The Food and Drug Administration (FDA)’s Cardiovascular and Renal Drugs Advisory Committee voted 8 to 7 in favor of the approval of terlipressin for the treatment of adults with 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). Results from the trial showed that a greater proportion of patients in the terlipressin arm achieved verified HRS reversal (primary end point defined as renal function improvement, avoidance of dialysis, and short-term survival) compared with placebo (29.1% [n=58] vs 15.8% [n=16]; P =.012).
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 a serum creatinine 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 renal replacement therapy/dialysis up to day 30 in 31.7% (n=63) of treated patients vs 15.8% (n=16) of patients receiving placebo (P <.003).
However, in meeting documents, the FDA committee noted that an exploratory analysis of treatment effects on clinical outcomes showed terlipressin was not associated with improved survival compared with placebo.
With regard to safety, the most common adverse events reported 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%). In the meeting, the panel raised concerns over the respiratory failure events, which they noted “may not be reliably predicted and managed.” They added that “most of the risk mitigation steps proposed by the applicant have not been tested.”
Although not bound by the committees’ recommendations, the FDA does take them into consideration when making decisions on approval.
Commenting on the committee vote, Steven Romano, MD, Executive Vice President and Chief Scientific Officer at Mallinckrodt, said: “We acknowledge the clinical challenges associated with treating this complex disease in such a critically ill patient population. We are committed to working closely with the FDA as it continues to review our application.”
A Prescription Drug User Fee Act (PDUFA) target action date of September 12, 2020 has been set for this application.
For more information visit fda.gov.