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.

The effects of terlipressin appear to give clinicians a way to “stabilize renal function and buy time,” making it more feasible to try to rush the patient to liver transplantation or at least to “stop their downward spiral” as patients with decompensated liver failure develop inadequate renal blood flow that produces an acute fall in kidney function, explained David N. Assis, MD.

Assis is a hepatologist at Yale Medical School in New Haven, Connecticut. “The reality is, nothing else is available, aside from renal replacement therapy and pressors. There is a need for a treatment that buys time,” he said. He voted to recommend approval.

That sentiment was notably echoed in comments from the two nonclinical members of the advisory committee.

“This treatment addresses a major gap in care,” said Jacqueline D. Alikhaani, the panel’s consumer representative. “Allow patients to decide if they want this treatment,” said Daniel Bonner, the committee’s patient representative. Both voted in favor of FDA approval.

Terlipressin has been a long-standing lynchpin for treating hepatorenal syndrome type 1 in Europe and other places outside the United States and Canada.

The most recent guidelines for managing patients with decompensated cirrhosis from the European Association for the Study of the Liver say that “[t]erlipressin plus albumin should be considered as the first-line therapeutic option for the treatment of hepatorenal syndrome and acute kidney injury” ( J Hepatol. 2018 Aug 1;69).

According to company representatives who presented the case for terlipressin during the meeting, bringing the drug onto the US market has been a 17-year journey, featuring three sequential trials:

  • A 112 patient placebo-controlled trial that the FDA accepted as the first of the two supportive trials needed for approval (Gastroenterology. 2008 May; 134:1360–1368);

  • A second trial with 196 patients that tested terlipressin plus albumin against placebo plus albumin and showed a nominal benefit from terlipressin that failed to achieve statistical significance (Gastroenterology. 2016 Jun;150:1579-1589);

  • The most recent trial, CONFIRM, which directly led to the advisory committee session. That trial enrolled 300 patients and met its primary endpoint. Data have not yet been published but have been reported at meetings.

One of the sources of controversy over the benefit from terlipressin centered on the primary endpoint used in CONFIRM, which required that the patient have two consecutive, low readings for serum creatinine, with levels no greater than 1.5 mg/dL while on treatment, and remain alive and free from need for renal replacement therapy for at least 10 days beyond this.

The FDA agreed to accept this as a primary endpoint but nonetheless considered it a surrogate.

According to FDA staffers who presented their take on the application, the agency accepted this primary endpoint “with the understanding that favorable trends in clinical outcomes, thought to be predicted by successful treatment of hepatic renal syndrome type 1, would be expected.”

The lack of many favorable trends in clinical outcomes helped foster the advisory committee’s divided response. The FDA’s staff uses its discretion when considering an advisory committee’s recommendations and making a final determination.

None of the advisory committee members have disclosed any relevant financial relationships.

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