FDA rejects Mallinckrodt's kidney drug over risk-benefit doubts

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The FDA has asked Mallinckrodt for more information to "support a positive risk-benefit profile." (FDA)

The FDA has rejected Mallinckrodt’s request for approval of terlipressin in a rare type of progressive kidney failure. Mallinckrodt suffered the setback despite hitting its primary endpoint in phase 3 and winning the backing of an advisory committee in a split decision.

Terlipressin is a vasopressin analogue selective for V1 receptors that came through a phase 3 clinical trial in 300 hepatorenal syndrome type 1 (HRS-1) patients last year. The phase 3 showed 29% of patients who took terlipressin experienced HRS reversal, as defined in part by serum creatine levels falling from 2.25 mg/dL and rising to below 1.5 mg/dL by Day 14 or discharge. Sixteen percent of placebo patients experienced such a change. 

The difference was big enough for the trial to hit its primary endpoint, but signs of trouble emerged when the FDA released briefing documents ahead of an advisory committee meeting in July. Notably, the FDA asked the committee to consider whether terlipressin’s effect on serum creatine levels “is accompanied by treatment effects on clinical outcomes.”

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The committee backed terlipressin by eight votes to seven but evidently failed to allay all of the FDA’s concerns. In disclosing the complete response letter, Mallinckrodt said the FDA “requires more information to support a positive risk-benefit profile for terlipressin for patients with HRS-1.”

Mallinckrodt Chief Scientific Officer Steven Romano, M.D., expressed surprise and disappointment in the rejection, adding that he disagrees with the decision and will pursue “all available options” to get the drug to the U.S. market.

Other companies have tried to achieve that goal. Terlipressin first went up for review at the FDA more than a decade ago. Orphan Therapeutics made that original attempt to bring terlipressin to the U.S. market despite missing its primary endpoint in phase 3. Ikaria picked up the North America rights to terlipressin in the wake of the FDA rejection, only for the drug to flunk another late-phase trial.

Mallinckrodt entered the story in 2015 when it paid $2.3 billion to buy Ikaria, primarily to get its hands on INOmax. After talking to the FDA, Mallinckrodt gained the confidence to take another run at bringing terlipressin to market. The phase 3 design was agreed in 2016. 

In disclosing the complete response letter, Mallinckrodt referenced the fact that the FDA had agreed on the “acceptability of the clinical design, endpoints and statistical data analyses” before the phase 3 got underway. Despite that, the author of the FDA briefing document and several members of the advisory committee had questions about whether the surrogate endpoint used in the phase 3 trial translates into meaningful clinical benefit that offsets risks including sepsis. 

Mallinckrodt was looking to the approval of terlipressin to provide some good news—and ultimately sales of $300 million a year—at a tough time for its business. Shares in Mallinckrodt have fallen more than 65% this year amid a range of problems, including discussions with “financial creditors and litigation claimants” that led it to opt against holding a Q&A session on its last quarterly results conference call.   

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