Terlipressin NDA for Hepatorenal Syndrome Type 1 Submitted for Review

Mallinckrodt announced the completion of its rolling submission of a New Drug Application (NDA) to the Food and Drug Administration (FDA) for terlipressin for the treatment of hepatorenal syndrome type 1 (HRS-1).

Terlipressin is a vasopressin analogue selective for V1 receptors. The NDA is supported by data from the phase 3 CONFIRM trial, a multicenter, double-blind, placebo-controlled trial that evaluated the efficacy and safety of terlipressin in patients with HRS-1 (N=300). Patients were randomized 2:1 to receive either terlipressin (n=199) intravenously as a bolus injection over 2 minutes at a dose of 1mg every 6 hours or placebo (n=101). 

Results showed that a greater proportion of patients in the terlipressin arm achieved Verified HRS Reversal (primary end point) compared with placebo (29.1% [n=58] vs 15.8% [n=16]; P =.012). Verified HRS Reversal was defined as renal function improvement, avoidance of dialysis, and short-term survival. Patients achieved Verified HRS Reversal if they had 2 consecutive serum creatinine (SCr) values ≤1.5mg/dL at least 2 hours apart by day 14 or hospital discharge, and lived at least 10 days without intervening renal replacement therapy (RRT) following discharge or treatment.

Additionally, terlipressin met key secondary end points with 36.2% (n=72) of terlipressin-treated patients demonstrating HRS reversal, defined as the proportion of patients with an SCr value ≤1.5mg/dL by day 14 or discharge, vs 16.8% (n=17) of patients in the placebo arm (P <.001). Terlipressin was also associated with HRS reversal maintenance without RRT/dialysis up to day 30 in 31.7% (n=63) of treated patients vs 15.8% (n=16) of patients receiving placebo (P <.003). Moreover, 33% (n=24/84) of terlipressin-treated patients with systemic inflammatory response syndrome achieved Verified HRS Reversal vs 6.3% (n=3/48) of the placebo arm (P <.001). 

With regard to safety, the most common adverse events in the terlipressin and placebo arms were abdominal pain (19.5% vs 6.1%) and nausea (16% vs 10.1%); the most commonly reported serious adverse events included respiratory failure (10% vs 3%) and abdominal pain (5% vs 1%), respectively.

“Completion of the NDA submission for terlipressin is another important step forward in our goal of bringing the first FDA-approved therapeutic option to patients in the US with HRS-1 – a life-threatening, difficult-to-treat condition,” said Steven Romano, MD, EVP and Chief Scientific Officer at Mallinckrodt. “We look forward to working with the FDA during the regulatory review process in the coming months, and are grateful to the patients, caregivers and investigators who participated in our clinical trial.”

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