Mallinckrodt plc announced the presentation of results from a retrospective analysis of three North American-centric, Phase III, randomized, placebo-controlled studies comparing the incidence of hepatorenal syndrome (HRS) reversal with baseline acute-on-chronic liver failure (ACLF) grade in adults with rapid reduction in kidney function treated with TERLIVAZ® plus albumin versus those treated with placebo plus albumin. Investigators will present the findings during an oral presentation at the SCCM 2023 Critical Care Congress on January 22, 2023 taking place in San Francisco, CA from January 21-24, 2023. TERLIVAZ is the first and only FDA-approved product indicated for the treatment of adults with HRS involving rapid reduction in kidney function, an acute and life-threatening condition requiring hospitalization. Terlipressin is recommended by the American Association for the Study of Liver Diseases (AASLD) guidance and the American College of Gastroenterology (ACG) guidelines. The retrospective analysis used pooled data from the OT-0401, REVERSE, and CONFIRM Phase III studies to compare the incidence of HRS reversal by baseline ACLF grade in patients treated with terlipressin plus albumin versus placebo plus albumin for up to 14 days. Severity of ACLF was graded according to the number of organ failures (ACLF grade 0-1, grade 2, and grade 3). The incidence of HRS reversal was defined as at least one serum creatinine value of =1.5 mg/dL while on treatment. In the pooled analysis population (n=607), 278 patients had ACLF grade 0-1 (terlipressin: n=164; placebo: n=114), 208 patients had ACLF grade 2 (terlipressin: n=116; placebo: n=92), and 121 patients had ACLF grade 3 (terlipressin: n=72; placebo: n=49). The incidence of HRS reversal in terlipressin-treated patients decreased with increasing ACLF grade (ACLF grade 0-1: 43% (n=71/164); ACLF grade 2: 28% (n=32/116); ACLF grade 3: 19% (n=14/72)), whereas HRS reversal was similar across ACLF grades in placebo-treated patients (ACLF grade 0-1: 18% (n=21/114); ACLF grade 2: 15% (n=14/92); ACLF grade 3: 14% (n=7/49)). Additionally, a higher percentage of terlipressin-treated patients with ACLF grade 0-1 or grade 2 achieved HRS reversal compared with those in the respective placebo-treated groups (ACLF grade 0-1: terlipressin 43% (n=71/164) vs placebo 18% (n=21/114); ACLF grade 2: terlipressin 28% (n=32/116) vs placebo 15% (n=14/92)) (p<0.0001 and p=0.02, respectively). No differences in the incidence of HRS reversal were observed between terlipressin- (19%; n=14/72) and placebo- (14%; n=7/49) treated patients with ACLF grade 3 (p=0.46).

Hepatorenal syndrome (HRS) involving rapid reduction in kidney function is an acute and life-threatening condition that occurs in people with advanced liver disease. HRS is classified into two distinct types – a rapidly progressive type that leads to acute renal failure where patients are typically hospitalized for their care and a more chronic type that progresses over weeks to months. HRS involving rapid reduction in kidney function is estimated to affect between 30,000 and 40,000 Americans annually. If left untreated, HRS with rapid reduction in kidney function has a median survival time of approximately two weeks and greater than 80% mortality within three months. TERLIVAZ is indicated to improve kidney function in adults with hepatorenal syndrome with rapid reduction in kidney function. Patients with a serum creatinine >5 mg/dL are unlikely to experience benefit. ERLIVAZ may cause serious or fatal respiratory failure. Patients with volume overload or with acute-on-chronic liver failure (ACLF) Grade 3 are at increased risk. Assess oxygenation saturation (e.g., SpO2) before initiating TERLIVAZ. Do not initiate TERLIVAZ in patients experiencing hypoxia (e.g., SpO2 <90%) until oxygenation levels improve. Monitor patients for hypoxia using continuous pulse oximetry during treatment and discontinue TERLIVAZ if SpO2 decreases below 90%. TERLIVAZ is contraindicated: In patients experiencing hypoxia or worsening respiratory symptoms. In patients with ongoing coronary, peripheral, or mesenteric ischemia. Warnings and Precautions: Serious or Fatal Respiratory Failure: Obtain baseline oxygen saturation and do not initiate TERLIVAZ in hypoxic patients. Monitor patients for changes in respiratory status using continuous pulse oximetry and regular clinical assessments. Discontinue TERLIVAZ in patients experiencing hypoxia or increased respiratory symptoms. Ineligibility for Liver Transplant: TERLIVAZ-related adverse reactions (respiratory failure, ischemia) may make a patient ineligible for liver transplantation, if listed. For patients with high prioritization for liver transplantation (e.g., MELD =35), the benefits of TERLIVAZ may not outweigh its risks. Ischemic Events: TERLIVAZ may cause cardiac, cerebrovascular, peripheral, or mesenteric ischemia. Avoid use of TERLIVAZ in patients with a history of severe cardiovascular conditions or cerebrovascular or ischemic disease. Discontinue TERLIVAZ in patients who experience signs or symptoms suggestive of ischemic adverse reactions.
Embryo-Fetal Toxicity: TERLIVAZ may cause fetal harm when administered to a pregnant woman. If TERLIVAZ is used during pregnancy, the patient should be informed of the potential risk to the fetus. Adverse Reactions: The most common adverse reactions (=10%) include abdominal pain, nausea, respiratory failure, diarrhea, and dyspnea.