FDA ‘conflicted’ on Lilly and Incyte’s refiled baricitinib

Eli Lilly and Incyte’s second attempt to get U.S. approval of rheumatoid arthritis drug baricitinib could be scuppered again by lingering FDA concerns about safety.

A briefing document published ahead of the April 23 advisory committee meeting on baricitinib suggests that Lilly and Incyte’s lightning-fast amendment and refile of the dossier hasn’t added enough data to persuade the FDA to change its stance on the risk of blood clots with the JAK inhibitor.

Incyte shares yo-yoed yesterday as investors tried to work out the implications of the document, and rival JAK inhibitor developers Gilead Sciences and AbbVie also came under pressure. All the players are in pursuit of Pfizer's fast-growing JAK inhibitor Xeljanz (tofacitinib), which made $1.35 billion in sales last year.

The sticking point for the agency is that most studies of baricitinib used a 4mg daily dose of the drug which seems to offer only limited improvement over a lower 2mg dose—but raises the risk of safety issues such as pulmonary embolism and deep vein thrombosis.

Lilly and Incyte have suggested that patients should start on the lower dose and transition to the higher if necessary, but the regulator isn’t comfortable with that as the trial program for the drug wasn’t intended to support that strategy. An additional trial (JAGS) added into the refiled dossier only included the 4mg dose group.

In a research note, Credit Suisse analysts said their reading of the reviewers’ document is that FDA is “clearly comfortable with the efficacy of the product” but also “cautious on the safety profile of the higher 4mg dose [and] struggling with the more limited safety data they have for the lower 2mg dose.”

The analysts point out that there are different opinions from different FDA reviewers on the “complicated application” which will make Monday’s adcomm meeting an enticing prospect, particularly as the FDA has asked the panel to assess the risk/benefit of each dose separately. And they think that the wording of the FDA document suggests that the safety concerns could be specific to baricitinib, so other JAK inhibitors—i.e. AbbVie’s upadacitinib and Gilead’s filgotinib—will be evaluated “for their own unique profile.”

Analyst Josh Schimmer of Evercore ISI said he felt baricitinib would “squeak by” the advisory committee on Monday, but would have “dosing questions that will be a potential disadvantage relative to the profile of [AbbVie’s] upadacitinib.”

He adds: “If the panel or FDA reject the drug in favor of more 2mg (or 1mg) studies, downside to estimates and sentiment could be meaningful.”

Baricitinib was approved in Europe and Japan last year under the Olumiant brand name, and has just started to develop sales traction, with Lilly reporting $46 million in sales last year but half of that total coming in the fourth quarter alone.

For Incyte the JAK inhibitor has assumed much greater importance in the wake of the failed trial of its IDO1 inhibitor epacadostat and Merck & Co’s Keytruda (pembrolizumab) in melanoma.