Terlipressin Squeaks by FDA Review for Hepatorenal Syndrome 1

The US Food and Drug Administration’s (FDA’s) Cardiovascular and Renal Drugs Advisory Committee narrowly recommended, by an 8-7 vote, that the agency grant marketing approval to terlipressin for the treatment of hepatorenal syndrome type 1, a severe, rare, and often rapidly lethal disease. No drugs are currently licensed in the United States for this indication.

The advisory committee’s discussion and vote on July 15 showcased the struggle the 15 members faced parsing data that hinted at efficacy but also featured clear flaws and limitations, with meager evidence showing clinically meaningful patient improvements.

Several advisory committee members voiced their dilemma balancing the desperation of patients and clinicians to have an effective agent to treat a frequently fatal condition against spotty evidence of efficacy.

Their uncertainty over benefit was exacerbated by the substantial rate of serious adverse events compared with placebo. These events included respiratory failure, which occurred an absolute 9% more often among patients treated with terlipressin than among those who received placebo in the drug’s recent pivotal trial, and sepsis and septic shock, with an absolute 7% excess rate with terlipressin in comparison with placebo.

“This is an important, unmet need, and I want this drug, but the data are not clear that the benefits outweigh the risks,” commented Steven F. Solga, MD, a transplant hepatologist at the University of Pennsylvania in Philadelphia, who is a committee member.

“When you have sick patients with few treatment options, you grope for something to use, but I worry that this won’t help patients,” he said when explaining his vote against approval.

“I look forward to using this medication if I could figure out which patients could benefit from it,” he said.

“Allow Patients to Decide if They Want This Treatment”

Experts estimate that the annual incidence of hepatorenal syndrome type 1 in the United States is about 35,000 patients.

“I would have liked to vote yes, because terlipressin was associated with a short-term increase in renal function, but there was also clear evidence for the risk of sepsis and respiratory failure, and no evidence that it improved survival,” said panel member Patrick H. Nachman, MD.

Nachman, professor of medicine and director of the Division of Nephrology and Hypertension at the University of Minnesota in Minneapolis, voted against approval.

Several who voted in favor of terlipressin also shared these misgivings.

“The trend for benefit was quite small, I’m very worried about respiratory failure, and I’m uncomfortable with the postrandomization analyses” used by the developer of terlipressin (Mallinckrodt) to buttress the efficacy claims, explained panel member Paul M. Ridker, MD.

“So why did I vote yes? The problem is the enormous unmet need. Patients are in desperate shape, and the standard treatments are used off label, with no data. Here, we have data, and the primary endpoint was met,” said Ridker, who is professor of medicine at Harvard Medical School in Boston and director of the Center for Cardiovascular Disease Prevention at Brigham and Women’s Hospital in Boston.