FDA Arthritis Advisory Committee gives Eli Lilly’s JAK inhibitor, Olumiant, a hesitant thumbs-up for approval despite lingering concerns

In an ongoing saga over the regulatory approval of JAK (janus kinase) inhibitors, the FDA convened an Arthritis Advisory Committee (AdCom) on April 23, 2018, to discuss a revised NDA application for Eli Lilly’s JAK inhibitor, baricitinib (marketing name: Olumiant).

The entry of the oral JAK inhibitors into the G7 markets (United States, EU5, and Japan) has been an exciting development for the treatment of a number of immune disorders, where the dominant targeted therapies available were biologics requiring intravenous or subcutaneous administration. The first JAK inhibitor, Pfizer’s Xeljanz (tofacitinib), was approved for the treatment of rheumatoid arthritis (RA) in the United States and Japan in 2012. However, the EMA initially rejected Xeljanz due to concerns about its safety profile, ultimately delaying approval until March 2017 after Pfizer performed additional clinical trials1,2.

The second-to-market JAK inhibitor, Olumiant was also approved in Europe and Japan in 2017 for rheumatoid arthritis. The EMA approved Olumiant in February, one month before Xeljanz, giving Olumiant a small head-start to capture JAK inhibitor market share in Europe. Eli Lilly reported strong launch uptake in Germany by the end of 2017 while Pfizer reported growth from Xeljanz primarily in the US3,4. Given the much earlier U.S. approval of Xeljanz, the market dynamics of JAK inhibitors in Europe will be different from the United States. In addition, Xeljanz XR is not yet available in Europe, further differentiating Olumiant as the only once-daily JAK inhibitor currently on the European market.

In a moment of déjà vu for those familiar with Xeljanz’s rejection by the EMA, Eli Lilly announced at least an 18-month delay following an FDA complete response letter (CRL) for Olumiant in April 20175,6. Such a delay would have put the launch of Olumiant behind AbbVie’s JAK inhibitor, upadacitinib, for which AbbVie is expected to submit an NDA by the end of 2018 and much nearer to Galapagos/Gilead’s JAK inhibitor, filgotinib, expected to launch in 2020. However, in a stunning development, following talks with the FDA, Lilly announced in August 2017 a plan to resubmit their application for Olumiant before the end of January 20187.

Following this sooner-than-expected resubmission, an April 23rd AdCom was convened to discuss this new application for Olumiant, which sought to assess the FDA concerns leading to its CRL – namely, an imbalance in thromboembotic events in Olumiant vs. placebo groups and inadequate evidence for using a 4 mg dose instead of a lower 2 mg dose, especially in-light of dose-dependent safety concerns.

In an attempt to address these FDA concerns from the CRL, Eli Lilly performed post-hoc analyses and provided additional data from long-term extension studies that had been collected after the previous submission. However, the FDA Briefing Document released prior to the meeting suggested that the FDA remained unconvinced by the demonstrated risk/benefit profiles between the 2 mg and 4 mg doses, partly because the 2 mg dose had only been tested in two clinical trials8. In addition, the FDA document and subsequent AdCom presentation cited continued concern about Olumiant’s safety profile including elevated platelet counts that may be due to Olumiant’s binding specificity and lead to a potentially higher risk of arterial and venous thromboses.

Although the committee agreed with the FDA review team’s assessment that both the 2-mg and 4-mg doses were efficacious (voting 14 to 1 and 15 to 0, respectively), they also shared the FDA’s concerns about Olumiant’s risk/benefit profile and safety signals, particularly those of the 4 mg per day dosage. In the end, only 4 of the 15 committee members voted that the 4 mg dose had a sufficient safety profile to support approval.

During discussions the committee grappled with the lack of quantitative safety data for the 2 mg dose and how to interpret rare events of deep vein thrombosis and pulmonary embolism in RA patients, a population that is known to be at higher risk for such events. In the end, 10 of 15 committee members voted for approval of the 2 mg dose while only 5 of 15 members voted for approval of the 4 mg dose. However, even the yes votes felt lukewarm, with members stating that they could have gone either way or that the studies were not properly powered. Other members voting ‘yes’ for Olumiant’s approval requested required postmarketing safety studies and/or additional package labeling.

With the ball now in the FDA’s court, Eli Lilly, Pfizer, and AbbVie are no doubt eagerly waiting for a final decision that may reshuffle which JAK inhibitor will be next to the U.S. market. Although DRG’s 2017 Rheumatoid Arthritis DL&F predicts that the JAK inhibitor class will be the fastest growing class of RA therapies, increasing from 4% of RA sales in 2016 to 15% in 2026, the FDA appears to have increasingly stringent expectations when considering new therapies for RA9. With multiple drug classes now available for RA and lingering concerns about the safety of the JAK inhibitor class, manufacturers of emerging JAK inhibitors, AbbVie (upadacitinib) and Gilead/Galapagos (filgotinib), would do well to learn from Eli Lilly’s predicament, carefully considering their safety end points and dosing expectations, when designing clinical trials for regulatory approval.



  1. European Medicines Agency. Refusal of the marketing authorisation for Xeljanz (tofacitinib). Accessed April 30, 2018.


  1. XELJANZ® (tofacitinib citrate) Receives Marketing Authorisation in the European Union for the Treatment of Moderate to Severe Active Rheumatoid Arthritis (RA). Accessed May 4, 2018.


  1. Lilly Reports Strong Fourth-Quarter and Full-Year 2017 Revenue Growth, Increases 2018 EPS Guidance. Accessed May 4, 2018.


  1. Pfizer reports fourth-quarter and full-year 2017 results. Accessed May 4, 2018. https://investors.pfizer.com/investor-news/press-release-details/2018/PFIZER-REPORTS-FOURTH-QUARTER-AND-FULL-YEAR-2017-RESULTS/default.aspx
  2. S. FDA Issues Complete Response Letter for Baricitinib. Accessed May 4, 2018.


  1. Lilly and Incyte Provide Update on Baricitinib. Accessed May 4, 2018.


  1. Lilly to File Baricitinib Resubmission to U.S. FDA before end of January 2018. Accessed May 4, 2018.


  1. Briefing Information for the April 23, 2018 Meeting of the Arthritis Advisory Committee (AAC). FDA website. Accessed April 30, 2018 https://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ArthritisAdvisoryCommittee/ucm605060.htm.
  2. DRG’s 2017 Rheumatoid Arthritis Disease Landscape and Forecast Report.



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