Mallinckrodt announced positive top-line results from its pivotal Phase 3 CONFIRM clinical study evaluating the efficacy and safety of terlipressin in 300 adults with hepatorenal syndrome type 1 (HRS-1). The study met its primary endpoint of verified HRS-1 reversal (p=0.012). Verified HRS-1 reversal includes three components: renal function improvement, avoidance of dialysis and short-term survival. The company plans to present the data at an upcoming medical meeting.

HRS-1 is a life-threatening, rare and acute disease characterized by complications of liver disease that lead to kidney failure. HRS-1 has a very poor prognosis, with a median survival time of less than two weeks and greater than 80 percent mortality within three months. At present, there are no approved drug therapies for HRS-1 in the U.S. or Canada. HRS-1 is estimated to affect between 30,000 and 40,000 patients in the U.S. annually.

The company plans to submit a New Drug Application to the U.S. Food and Drug Administration (FDA) in early 2020. Terlipressin is an investigational product and its safety and effectiveness have not yet been established by the FDA or Health Canada.

"The initial results from the Phase 3 CONFIRM study are very encouraging in that they demonstrate terlipressin reversed the course of HRS-1 as measured by improvement in renal function, avoidance of dialysis and short-term survival. The study met nearly all of the pre-specified secondary endpoints," said lead investigator Arun Sanyal, M.D., Z. Reno Vlahcevic Professor of Medicine, Physiology and Molecular Pathology at Virginia Commonwealth University. "HRS-1 is a life-threatening disease that is extremely difficult to treat. We anticipate the complete results will continue to help inform the effectiveness and safety profile of terlipressin in this patient population with urgent unmet medical needs."

About the Pivotal Phase 3 CONFIRM Study (multi-center, randomized, placebo-controlled, double-blind trial in the U.S. and Canada):

Designed to confirm efficacy and safety of terlipressin to treat HRS-1

Largest prospective trial ever conducted (n=300) in HRS-1 patients

Eligibility criteria included adults with liver cirrhosis and ascites with rapidly worsening renal function and no response to diuretics or albumin

Primary endpoint of verified HRS reversal was intended to evaluate renal function improvement, avoidance of dialysis and short-term survival

In 2016, Mallinckrodt and the FDA reached agreement on the CONFIRM protocol design and data analysis under the agency's special protocol assessment (SPA) process. A SPA is an advanced agreement with the FDA for the acceptability of the clinical design, endpoints and statistical data analyses for a Phase 3 trial before the start of the trial.

"At Mallinckrodt, we are committed to advancing therapies that treat underserved patients with severe and critical conditions, including patients with this devastating condition. We are pleased and encouraged by the positive top-line results of the CONFIRM trial, the largest-ever prospective trial in HRS-1," said Steven Romano, M.D., Executive Vice President and Chief Scientific Officer at Mallinckrodt. "The CONFIRM trial will support regulatory submissions of terlipressin as a treatment for HRS-1 in the U.S and Canada, and we look forward to sharing full results soon."

Terlipressin is a potent, vasopressin analogue selective for V1 receptors being investigated for the treatment of HRS-1 in the U.S. and Canada. Terlipressin is an investigational product in these countries as the safety and efficacy have not been established with, nor has approval been granted by regulatory authorities in either country. Terlipressin is approved for use outside the U.S. and Canada.

HRS-1 is a life-threatening, rare, and acute disease characterized by complications of liver disease that leads to kidney failure.1 HRS-1 has a very poor prognosis, with a median survival time of less than two weeks and greater than 80 percent mortality within three months. At present, there are no approved drug therapies for HRS-1 treatment in the U.S. or Canada.

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