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In February 2022, the FDA had issued a complete response letter in order to inspect a new third-party packaging and labeling facility.
Mallinckrodt Pharmaceuticals has resubmitted the new drug application (NDA) for terlipressin to treat adults with hepatorenal syndrome (HRS) involving rapid reduction in kidney function. Hepatorenal syndrome is serious complication of liver cirrhosis that can cause kidney failure. HRS is estimated to affect between 30,000 and 40,000 Americans annually. If left untreated, patients who rapidly progress to renal failure have a median survival time of about two weeks.
The FDA had issued a complete response letter (CRL) on Feb. 18, 2022. Mallinckrodt had identified a new third-party packaging and labeling facility and an FDA inspection of the facility could not be completed by the February PDUFA date, resulting in the receipt of the CRL. This was the only outstanding issue noted in the CRL; no safety or efficacy issues cited.
This was the second CRL received from the agency. The first was in September 2020 and the FDA at that time request additional information to support a positive risk-benefit profile for terlipressin for patients with HRS-1.
The NDA is based on data from the phase 3 CONFIRM study, in which terlipressin met its primary endpoint of verified HRS reversal, which is defined as renal function improvement, avoidance of dialysis and short-term survival at day 30 and HRS reversal.
The trial met three of the four pre-specified secondary endpoints of the study including HRS reversal, HRS reversal without renal replacement therapy by day 30 and HRS reversal in the systemic inflammatory response syndrome (SIRS) subgroup. The fourth pre-specified secondary endpoint of verified HRS reversal without HRS recurrence by day 30 was 50% greater in the terlipressin group but did not reach statistical significance.
Data were presented at the November 2019 The Liver Meeting, the annual meeting of the American Association for the Study of Liver Diseases and published in the New England Journal Medicine.
“Results from CONFIRM provide critical information on a potential treatment option for HRS-1 and these data indicate that, if approved, terlipressin has the potential to reverse the course of HRS-1 in the appropriate patients and help the healthcare community better manage this critically ill and underserved patient population,” lead author Florence Wong, MBBS, M.D., said in a press release at the time. Wong is a hepatologist at Toronto General Hospital and professor of medicine at the University of Toronto.
At the same time, Mallinckrodt announced that it expects to complete its reorganization process, emerge from Chapter 11 in the next few days. The bankruptcy was filed in October 2020 and was the result opioid lawsuits. The company plans to set aside $1.7 billion to resolve lawsuits accusing it of deceptively marketing opioids is a fair settlement, according to a Reuters story in January 2022.