Mallinckrodt plc’s decade-long frustration with getting approval for its vasopressin analogue selective for V1 receptors, terlipressin, for use in hepatorenal syndrome type 1 (HRS-1) continues as the FDA issued the company a third complete response letter (CRL) for the drug.

According to Mallinckrodt, of Staines-upon-Thames, U.K., the FDA said it cannot approve terlipressin’s NDA in its current form and that it requires more information supporting a positive risk-benefit profile.

Steven Romano, Mallinckrodt’s executive vice president and chief scientific officer, stood fast, saying the company remained confident in terlipressin’s data from the phase III CONFIRM study, the largest clinical trial ever conducted for the indication.

Terlipressin, for treating adults with HRS-1, had a Sept. 12 PDUFA that came and went over the weekend. There is no FDA-approved treatment for HRS-1, an acute and life-threatening syndrome involving acute kidney failure in people with cirrhosis. It is however approved for treating HRS-1 in several countries outside the U.S.

The drug received its first CRL in 2009, when the FDA asked, as it did in the second CRL, for another trial by saying the results were not statistically significant. A July 15 Cardiovascular and Renal Drugs Advisory Committee meeting focused on the results of a third randomized, blinded, placebo-controlled trial, CONFIRM, conducted under a special protocol assessment agreement. The adcom voted its approval 8-7.

The CONFIRM trial met its primary endpoint with 29% of patients in the terlipressin arm compared with 16% of patients in the placebo arm achieving verified HRS reversal.

SVB Leerink analyst Ami Fadia wrote Sept. 14 that the adcom discussion “was decidedly cautious” and it “struggled” to balance the high unmet need with no currently available treatment options “with concerns about lack of clinical benefit and an uncertain risk mitigation plan.” Fadia added that “there was no clear outline on what would be considered sufficient for approval.”

While the FDA agreed to the endpoint, the agency stressed that it was a surrogate endpoint that would have to be borne out in clinical outcomes. HRS-1 is associated with high mortality and patients also may require renal replacement therapy (RRT). According to the FDA briefing document for the adcom, RRT-free survival was slightly greater in the terlipressin arm as compared with placebo, but terlipressin was not associated with improved survival. The proportion of patients who died was slightly greater numerically in the terlipressin arm than in the placebo arm.

While the committee recognized the severity of hepatorenal syndrome type 1 and the significant unmet need in the space, they were divided on whether the FDA should follow the decades-old lead of regulators in 60 other countries in approving it.

The only definitive treatments for HRS in the U.S. are liver transplantation in patients with chronic liver disease and recovery of liver function in those with an acute but reversible cause of liver disease. However, patients who develop HRS may not make it to the “promised land of transplantation” due to the renal damage, according to a liver transplant specialist who testified in the public hearing session of the adcom meeting.

In March, Mallinckrodt completed its rolling submission of an NDA to the FDA and on April 22, the FDA accepted the NDA and assigned a Sept. 12 PDUFA.

The company’s stock (NYSE:MNK) closed down 8.3% on Sept. 14 at $1.10 per share.

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