Mallinckrodt announced that the US Food and Drug Administration (FDA) has issued a complete response letter (CRL) regarding the company’s New Drug Application (NDA) seeking approval for the investigational agent terlipressin to treat adults with hepatorenal syndrome type 1 (HRS-1).

The CRL stated that, based on the available data, the agency cannot approve the terlipressin NDA in its current form and requires more information to support a positive risk-benefit profile for terlipressin for patients with HRS-1. HRS-1 is an acute and life-threatening syndrome involving acute kidney failure in people with cirrhosis for which there is currently no FDA-approved treatment. HRS-1 is estimated to affect between 30,000 and 40,000 Americans annually, and often is a challenge to effectively diagnose in a timely manner due to its diagnosis of exclusion. If left untreated, HRS-1 has a median survival time of approximately two weeks and greater than 80 per cent mortality within three months. US discharge data in a recently published study indicated an in-hospital mortality rate of 34.2 per cent (n=1,133), while an additional 14.4 per cent (n=475) of patients were discharged to hospice.

“While we are disappointed that the FDA issued a complete response letter for terlipressin, we remain confident in the strength of the data from our Phase 3 CONFIRM study, which is the largest clinical trial ever conducted in this rare condition. HRS-1 is a complex disease that affects a critically ill patient population with no approved treatment in the US at present. We are surprised by and disagree with the FDA’s decision and remain committed to pursuing all available options as we continue working with the FDA toward approval of terlipressin in order to help address this difficult and life-threatening syndrome,” Steven Romano, Executive VP and Chief Scientific Officer at Mallinckrodt.

Terlipressin is an investigational agent being evaluated for the treatment of HRS-1 in the US, and its safety and effectiveness have not yet been established by the FDA.

In 2005, terlipressin was granted Fast Track designation by the FDA, which provides for expedited review to facilitate development of drugs intended to treat serious or life-threatening conditions and fill an unmet medical need. In 2016, Mallinckrodt and the FDA reached agreement on the Phase 3 CONFIRM trial protocol design and data analysis under the agency’s special protocol assessment (SPA) process. A SPA is an advance 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.

On July 15, 2020, the company announced that the Cardiovascular and Renal Drugs Advisory Committee of the FDA voted to recommend approval of its investigational agent terlipressin to treat adults with HRS-1 based, in part, on results from the Phase 3 CONFIRM trial. The CONFIRM trial was the largest-ever prospective study (n=300) conducted to assess the safety and efficacy of terlipressin in patients with HRS-1 for potential use in the US and Canada. Initial results were presented in a late-breaking session at The Liver Meeting 2019, the annual meeting of the American Association for the Study of Liver Diseases (AASLD).