Eli Lilly and Incyte acknowledged today that their resubmission of an New Drug Application (NDA) for the rheumatoid arthritis (RA) candidate baricitinib—requested by the FDA when it rejected the original application in April—will be delayed at least a year and a half while the companies assess options.

Those options, Lilly and Incyte said, include an additional clinical study sought by the FDA.

How long before the NDA is resubmitted will depend on the option decided upon, as well as further talks with the FDA, but is expected to be at least 18 months, the companies added.

“We are disappointed that resubmission will not occur this year, but are committed to bringing baricitinib to people with RA and we will work with the FDA on the path forward,” Christi Shaw, president of Lilly Bio-Medicines, said in a statement.

The delay comes as Lilly competitors pursue RA treatments. Regeneron and Sanofi in May won FDA approval for Kevzara® (sarilumab) for adults with moderately to severely active RA who have had inadequate response or intolerance to one or more disease-modifying antirheumatic drugs (DMARDs).

On June 7, AbbVie reported positive results from the Phase III SELECT-NEXT trial of its upadacitinib (ABT-494), saying both 15-mg and 30-mg doses met the study's primary endpoints of American College of Rheumatology 20 (ACR20) and low disease activity after 12 weeks of treatment. Gilead and Galapagos are in Phase III trials for their RA candidate filgotinib.

Today’s statement by Lilly and Incyte comes three months after the FDA issued a Complete Response Letter stating that it wanted additional clinical data to determine the most appropriate dose for baricitinib, as well as to further characterize safety concerns across treatment arms. The agency cited an imbalance in thromboembolic events occurring during the placebo-controlled period of the clinical program in seeking data on the benefit/risk profile across doses.

“We disagree with the FDA's conclusions, and believe the existing comprehensive clinical data demonstrate there is a positive benefit/risk profile that supports baricitinib's approval as a new treatment option for people suffering from RA in the United States,” Shaw added.

Baricitinib is a once-daily oral Janus kinase (JAK) inhibitor indicated for the treatment of moderate-to-severe RA—as well as for inflammatory and autoimmune diseases, for which the candidate is now in clinical studies.

Phase III Study Delay

However, while baricitinib is in Phase II development for atopic dermatitis and systemic lupus erythematosus, a Phase III study in psoriatic arthritis has been delayed and will not begin in 2017 as previously expected, Lilly and Incyte also disclosed today.

Lilly and Incyte have defended their original NDA, which included results of four Phase III clinical trials that met their primary endpoints and enrolled a total 3100 patients across the full spectrum of RA, from treatment-naïve to highly-treatment refractory.

Two of the four studies included prespecified comparisons to approved DMARDs: One study (RA-BEGIN) compared baricitinib to methotrexate, while another (RA-BEAM) compared the candidate to Humira® (RA-BEAM). An additional phase III study was carried out to support clinical development in China.

According to Lilly and Incyte, their clinical trial program for baricitinib included patients who are methotrexate-naïve, inadequate responders to methotrexate, inadequate responders to conventional synthetic disease-modifying antirheumatic drugs, or inadequate responders to bDMARDs including tumor necrosis factor (TNF) inhibitors.

Deep venous thrombosis (DVT) and pulmonary embolism (PE) were reported in five patients treated with baricitinib during the placebo-controlled period of two of seven completed Phase II or Phase III trials, Lilly and Incyte acknowledged. The companies added, however, that the rate of these events was consistent with that seen among the general population of treated RA patients within the overall baricitinib clinical program.

Baricitinib 2-mg and 4-mg tablets were approved for marketing under the name Olumiant® in February by the European Commission. Since then, the European Medicines Agency's (EMA) Committee for Medicinal Products for Human Use (CHMP) has agreed to update the label with a precaution for patients who have DVT and PE risk factors.

A similar caution was added to the label of baricitinib when it won approval earlier this month from Japan's Ministry of Health, Labor and Welfare, also under the name Olumiant. The drug won approvals in June in Kuwait and Switzerland.

In 2009, Lilly agreed to co-develop baricitinib and follow-on compounds for inflammatory and autoimmune diseases, gaining global rights through a global license and collaboration agreement in which it paid Incyte $90 million upfront and up to $665 million tied to achieving milestones.

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