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Terlipressin's successful third try at a significant pivotal trial efficacy result in hepatorenal syndrome type 1 (HRS-1) persuaded only a bare majority of an FDA advisory panel that the benefits outweigh the substantial risks.

The voted 8-7 in favor of recommending approval for the synthetic vasopressin analog for the more severe phenotype of HRS.

Voting was notably split along specialty lines with the cardiologists on the panel typically voting in favor and the nephrologists voting against what would be the first drug with an indication for HRS-1.

"As cardiologists, we're somewhat used to failing organs and having similar experience with vasoactive and inotropic agents," said David J. Moliterno, MD, of the University of Kentucky Medical Center in Lexington, explaining his yes vote. "This is a very severe disease, and we need to recognize this drug is not a cure. It's a temporizing agent that's shifting risk from a hepatorenal death to other maladies. It's a mitigating strategy while waiting for transplantation."

"I would have loved to vote yes," said Patrick H. Nachman, MD, a nephrologist at the University of Minnesota in Minneapolis. However, he pointed to the "clear risk of harm" without a good understanding of the mechanism behind it, no signal of survival benefit even with modeling for risk mitigation approaches, and even a signal of lower likelihood of liver transplant in those given the drug.

Terlipressin was initially declined by the FDA in 2009 based on a 112-patient trial that failed on its primary aim of keeping patients alive with reversal of high serum creatinine. Its sponsor, Mallinckrodt Pharmaceuticals, tried again with the but again failed for the primary endpoint of confirmed HRS reversal.

The company's third try, with the , 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.

However, adverse events were the big focus.

Respiratory failure serious adverse events occurred in 8.3% of terlipressin patients versus 2.4% on placebo across the three trials. Fatal respiratory failure events occurred in 7.7% vs 2.0% on placebo across the trials.

Chris Pappas, MD, JD, of Baylor College of Medicine in Houston, who spoke on behalf of the company, noted that these events increased across the 15 year development period for the drug and were most notably different in the CONFIRM study, coincident with changes in clinical practice toward an increased use of albumin that likely increased fluid overload. Mean total exposure to albumin increased almost 50% from REVERSE to CONFIRM.

Based on these findings, the company with labeling to largely restrict use to patients with:

• Serum creatinine <5 mg/dL and acute-on-chronic liver failure (ACLF) grade less than 3
• No new onset or worsening dyspnea, tachypnea, or significant respiratory disease until the patient is stabilized
• A protected airway for patients with worsening hepatic encephalopathy
• Close monitoring for signs of fluid overload (managed by reducing administration of albumin and other fluids and judicious use of diuretics)

Activation of the risk mitigation strategies would be expected to reduce risk of serious sepsis events by 40% and fully mitigate the risk of serious respiratory failure with a further substantial gain in HRS reversal and in a number of patients alive without renal replacement therapy by day 90, said Arun Sanyal, MD, of Virginia Commonwealth University in Richmond, also speaking on behalf of Mallinckrodt.

The company also proposed an education plan, enhanced pharmacovigilance, and a post-approval prospective cohort safety study.

However, the FDA presenters .

FDA Clinical Analyst Tzu-Yun McDowell, PhD, argued that CONFIRM's results were despite a protocol that cautioned investigators about evaluating for pulmonary edema and about albumin use in those with fluid overload, especially those with respiratory events.

"HRS patients have a high background rate of dyspnea, fluid overload and pneumonia," said McDowell. "It may be challenging to clinically implement."

Moreover, subgroup analysis showed no difference in risk of serious respiratory failure events by serum creatinine levels across all three studies. The risk was still present in those with levels under the proposed threshold.

Panelists, too, focused their questions and concerns on how well the mitigation strategies would work.

Moliterno said he was "not convinced that the mitigation measures proposed would be effective or implementable."

"This is an awfully important unmet need. My colleagues want it; I want it," said hepatologist Steven Solga, MD, of the University of Pennsylvania Perelman School of Medicine in Philadelphia. Still, he voted no.

"When you have sick patients and few options, there is a tendency to grope for something rather than not having something," he said. "I worry that, in the long run, that doesn't fix anything or help patients."

The FDA is not required to follow the advice of its advisory committees on drug approval but typically does. In general, the agency interprets close votes as no recommendation one way or the other.

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