On April 23, 2018 a meeting of the Arthritis Advisory Committee took place to review new drug application (NDA) 207924 sponsored by Eli Lilly and Company. The new molecular entity, baricitinib, is a Janus associated kinase inhibitor proposed for the treatment of active rheumatoid arthritis in adults who have not had an appropriate response to methotrexate. Lilly proposed a 2 mg and 4 mg oral dose of  baricitinib, to be taken once daily.

Rheumatoid arthritis can cause stiffness, functional impairment and pain. In most cases, the condition is chronic and progressive, with an increasing risk of morbidity and mortality as it progresses. Baricitinib acts as an immunosuppressant to treat the progression.

The sponsor presented 4 placebo- controlled, phase 3 trials supporting the efficacy of the 2 mg and 4 mg dose.  Both doses were found to be effective. Committee members raised concerns over the safety profile of the 4 mg dose. Thus, the 2 mg dose had a more acceptable benefit/risk profile. Safety concerns included increased risk of infection, arterial and venous thrombosis, herpes zoster, various malignancies, liver test elevations and elevated platelet counts; which were all specific to the 4 mg dose.

The panel had 2 discussion questions and 4 voting questions regarding safety, efficacy and risk/benefit ratio for each dose of the drug. The panel voted: 14 (Yes) to 1 (No) on whether the 2 mg dose was shown to be efficacious,  while voting: 15 (Yes) to 0 (No) on the efficacy of the 4 mg dose. Dr. Jon Russel explained that although the 2 mg dose was clinically efficacious, the radiographic assessment did not show any improvement.

The panel was then asked to assess the adequacy of the safety data for the 2 doses. The panel voted in support of the safety of the 2 mg dose: 9 (Yes) to 6 (No), while voting against the safety of the 4 mg dose, 5 (Yes) and 10 (No). Panelists expressed concern over the risk thromboembolic events.

The final 2 votes evaluated the benefit-risk profile of each dose, with the panel voting 10 (Yes) to 5 (No) for the 2 mg dose and 5 (Yes) and 10 (No) for the 4 mg dose. The panel members indicated that the drug should only be used if patients do not improve after using biologics; and asked for more data through a mandatory post marketing safety study.

The agency is not obligated to follow its panel’s recommendation, but normally does so. On June 1^st, 2018, the FDA approved Olumiant (baricitinib) 2 mg oral tables for treatment of adults with moderate to severely active rheumatoid arthritis. The 4 mg dose was not approved.

ISS has almost two decades of experience in developing regulatory strategies including support for FDA Advisory Committee meetings. We are involved in more FDA AdComms per year than even the largest pharmaceutical companies. For more information on how ISS can help you prepare for your next meeting, contact info@innovativescience.net

This post was authored by Sami Mourad. Sami is a summer intern at ISS and a 3rd year pharmacy student at the Rutgers University Ernest Mario School of Pharmacy