Mallinckrodt plc today announced it has resubmitted the New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for the investigational agent terlipressin to treat adults with hepatorenal syndrome (HRS-1) involving rapid reduction in kidney function. HRS-1 an acute and life-threatening condition for which there is currently no FDA-approved treatment

The resubmission follows ongoing discussions with the FDA resulting from a Complete Response Letter (CRL) received on February 18, 2022. In the two weeks before the PDUFA date of February 18, 2022, Mallinckrodt had to identify a new third-party packaging and labeling facility. Although the company found a new facility, there was not enough lead time for FDA to complete an inspection by the February PDUFA date. Mallinckrodt notes that this was the only outstanding issue noted in the CRL, as there were no safety or efficacy issues cited.

The drug has been approved outside the United States for more than 30 years, is available on five continents, and is considered the standard of care for its two indications in the countries where it is approved, Mallinckrodt executives note. Terlipressin is a potent vasopressin analogue selective for V1 receptors, and together with albumin, is currently the standard of care for HRS-1 in countries where it is available.

This was the second time Mallinckrodt had received a Complete Response Letter for terlipressin. The first CRL came in September 2020, which stated that based on the available data, FDA could not approve the terlipressin NDA in its current form and requiresd 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 percent mortality within three months.

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.

The company in October 2020 announced results from two post-hoc studies of terlipressin in adults with HRS-1. he results, based on pooled analyses of three Phase III trials including the pivotal CONFIRM study, found that HRS-1 patients treated with terlipressin (N=352) required renal replacement therapy (RRT) (dialysis) less often and had improved RRT-free survival up to Day 90 compared to placebo (N=256).

Results from this pooled analysis showed: at Day 30, 26 percent in the terlipressin group (56/218) needed RRT compared with 42 percent of those on placebo (70/166); at Day 60, 27 percent of the terlipressin group (52/193) required RRT versus 45 percent on placebo (64/143); and at Day 90, 29 percent of surviving patients in the terlipressin group (52/182) needed RRT compared with 45 percent in the placebo group (60/133).

The pooled analysis also showed that RRT-free 90-day survival was higher among patients treated with terlipressin versus placebo in all three trials. The pooled RRT-free survival rate for patients treated with terlipressin was 37 percent (130/352) versus 29 percent in the placebo group (73/256) across the three trials (p=0.03).

“The findings presented from the post-hoc and pooled analyses support the positive results of the Phase 3 CONFIRM trial among HRS-1 patients, showing the potential for terlipressin to help patients reduce the need for renal replacement therapy and improve RRT-free survival,” said presenting author Juan Carlos Q. Velez, MD, chair of nephrology at Ochsner Health System, New Orleans, La. “These findings add to the breadth of existing knowledge and data of terlipressin, which has been extensively studied around the world for decades, and are important as HRS-1 is typically fatal and marked by rapid decline within three months if left untreated.”