The Food and Drug Administration Arthritis Advisory Committee has voted to recommend the 2-mg dose of baricitinib, an orally administered Janus kinase (JAK) inhibitor, to treat adults with moderate to severe rheumatoid arthritis who have responded inadequately or poorly to methotrexate but rejected a 4-mg dose of the same drug.
In separate votes on efficacy of the 2-mg and 4-mg doses of baricitinib (14-1 and 15-0, respectively), on their safety (9-6 and 4-11), and on their benefit-risk ratio (10-5 and 5-10), the advisory committee consistently backed the 2-mg dose, but the committee rejected the 4-mg dose despite its effectiveness in improving the symptoms of rheumatoid arthritis. Although the FDA does not always follow the advice of its advisory committees, it generally does.
The New Drug Application was resubmitted by Eli Lilly and Incyte. The proposed doses included a 2-mg once-daily dose and a 4-mg dose for some patients. The original submission was filed in January of 2016 with an indication to treat moderate to severe rheumatoid arthritis, but that application was rejected primarily because of concerns about thrombotic events. Other issues with the original application included inadequate safety exposure for the 2-mg dose of baricitinib, as well as inconsistent findings concerning the efficacy of the higher 4-mg dose.
The resubmission addressed several of the issues noted by the FDA, and changed the indication to treat patients with moderate to severe RA who have had an inadequate response to methotrexate. Along with the different indication, the dosing regimen shifted to 2 mg once daily. For patients who did not adequately respond to disease-modifying antirheumatic drugs (DMARDS) or had an intolerance for one or more of these drugs, a 4-mg dose was recommended; after disease activity had been controlled, a taper to 2 mg once daily could be considered.
Apart from changes in the drug dosage and indication, the resubmission also included accumulated safety data, comparative epidemiologic data concerning venous thromboembolism and pulmonary embolism, and efficacy analyses to support the new dosing recommendations.
“The risk-benefit ratio may be less good here,” stated Donald Miller, PharmD, a professor of pharmacy practice at North Dakota State University, Fargo. “If there is a safety issue, it’s more likely to be a problem with the 4-mg dose.”
Jon Russell, MD, PhD, medical director of Fibromyalgia Research and Consulting, San Antonio, felt that the manufacturer understood that the safety signal indicated that the benefits outweighed the risks with the 4-mg dose of baricitinib.