FDA Approves Terlivaz for Kidney Dysfunction Syndrome

The FDA has approved Mallinckrodt’s Terlivaz (terlipressin). Terlivaz is the first therapy approved to improve kidney function in patients with hepatorenal syndrome (HRS), a rare form of kidney disfunction. An injection, Terlivaz is approved for adults who have a rapid reduction in kidney function, which is an acute and life-threatening condition requiring hospitalization.

Hepatorenal syndrome is characterized by a progressive deterioration in kidney function in people with advanced liver disease. This is most common in those with advanced cirrhosis and ascites, an abnormal buildup of fluid in the abdomen that is often related to liver disease. The prognosis is very poor. Hepatorenal syndrome involving rapid reduction in kidney function is estimated to affect between 30,000 and 40,000 Americans annually. The only cure is a liver transplantation.

Steven Romano, M.D.

“Diagnosing and treating HRS can be challenging, and every minute counts when managing patients who have it,” Steven Romano, M.D., executive vice president and chief scientific officer at Mallinckrodt,” said in a press release.

The approval is based on results from the phase 3 CONFIRM trial with 300 patients in the United States and Canada. The trial met its primary endpoint of Verified HRS Reversal, defined as renal function improvement, avoidance of dialysis and short-term survival. To be included in the primary efficacy endpoint analysis, patients had to be alive and without intervening renal replacement therapy at least 10 days after achieving Verified HRS Reversal.

The trial, which was published in the New England Journal of Medicine in March 2021, found that Terlivaz was more effective than placebo in improving renal function but was associated with serious adverse events, including respiratory failure. Verified reversal of hepatorenal syndrome was reported in 63 patients (32%) in the Terlivaz group and 17 patients (17%) in the placebo group.

At day 90, liver transplantations had been performed in 46 patients (23%) in the Terlivaz group and 29 patients (29%) in the placebo group, and death occurred in 101 (51%) of patients Terlivaz group and 45 (45%) in the placebo group. Death within 90 days due to respiratory disorders occurred in 22 patients (11%) in the Terlivaz group and 2 patients (2%) in the placebo group.

“The durability of HRS reversal with terlipressin in CONFIRM persisted to Day 30 without the need for renal replacement therapy (RRT). This is a clinically significant observation, as RRT poses many challenges for patients with advanced cirrhosis,” lead author Florence Wong, MBBS, MD, hepatologist at Toronto General Hospital and professor of medicine at the University of Toronto, said in a press release when the results were released last year.

Related: Mallinckrodt Resubmits Application for Terlipressin

In June, Mallinckrodt has resubmitted its application for Terlivaz after the FDA had issued a complete response letter to inspect a new third-party packaging and labeling facility. Mallinckrodt had identified a new third-party packaging and labeling facility and an FDA inspection of the facility could not be completed by the February PDUFA date, resulting in the receipt of the CRL. This was the only outstanding issue noted in the CRL; no safety or efficacy issues cited.