University of Texas MD Anderson Cancer Center, told Reuters.
A consensus of analyst data analyzed by Thomson Reuters has projected sirukumab average global sales to reach about $450 million by 2020, compared with about $667 million by 2020 for Kevzara.