FDA's AAC Rejects Janssen Biotech's Sirukumab

The FDA’s Arthritis Advisory Committee (AAC) did not recommend the approval of Janssen Biotech’s sirukumab, a proposed monoclonal antibody for the treatment of moderate to severe rheumatoid arthritis (RA) in adults who have an inadequate response to, or an intolerance of, 1 or more disease modifying anti-rheumatic drugs (DMARDs).

Sirukumab blocks the IL-6 pathway differently than the approved IL-6 inhibitors in the marketplace, and the drug maker hoped that the product could provide a treatment option for patients who had not achieved adequate control of their RA through other therapies.

Despite enthusiasm for the potential addition of a new therapy to the range of options for the treatment of RA, the AAC had substantial concerns about the safety data presented from sirukumab’s phase 3 development program, which evaluated patient response to 50 mg and 100 mg doses of sirukumab every 4 and 2 weeks, respectively, in 3000 patients whose RA was active despite previous DMARD and biologic treatment. During the study, 35 patient deaths were reported, 34 of which occurred in the sirukumab arm. The most common causes of death included major cardiac adverse events (AEs), infection, and malignancy.

The FDA said in its briefing document for the AAC meeting that a signal for a safety finding was a trend in increased overall mortality with sirukumab over the placebo, and the fact that increased mortality was seen in both of the sirukumab doses at comparable rates.

Sirukumab was also associated with laboratory abnormalities including decreased neutrophil count, increased liver function test values, and increased lipid parameters (low-density lipoprotein, high-density lipoprotein, and triglycerides). These abnormalities were documented with both doses of the drug. The FDA noted that immunosuppression-related AEs and laboratory parameter changes were similar to those related to other products targeting the IL-6 pathway, but the increased overall mortality demonstrated in the study was cause for concern.

"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.

Janssen’s head of immunology development, Newman Yielding, MD, said, “We are disappointed and disagree with the group's interpretation of the sirukumab benefit-to-risk profile,” and added that the company will continue to discuss the drug with the FDA.

The news comes just after Merck and Samsung Bioepis launched their infliximab biosimilar, Renflexis, at a 35% discount to Janssen’s reference product, Remicade, which earned Janssen $7.83 billion in global sales last year. With its market share for infliximab at risk of erosion from biosimilar competition, Janssen had likely hoped to recapture a portion of the RA market with sirukumab, given its broad proposed indication. It remains to be seen whether Janssen will continue to invest in further studies in an effort to demonstrate that the benefits of its product outweigh its risks.