Mallinckrodt’s Kidney Failure Drug Narrowly Wins Backing of FDA Panel

An experimental Mallinckrodt Pharmaceuticals drug for a rare type of kidney failure has won the support of an FDA advisory panel by the thinnest of margins.

The committee of mostly physicians concluded that the benefits of the drug, terlipressin, outweigh its safety risks as a treatment for hepatorenal syndrome type 1 (HRS-1), and panelists voted 8-7 on Wednesday to recommend regulatory approval. The FDA is not obligated to follow advisory panel recommendations, but their deliberations are taken into consideration. A decision for the Mallinckrodt (NYSE: [[ticker:MNK]]) drug is expected by Sept. 12.

Hepatorenal syndrome is a life-threatening complication of liver disease characterized by deteriorating function of the kidneys. There are two types. Type 1, the more rapidly progressing form of the disorder, leads to renal failure. There are no FDA-approved therapies for HRS-1, though terlipressin does have regulatory nods in Europe, Australia, and New Zealand. Dialysis can be used to treat some patients but it doesn’t remedy the underlying condition. The only cure is a liver transplant, which addresses both the liver disease and the associated kidney dysfunction. But many patients don’t qualify for that option.

The exact cause of HRS-1 isn’t known, but the National Organization of Rare Disorders notes that researchers point to abnormal blood flow. In HRS-1 patients, a widening of arteries in much of the body leads to a narrowing of blood vessels carrying blood to the kidneys. Terlipressin is an engineered version of vasopressin, a hormone that plays a role in blood pressure regulation and kidney function. The intravenously administered Mallinckrodt drug is a vasodilator—it’s designed to constrict blood vessels in the body. By restoring proper blood flow in the rest of the body, the drug is intended to improve the blood flow to the kidneys, helping them function better.

Last November, Staines-Upon-Thames, UK-based Mallinckrodt reported data from a 300-patient Phase 3 clinical trial showing that 29.1 percent of those treated with terlipressin achieved a reversal of HRS, the main goal of the study, compared with just 15.8 percent of those given a placebo. HRS reversal was defined as showing improved kidney function, avoiding dialysis, and patient survival. It was verified by measuring blood levels of creatinine, a muscle waste product filtered by the kidneys. Testing creatinine levels is one way to assess whether kidneys are functioning properly.

Though the Mallinckrodt drug met the goals of its pivotal study, the results are clouded by safety problems. FDA reviewers noted that the percentage of patient deaths was higher in the terlipressin arm compared with the placebo group. Complications associated with respiratory failure, sepsis, and septic shock were also reported at higher rates in the terlipressin group.

Concerns about terlipressin’s safety kept some of the panelists from voting in favor of the Mallinckrodt drug. But those in the narrow majority supporting the drug’s approval noted that there are no FDA-approved treatments for HRS-1.

Terlipressin was initially developed by Orphan Therapeutics, which advanced the drug through pivotal testing and an FDA submission in 2009, according to Mallinckrodt’s briefing documents. The agency rejected the drug, advising the company to conduct another clinical trial. Months later, New Jersey-based biotech Ikaria licensed North American rights to the drug and pressed ahead with another Phase 3 test. That study did not meet its main goal, but in 2015 Ikaria resubmitted the drug again anyway based on the totality of evidence from clinical testing. The agency deemed that application incomplete.

Mallinckrodt added terlipressin to its pipeline five years ago via the $2.3 billion acquisition of Ikaria. The centerpiece of that deal was an inhaled nitrous oxide product the New Jersey-based biotech marketed as INOmax. The drug is a vasodilator approved to treat hypoxic respiratory failure in infants. Last year the product generated $571.4 million in sales, a 5.4 percent increase over sales in 2018, Mallinckrodt reported.

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