Reviewers Voice Olumiant Safety Concerns
FDA medical reviewers say they have concerns about the safety of Lilly’s Olumiant (baricitinib) being proposed to treat adults with moderately to severely active rheumatoid arthritis who have had an inadequate response or are intolerant to methotrexate. The company’s NDA will be considered at a 4/23 meeting of the agency’s Arthritis Advisory Committee. The reviewers’ comments were included in an agency briefing document distributed in advance of the meeting.
Safety concerns, including the risk of thrombosis, were first identified when the NDA was originally submitted 1/14/16, the briefing says, and the application was issued a complete response letter 4/12/17 because the overall benefit-risk assessment for the proposed 2 mg and 4 mg once-daily doses was not favorable.
The company resubmitted its application 12/4/17. The reviewers say there is general agreement that the data submitted demonstrate efficacy for Olumiant in rheumatoid arthritis at doses of 2 mg and 4 mg once daily. However, they say they identified a safety profile “consistent with that of a potent immunosuppressant with major safety risks of serious and some fatal infections, including opportunistic infections and tuberculosis, malignancy, laboratory abnormalities of increase in platelet counts, decrease in neutrophil counts, and increases in lipid parameters, and serum creatine phosphokinase.” The briefing says that many of the adverse reactions appear to be dose-dependent. Also, it says, arterial and venous thromboses were observed in association with Olumiant treatment.
One of the questions the agency is asking advisors is whether the benefit-risk assessment is favorable for either the 4 mg or 2 mg dose. The reviewers note that in its resubmission, the company proposed a different, more complicated, dosing strategy that deviates from labeling for other non-biologic disease-modifying antirheumatic drugs (DMARDs). “This is problematic given that the clinical development program was not designed to support the proposed dosing strategy,” the reviewers say. “While Lilly submitted a rationale for the dosing recommendations, it is primarily based on post-hoc analyses which do not provide convincing evidence that the relative benefit of the two doses differs according to degree of prior DMARD use, or that the 4 mg dose provides meaningful added benefit over 2 mg in the proposed subpopulation of patients with an inadequate response or intolerance to two or more DMARDs.”
The briefing document contains five detailed questions for committee members to discuss.