FDA Review: Take Two for Baricitinib Save

FDA staff remain worried about the safety of baricitinib, an oral JAK inhibitor intended for treatment of rheumatoid arthritis, according to briefing documents prepared for an advisory committee meeting on Monday.

The Arthritis Advisory Committee will meet to reconsider Eli Lilly's marketing application, which the agency turned down a year ago. Lilly wants to market baricitinib for moderately to severely active rheumatoid arthritis (RA) in patients who have had an inadequate response to methotrexate.

In April 2017, the FDA told the company that it would not approve the drug because of concerns about safety and dosing, confirming its rejection in a so-called complete response letter that stated, "The overall benefit-risk assessments of the baricitinib 2- and 4-mg once-daily doses have identified safety concerns that outweigh efficacy observed with the proposed dosing regimen."

Baricitinib had previously been approved in Europe in dosages of 2 and 4 mg/day. In the original submission, 4 mg/day was the recommended dosage, with an option for 2 mg/day for some patients.

The resubmission has revised the dosing recommendations so that clinicians can adjust the dose according to patients' history of disease-modifying anti-rheumatic drugs (DMARDs). The recommended dose now is 2 mg once daily, but for patients who have an inadequate response or intolerance to more than one DMARD, a dosage of 4 mg/day is recommended. In addition, tapering to 2 mg once daily may be considered for patients who have sustained control of disease activity with the 4-mg dose.

"Currently in over 40 countries we have both the 2 and 4 mg approved," said Christi Shaw, president of Lilly Bio-Medicines. "What we've done this time is to incorporate feedback to show what populations specifically had the highest benefit-risk ratio. So if you look at the data where patients have tried multiple other therapies and failed, those are the patients who responded best to 4 mg. We're trying to give options to both patients and physicians," she told MedPage Today.

In briefing documents made available before the meeting, the FDA's executive summary stated that "specific deficiencies included the potential thrombotic risk, inadequate safety exposure for baricitinib 2 mg, inability to demonstrate consistent efficacy advantage of baricitinib 4-mg over 2-mg dose, and questions regarding dose-selection, given identified dose-related toxicities."

The drug's clinical development program included four pivotal phase III trials. All four studies included the 4-mg dose, because that was the dose the company planned to market, and the 2-mg dose was only included in two of the trials. This discrepant exposure to the two doses presented an obstacle to interpretation of the risk:benefit ratio, the FDA document explained.

With regard to efficacy, the FDA reviewers indicated that both doses were effective based on the response criteria from the American College of Rheumatology and also were associated with benefits for physical function on the Health Assessment Questionnaire-Disability Index. For structural progression, efficacy was seen for the 4-mg dose, but in the single trial that considered radiographic progression for the 2-mg dose, the data were less clear.

For safety, the FDA reviewers noted that the data suggest that baricitinib is "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."

They indicated that in the overall program for RA, there had been 10 potential opportunistic infections, including esophageal candidiasis and Pneumocystis pneumonia, as well as eight cases of tuberculosis.

Among all RA patients exposed to baricitinib, 20 experienced a thrombotic event, with 15 being serious, and the incidence rate was 0.46/100 patient-years. In Lilly's briefing document, the company stated, "Given the seriousness of thrombotic events and the need to raise awareness of this safety concern, the prescribing information will include data regarding the risk of thrombosis with baricitinib."