The FDA Arthritis Advisory Committee today provided the agency with mixed messages as to the safety and efficacy of the JAK inhibitor baricitinib (proposed trade name Olumiant) as a treatment for use in moderately to severely active rheumatoid arthritis (RA) in patients who have failed or were intolerant of methotrexate.
Of particular concern has been a safety signal for thromboembolism, but the committee was unable to achieve consensus as to whether or not this was clinically meaningful. "We didn't make FDA's life any easier today," commented acting committee chair Jose U. Scher, MD, of New York University School of Medicine in New York City.
The proposed application is for the drug to be approved for daily doses of 2 mg or 4 mg. With regard to safety, the vote was nine in favor of approval and six opposed for the 2-mg dose, while for the 4-mg dose the vote was five in favor and 10 opposed.
As to whether the benefit-risk profile is adequate to support approval of the 2-mg dose, the vote was 10 in favor and five opposed, and for the 4-mg dose, the vote was five in favor and 10 opposed.
With regard to efficacy, the results were clearer -- for the 2-mg dose, the vote was 14 to one in favor, and for the 4-mg dose, it was 15 to zero.
Difficulties with regard to safety for the 2-mg dose focused on the number of patients who were exposed to this dose. The 4-mg dose was included in all four pivotal phase III trials but in only two of the trials including a 2-mg dose, providing only 400 patients on the low dose. The original intent had been for 4 mg/day to be the marketed dose.
In any case, several committee members pointed out that phase III trials are not powered to detect rare events such as deep venous thrombosis and pulmonary embolism (PE), but rather are primarily concerned with efficacy.
Last April, the FDA rejected sponsor Eli Lilly's application, citing safety concerns that outweigh its efficacy, and issued a complete response letter calling for more data. The company subsequently resubmitted the application, suggesting a dosing regimen according to patients' previous use of disease-modifying anti-rheumatic drugs (DMARDs). The proposed recommended dose is now 2 mg/day, but for patients who have had an inadequate response or intolerance to more than one DMARD, the recommended dose is 4 mg/day. Those on the higher dose who achieve sustained control of disease activity can then consider the lower dose.
During the placebo-controlled phase, through week 16, there was one thromboembolic event in the placebo group with 308 patient-years of exposure, two in the baricitinib 2-mg group with 140 patient-years, and six in the baricitinib 4-mg group with 298 patient-years. Through week 52, there were two events in the placebo group, five in the 2-mg group, and nine in the 4-mg group, with 406, 335, and 900 patient-years of exposure, respectively.
Overall, among all RA patients exposed to baricitinib, there have been 20 thrombotic events, with 11 being PEs. The incidence rate of any thrombotic event was 0.46/100 patient-years.
In his vote opposed to approval because of safety concerns, Scher pointed out that the first manifestation of PE can be sudden death. In contrast, in voting "yes" regarding safety of the 4-mg dose, I. Jon Russell, MD, PhD, of the Arthritis and Osteoporosis Center of South Texas in San Antonio, said, "RA is a devastating disease. Organs are being destroyed. It's war, and we have to fight it like it's war."
Several committee members who voted "yes" also stipulated that there should be careful postmarketing safety evaluations.
An additional concern was elevations in platelets that were dose dependent. However, no correlation could be found between platelet counts and thromboembolic events.