Hepatorenal Syndrome Drug Hopes Third Time’s a Charm With FDA

Respiratory failure risk loomed large in an FDA staff review of data supporting terlipressin for an indication in the more severe type 1 phenotype of hepatorenal syndrome (HRS-1).

In documents released ahead of Wednesday’s meeting of the Cardiovascular and Renal Drugs Advisory Committee, the agency noted that the novel vasopressin analog could be the first therapy approved for the treatment of HRS.

This serious condition can develop in patients with acute or chronic liver disease with advanced hepatic failure and portal hypertension, and is thought to be due to vasodilatation in the splanchnic circulation, which leads to renal vasoconstriction, an acute increase in serum creatinine, and a decrease in urine output.

An excess in respiratory failure serious adverse events (14% vs 5.1% with placebo) was seen in the CONFIRM trial being used to support the application, which the FDA document noted is “a significant safety concern and a topic of active discussion — both within FDA and with the applicant [Mallinckrodt Pharmaceuticals].”

Most of those events were fatal in the terlipressin group, but not in the placebo group (61% vs 20% [one of five]).

The incidence and severity of respiratory failure events increased with each of the drug trials, “coinciding with increased use of albumin as part of standard of care for the treatment of HRS,” the FDA noted. “From a mechanistic standpoint, it is plausible that terlipressin could increase the risk of respiratory failure and fluid overload via effects on V1a and/or V2 receptors.”

The advisory panel is being asked to weigh both the respiratory failure risk and sepsis (which dominated among the excess in serious infections also seen with terlipressin) and whether these risks might be mitigated by some means like monitoring and patient selection.

Terlipressin was declined by the FDA in 2009 based on a 112-patient trial that failed on its primary endpoint of percentage of patients alive with serum creatinine ≤1.5 mg/dL with at least two measurements 48 hours apart. Mallinckrodt Pharmaceuticals tried again with the REVERSE trial, which again failed for the primary endpoint of confirmed HRS reversal.

The company’s third try, with the 300-patient CONFIRM trial, will be considered by the advisory panel.

CONFIRM met its primary endpoint with a 29% rate of verified HRS reversal with terlipressin versus 16% with placebo (P=0.012). That meant consecutive serum creatinine values ≤1.5 mg/dL at least 2 hours apart, while on treatment (by day 14) or at discharge, and alive without renal replacement therapy for at least 10 days after reversal.

The drug was given double-blind as a 1-mg IV bolus injection every 6 hours for a maximum of 14 days, and participants were randomized 2:1 to terlipressin or placebo. Secondary endpoints that looked at HRS reversal by different criteria all at least trended in the right direction.

Because the primary endpoint captured treatment effects on a laboratory parameter (serum creatinine), FDA considered it a surrogate endpoint and wanted to see favorable trends in clinical outcomes as well. The panel is being asked to weigh in on how reassuring the trial is in terms of efficacy both on verified HRS reversal and clinical outcomes.

Renal replacement therapy-free survival was slightly greater in the terlipressin arm as compared to the placebo arm (34% vs 28%), yet 90-day mortality was slightly greater, numerically, with terlipressin (51% vs 44%).

Treatment-emergent adverse events were more common with the drug, as expected from the drug’s mechanism and experience in other countries, with more ischemia-associated events (4.5% vs 0%), respiratory events (39.5% vs 25.3%), gastrointestinal events (47.5% vs 35.4%), and bradycardia (5% vs 0%).

The FDA is not required to follow the advice of its advisory committees on drug approval but often does.