Drugs

FDA Turns Down Mallinckrodt NDA for Terlipressin

FDA has issued Mallinckrodt a complete response letter on its NDA for terlipressin and its use in treating adults with hepatorenal syndrome Type 1 (HRS-1). The letter said that, based on the available data, the agency cannot approve the NDA in its current form and it requires more information to support a positive risk-benefit profile. “We are surprised by and disagree with the FDA's decision and remain committed to pursuing all available options as we continue working with the FDA toward approval of terlipressin in order to help address this difficult and life-threatening syndrome,” the company said.

Terlipressin is a potent vasopressin analog selective for V1 receptors, according to Mallinckrodt. It describes HRS-1 as an acute and life-threatening syndrome involving acute kidney failure in people with cirrhosis. It has a median survival time of about two weeks and greater than 80% mortality within three months if left untreated, it says. It is estimated to affect between 30,000 and 40,000 patients in the U.S. annually.

The submission was based on data from the Phase 3 CONFIRM trial that showed the drug improved renal function and reversed HRS-1 among patients with progressive advanced liver disease, Mallinckrodt said, adding that the response was durable and associated with less need for early renal replacement therapy.

In July, FDA’s Cardiovascular and Renal Drugs Advisory Committee offered a mixed vote (8 to 7) in favor of approval for terlipressin. In a briefing document, FDA reviewers acknowledged that trial data met the primary endpoint of HRS reversal with 29% of patients in the terlipressin arm compared to 16% in the placebo arm achieving verified HRS reversal. However, the briefing document raised safety problems, noting that the percentage of patient deaths was higher in the terlipressin arm compared with the placebo group. Other complications associated with the drug included respiratory failure, sepsis, and septic shock.

The safety concerns were the driving factor in panel members voting not to recommend approval, and other panel members agreed that the benefits outweighed the risks because there are no FDA-approved treatments for HRS Type 1.

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