FDA’s insider review raises serious safety issues as Eli Lilly’s quick comeback shot for baricitinib heads for expert showdown

Eli Lilly $LLY has got some explaining to do. 

And unlike the FDA, which abruptly reversed course on their rejection of Lilly’s baricitinib for rheumatoid arthritis without ever fully outlining the reasons for the about-face, there’s no getting around the challenge for the pharma giant.

David Ricks

It’s clear from the agency’s internal review, which includes conflicting conclusions from different FDA officials on the safety and benefit of the drug, that the agency had a big problem with evidence that Lilly’s drug triggered thrombosis in patients. Like any powerful immune suppressant, the Lilly drug was linked with a variety of related symptoms, but thrombosis — dangerous blood clotting — is not common to the class.

The negative tone of many of the regulators’ comments was hard to miss, and shares of Eli Lilly dropped 3% alongside a 4.5% plunge for its partners at Incyte, which just suffered a serious setback on their lead IDO drug candidate. This drug once earned rave reviews from analysts, with peak sales projections of up to $2 billion.

This is a particularly critical review for the FDA. The agency reversed course on three separate rejected drug applications following the arrival of Commissioner Scott Gottlieb, who took the helm with a mandate to speed new approvals. In each case, the FDA had demanded more work on the drugs involved, including key therapies for Amicus and TherapeuticsMD. And then they waved off the rejections and allowed the applications to proceed.

In the wake of the FDA’s rejection for baricitinib — a major blockbuster drug candidate for Lilly — the pharma giant’s team did a switch. Instead of seeking approval for a recommended 4 mg dose with occasional use of a 2 mg dose, they went to a recommended dose starting at 4 mg and then tapering to 2 mg, with treatment-resistant patients staying on 4 mg.

But some of the insiders at the FDA say that Lilly doesn’t have the safety and efficacy data it needs to back up the new dosing recommendation. There’s a clear lack of data on the safety of the 2 mg dose, they note, and not enough insight on the efficacy of the 4 mg. And they have problems with the switch-up on the dosing strategy. From the executive summary:

The proposed dosing strategy in the re- submission is more complicated and deviates from labeling for other non-biologic DMARD (disease modifying) RA products. This is also problematic, given that the clinical development program was not designed to support the proposed dosing strategy. While Lilly submitted a rationale for the dosing recommendations, it is primarily based on post-hoc analyses which do not provide convincing evidence that the relative benefit of the two doses differs according to degree of prior DMARD use, or that the 4 mg dose provides meaningful added benefit over 2 mg in the proposed subpopulation of patients with an inadequate response or intolerance to two or more DMARDs.

They want the independent experts on the panel to closely examine the data on the 2 mg and 4 mg dose before making their recommendation on an approval.

That will be complicated by the difference of opinion between the FDA’s cross disciplinary team and the division director, Badrul Chowdhury, who just left the FDA to join AstraZeneca. The cross disciplinary team was fine with both the 2 mg and 4 mg doses, but Chowdhury would only support the 2 mg dose. Here’s why:

Thrombosis has not previously been seen with either small molecule or biologic DMARDs. Safety findings of note with baricitinib were an increased risk of malignancy, opportunistic infections, tuberculosis, herpes zoster infection, and GI perforation. Malignancy and MACE tended to occur at higher rate with baricitinib 4 mg compared to 2 mg, with the imbalance driven primarily by >52 week data. The number of patients >52 weeks was too small, particularly for baricitinib 2 mg group, for conclusive comparative assessment. There were 7 cases of tuberculosis in baricitinib 4 mg group, compared to none in the baricitinib 2 mg group and placebo group. Baricitinib treatment was associated with laboratory abnormalities including increase in platelet count, decreases in neutrophil count, increase in lipid parameters, and increase in CPK, all appeared to be dose-related.

That all creates a stiff headwind for Lilly, which will push hard for an approval in order to keep up with its promised stream of major new drug approvals, a pledge to investors that new CEO Dave Ricks has committed to after Lilly dropped a commitment for two or more OKs per year. Baricitinib’s setback last year scuttled that pledge.

The panel meets Monday.

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