Terlipressin Shows Benefit in Hepatorenal Syndrome but Risks Spark Concern

By Gene Emery

March 04, 2021

NEW YORK (Reuters Health) - Details of the phase-3 CONFIRM trial show the vasopressin analog terlipressin can reverse the effects of type 1 hepatorenal syndrome (HRS-1), although not without potentially serious side effects.

The study, published in the New England Journal of Medicine, examined the experimental drug in HRS-1 patients who also had cirrhosis, ascites and rapidly progressing kidney failure. Albumin therapy was strongly recommended for all patients.

Terlipressin is widely used for HRS-1 outside North America and the study, financed by Dublin-based Mallinckrodt Pharmaceuticals, was designed to support its approval in the United States to help the 30,000 to 40,000 Americans with cirrhosis who face acute kidney failure. The median survival time without treatment is usually two weeks. There is no therapy approved by the U.S. Food and Drug Administration (FDA).

In September, the FDA rejected the company's application to use the drug against the rare type of progressive kidney failure in spite of the CONFIRM findings, citing the need for additional data.

With 300 volunteers at 60 sites in the United States and Canada, CONFIRM was the largest randomized, placebo-controlled test of a treatment for the syndrome.

A team led by Dr. Florence Wong of Toronto General Hospital in Ontario, Canada, found that reversal of HRS-1 occurred in 32% of terlipressin recipients versus 17% of those receiving placebo (P=0.006).

Now, because of the FDA decision, patients with HRS-1 "are left high and dry because they don't have terlipressin," Dr. Wong told Reuters Health in a telephone interview.

"These patients with hepatorenal syndrome are sick patients," said Dr. Wong. "They don't have just one organ failure. They have kidney failure. Frequently they have several organs that have failed."

"If we can fix the renal failure, at the least the patients will have an opportunity to wait for their liver transplant," she said.

Dr. Wong added that "in a small proportion of patients, for example patients who have an acute event that has precipitated the hepatorenal syndrome, such as alcoholic hepatitis . . . by reversing the hepatorenal syndrome you actually give the patients time to recover from the alcoholic hepatitis."

"For example, in patients who are usually very stable with ascites, if an infection comes along and disturbs the hemodynamics, these patients can get into hepatorenal syndrome," she said. "If you give the antibiotics time to work, then the patients can recover their liver function and their hemodynamics while you fix up the renal syndrome with terlipressin."

In the study, she and her colleagues conclude that "overall or transplantation-free survival up to 90 days did not differ significantly between the two groups." By day 90, 51% of terlipressin recipients had died versus 45% in the control group.

"Unfortunately, respiratory failure occurred in a higher percentage of patients who received terlipressin . . . as did death from respiratory failure," said Dr. Guadalupe Garcia-Tsao of the Yale School of Medicine in a linked editorial.

While 2% in the placebo group died within 90 days due to respiratory disorders, the rate was more than five times higher - 11% - in the patients getting terlipressin.

Dr. Wong said physicians who use the drug are familiar with its side effects and no new problems surfaced in the study.

Among the 58 patients who had a reversal of their HRS and completed their 30-day follow-up, 10 had a recurrence, demonstrating that "terlipressin addresses the hemodynamic abnormalities behind HRS-1 but does not eliminate the clinical milieu of advanced cirrhosis from which the syndrome arises," the researchers note.

The FDA has rejected the drug three times, first more than a decade ago when it was owned by Orphan Therapeutics, then when Ikaria took it over, and finally after Ikaria was bought by Mallinckrodt in 2015.

SOURCE: https://bit.ly/3sK3fxq and https://bit.ly/3kvlMKO The New England Journal of Medicine, online March 3, 2021.