FDA recommends approval of terlipressin for treatment of HRS-1 despite concerns
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FDA Cardiovascular and Renal Drugs Advisory Committee voted 8-7 to recommend approval of terlipressin for the treatment of hepatorenal syndrome type 1 in patients with cirrhosis.
Terlipressin, developed by Mallinckrodt plc, is an investigational agent that consists of a synthetic, 12-amino-acid peptide analog of vasopressin.
“I voted ‘yes’ albeit with some reservation,” David N. Assis, MD, said during his final remarks. “Currently there is nothing else available or close to effective to give these patients. The benefit vs. risk is a critical issue today and a better definition of predictors of complications such as respiratory failure is really absolutely key and that needs to be better studied by the FDA prior to approval.”
The meeting’s focus concerned the results from the CONIFIRM study, a randomized, double-blind, placebo-controlled trial of 300 critically ill patients with HRS-1 who received either intravenous terlipressin or placebo. The primary endpoint was verified HRS reversal, which was defined by renal function improvement, avoidance of dialysis and short-term survival. Verified HRS reversal was achieved when patients had two consecutive serum creatinine values of 1.5 mg/dL or less, at least 2 hours apart by day 14 or hospital discharge and be alive without need for renal replacement therapy for at least 10 days after discharge or treatment.
Results showed 29% of patients who received terlipressin plus albumin achieved verified HRS reversal vs. 15.8% of patients given placebo plus albumin (P = .12). Further, more patients in the terlipressin arm experienced HRS reversal while on treatment by day 14 or discharge than those in the placebo arm (36% vs. 17%; P < .001) as well as HRS reversal without renal replacement therapy to day 30 (32% vs. 16%; P = .003).
However, in two previous studies, the primary end point did not achieve statistical significance.
Eight committee members voted yes and seven voted no. During the discussion, there was one common concern the committee members had despite voting results: risk mitigation strategy for respiratory failures and related respiratory and sepsis events was not supported by data.
“I also have the same problem that everyone does with the mitigation strategy,” Assis said. “It is vague and it’s not quite clear if its pre-use mitigation or on-use mitigation in particularly with fluid overload. This is a scenario in which a lot of education would be necessary for hepatologists. This drug would be used on a liver floor and ICU and to get hepatologists used to monitoring these potential complications early on is extremely important for any success.”
During the final comments, Assis suggested the pooled international stance on terlipressin should be looked at more closely because the drug has been used around the world already. He also said the FDA should work with Mallinckrodt plc on their own dataset.
Perspective
Back to TopMichael Curry, MD
It’s important to realize that hepatorenal syndrome type 1 (HRS-1) is a very serious condition that affects approximately 35,000 patients per year. HRS-1 is a severe complication of advanced end-stage liver disease and poses a significant mortality risk for patients. However, up to present time, we have not had an effective treatment for this disease.
The decision made by the Advisory Committee today brings us a step closer to provide patients with HRS-1 an appropriate treatment, a treatment that has been available outside of the U.S. for 2 decades and a treatment that will allow us to reverse their renal failure.
This is a medication that will be used only for hospitalized patients for the treatment of HRS-1; it is not a medication that will be approved for outpatient use.
The FDA Advisory Committee today expressed some concerns about the safety of using terlipressin. We have taken the committee’s concern seriously and look forward to working with the FDA to address this concern, but we have confidence that terlipressin is an effective and safe therapy for patients with HRS-1.
Today’s decision by the Advisory Committee will be reviewed in detail by the FDA and we welcome the opportunity to work with the FDA to resolve any concerns and make this treatment available for patients with HRS-1.
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FDA Cardiovascular and Renal Drugs Advisory Committee Meeting on NDA 22231 Terlipressin. Available at: www.fda.gov/media/139963/download. Accessed July 15, 2020.
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