FDA panel to chew over endpoint, safety strategies for Mallinckrodt's terlipressin

Mallinckrodt unveiled phase 3 data in November showing its rare disease med terlipressin beat placebo at reversing a type of kidney failure. An FDA panel will convene on Wednesday to help the agency decide the drug’s fate—and their key question will be about the study’s surrogate endpoint.

The company is developing the drug, terlipressin, to treat hepatorenal syndrome type 1 (HRS-1), a type of quickly progressing kidney disease that affects people with cirrhosis. The phase 3 study pitted terlipressin against placebo in 300 patients, finding that the drug reversed HRS in 29% of patients compared to 16% for placebo.

The FDA had agreed to use HRS reversal as the study’s primary endpoint. To meet the endpoint, patients had to record serum creatinine levels of 1.5 mg/dL or lower, measured at least two hours apart on day 14 of treatment or discharge from hospital. They also had to be alive without renal replacement therapy (RRT)—which includes dialysis, hemofiltration and a kidney transplant—for at least 10 days after meeting the serum creatinine threshold.

Now, the FDA is asking its Cardiovascular and Renal Drugs Advisory Committee if “terlipressin’s effect on verified HRS reversal is accompanied by treatment effects on clinical outcomes,” including how long patients lived without needing RRT and how long they had to stay in the intensive care unit. The agency is also interested in post-transplant outcomes, that is, if patients lived longer or had better kidney function after undergoing a liver transplant.

The panel’s second question, of course, will be safety. The terlipressin and placebo groups experienced serious side effects at roughly the same rate: 65% versus 61%. The most common serious side effect was respiratory failure, which occurred in 10% of terlipressin patients and 3% of placebo patients, followed by abdominal pain (5% versus 1%).

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Patients died at roughly the same rate in the first 30 days after treatment (42% for terlipressin versus 40% for placebo), but the death rates separated as time went on, FDA staff noted in briefing documents released ahead of the panel meeting. In the first 90 days after treatment, 51% of terlipressin patients died, compared to 44% of placebo patients.

Most of the patients died from “hepatic disorders”—which is expected in HRS—with a slightly higher incidence in placebo patients compared to terlipressin patients. It was the opposite with other causes of death, including respiratory failure, sepsis and septic shock—the death rates for terlipressin were 9%, 3% and 6%, respectively, while the rates for placebo were 1%, 0% and 2%, respectively.

Mallinckrodt has proposed a few ways to manage these side effects. A key question for the panel is whether they will be enough.

SVB Leerink analysts called the briefing documents “balanced,” but added that “it appears there is some uncertainty around the clinical outcomes benefit or how the company will mitigate some serious AEs.”

Overall though, they think that terlipressin will meet a “favorable outcome,” as it’s a “high-unmet need condition with no approved therapies.”