Mallinckrodt is a global professional pharmaceutical company headquartered in the United Kingdom. Recently, the company announced that the US Food and Drug Administration (FDA) has accepted a new drug application (NDA) for terlipressin, which is used to treat type 1 hepatorenal syndrome (HRS-1). On March 17 this year, the company announced that it has completed a rolling submission of terlipressin NDA. The FDA has designated a prescription drug user charging method (PDUFA) target date of September 12, 2020.
If approved, terlipressin will be the first drug to treat HRS-1 adult patients in the United States. Previously, the FDA granted terlipressin fast-track qualification (FTD) and orphan drug qualification (ODD).
Hepatorenal syndrome (HRS) is a serious complication that occurs in patients with severe liver disease such as cirrhosis with ascites, acute liver failure, and alcoholic hepatitis. Hepatorenal syndrome type 1 (HRS-1) is an acute life-threatening syndrome that causes rapid progressive acute renal failure in patients with liver cirrhosis. If not treated, the median survival time of the disease is about 2 weeks The mortality rate exceeded 80% within 3 months. In the United States, HRS-1 affects 30,000 to 40,000 patients each year, and there is currently no approved drug therapy for HRS-1.
Terlipressin is a potent vasopressin analog, which selectively acts on the V1 receptor on smooth muscle cells of small arteries. In the United States and Canada, the drug is being studied for the treatment of HRS-1. Outside the United States and Canada, terlipressin has been approved for use.
Terlipressin chemical structural formula (Photo source: medchemexpress.cn)
The drug NDA is based in part on the results of the Phase III CONFIRM trial (NCT02770716). This is the largest prospective study (n = 300) ever conducted on HR-1 patients, and it is the result of developing terlipressin for the US and Canada for 17 years. The preliminary results of the study have been announced at the 2019 American Association for the Study of Liver Diseases (AASLD) annual meeting. Compared with the placebo + albumin treatment group, the terlipressin treatment group has significantly reversed renal function deterioration, lasting remission, and early renal replacement therapy (RRT ) The demand is reduced.
The CONFIRM trial applied strict criteria to define HRS-1. The results showed that compared with the placebo + albumin treatment group, there was a statistically significantly higher percentage of patients in the terlipressin + albumin treatment group who achieved a confirmed HRS reversal (VHRSR). The primary end point (29.1% vs 15.8%, p = 0.012). VHRSR is defined as: 2 consecutive serum creatinine [SCr] values ≤ 1.5mg / dL, at least 2 hours apart before the 14th day or before discharge, after the second SCr ≤ 1.5mg / dL, the subject was In the case of renal replacement therapy [RRT], survive for at least 10 days.
In addition, terlipressin also showed advantages in the four pre-specified secondary endpoints of the study, including: (1) HRS reversal, defined as SCr ≤ 1.5 mg / dL before day 14 or before discharge (patient ratio: 36.2% vs 16.8%, p <0.001). (2) Persistent / maintain HRS reversal, defined as maintaining HRS reversal within 30 days without RRT / dialysis (patient ratio: 31.7% vs 15.8%, p <0.003). (3) HRS reversal in the subgroup of systemic inflammatory response syndrome (SIRS) (proportion of patients: 33.3% vs 6.3%, p <0.001). (4) Before the 30th day, confirm the reversal of HRS without recurrence of HRS (proportion of patients: 24.1% vs 15.8%, p = 0.092).
In terms of safety, adverse events (AE) were similar in the 2 groups. 65% (n = 130) of patients in the terlipressin treatment group had serious adverse events and 60.6% (n = 60) in the placebo group. The most common serious adverse events include respiratory failure (10% vs 3%) and abdominal pain (5% vs 1%).
Mallinckrodt Executive Vice President and Chief Scientific Officer Steven Romano, MD, said: "We are very pleased that the FDA has accepted our new drug application (NDA), which is an important milestone in our terlipressin clinical development project and will address The extremely high demand of doctors, these patients have historically limited treatment options. We look forward to working with the agency during the FDA review of our NDA. "(Bioon.com)