FDA panel offers a wavering thumbs up for Eli Lilly’s 2 mg baricitinib, thumbs down on 4 mg

A large panel of outside rheumatoid arthritis experts gathered at the FDA to discuss Eli Lilly’s $LLY controversial re-application for an approval of baricitinib, voting in lopsided favor of the efficacy and safety of the 2 mg dose of the rheumatoid arthritis drug, but turned their thumbs down on the 4 mg dose.

Ten voted in favor of the risk/benefit balance of the 2 mg dose, 5 against. The numbers were reversed for the 4 mg, falling 10 against and 5 in favor.

Jose Scher

These expert votes hinged on a considerable amount of confusion and uncertainty, though, which several members were quick to acknowledge.

Said one member who voted yes on the adequacy of the safety data of the 2 mg dose: “This whole thing is a house of cards and I could have gone either way.”

Another: ”My best guess is yes.”

Erica Brittain: “I voted yes, I could have definitely voted no.”

“We still don’t have enough data,” said one member who voted in favor of the adequacy of the 2 mg dose.

“I would urge the sponsor to get as much data as possible on the safety side,” commented committee chair Jose Scher, who voted against both the 2 mg and 4 mg doses based on inadequate safety data.

That all could emerge as a major headache for Eli Lilly and its partners at Incyte $INCY, as the company wants to start treatment-resistant patients at 4 mg and then taper down to 2 mg if they stabilize their disease.

Lilly’s shares initially dropped 3% in early trading Tuesday, then managed to climb back up into the green, barely. Incyte shares, though, are still down 5% in mid-morning trading.

The panel discussion included a meandering series of comments, with some voices supporting an approval to offer a new option for patients and a few flagging some serious safety issues and others uncertain just what was demonstrated by the data on display.

On one point, the advisory committee found clear consensus around efficacy. By a vote of 14 to 1 they concluded that there was clear evidence of the “substantial evidence” that backed the drug’s efficacy, with a unanimous vote in favor of efficacy as a second-line therapy after patients had failed on their frontline drug.

Much of the discussion, though, centered on the safety of the drug, where regulators raised some of their most serious objections to the drug, with a startling signal on thromboembolism.

One committee member noted a discussion concerning whether rheumatologists are used to looking for and monitoring for adverse events. But, he added, “rheumatologists do not typically look for thromboembolic events, that’s not on the list of things that are traditionally watched for.”

There was a considerable discussion whether the committee had the data needed to make a conclusion on the drug’s safety, particularly when it came to the 2 mg dose. 

“None of these studies are powered to look for rare events,” said Scher, highlighting studies that weren’t powered to determine the risk of thromboembolisms, or blood clots, and noting that there was considerable confusion about the data and the conclusions that could be drawn from them — particularly relating to the 2 mg dose, where the data were lacking.

Baricitinib is a remarkable test case for the FDA. Rejected in 2017 in a stunning setback for a drug that had been billed as a blockbuster in the making, the agency reversed course and allowed Lilly to refile for an approval as a second-line therapy without the added data that had been insisted on. The agency’s review makes clear that while Eli Lilly investigators provided more information, none of it addressed their core concerns, especially regarding a higher rate of thrombosis that appeared for the first time in the field.

FDA reviewers disagreed on the data offered for the 2 mg and 4 mg doses, with some willing to wave it through and others noting that the study data for the 2 mg never provided sufficient information for a decision on safety and efficacy. There was also no consistent data to back up the 4 mg dose over the 2 mg dose, according to regulators. 

Even if it gets an approval now, Lilly is going to have an uphill fight against Pfizer’s Xeljanz (tofacitinib), the first JAK inhibitor to make it to the market — without the harsh FDA criticism or issues with thrombosis that promise to capsize Lilly’s launch.

Why offer an approval now if there are other drugs on the market that could do as well or better? And if it is approved, will this drug be reserved for last-chance opportunities?

“We know we didn’t make your lives any easier,” said Scher as he turned at the end to the FDA’s representatives.

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