Pooled data from phase III studies, shows terlipressin was associated with improved overall and transplant-free survival in hepatorenal syndrome type 1 patients.- Mallinckrodt

Mallinckrodt plc , announced results of a pooled analysis of terlipressin clinical trial data in patients with hepatorenal syndrome type 1 (HRS-1) at The Liver Meeting 2018, the annual meeting of the American Association for the Study of Liver Diseases (AASLD), held Nov. 9-13 in San Francisco. The post-hoc pooled analysis of data from two previously completed Phase III, randomized, double-blind, placebo-controlled studies conducted in North America showed that treatment with terlipressin was associated with improved overall and transplant-free survival in HRS-1 patients with lower baseline mean arterial pressure (MAP). This effect was seen independent of HRS reversal, and may relate to a marked improvement in MAP and renal function in this patient group following administration of terlipressin.

MAP is calculated using systolic and diastolic blood pressure, and can ascertain whether there is enough blood flow, resistance and pressure to supply blood to all major organs. Low MAP is common in patients with decompensated cirrhosis and HRS-1 in the absence of overt shock, and indicates a more progressed liver disease. Terlipressin is being investigated for the treatment of HRS-1, a rare, acute, rapidly progressing and life-threatening complication of liver cirrhosis that leads to renal failure. The safety and effectiveness of terlipressin have not yet been established by the FDA. There are no currently approved drug therapies for HRS-1 in the U.S. or Canada.

Patients with HRS-1 have an extremely poor prognosis and often progress to life-threatening renal failure within days.

"Terlipressin Treatment Is Associated With Significantly Increased Survival in Patients With Hepatorenal Syndrome Type 1 (HRS-1) and Low Baseline Mean Arterial Pressure (MAP), Independent of HRS Reversal" � the Mallinckrodt-sponsored analysis � sought to characterize the relationship between low baseline MAP and improved survival in patients with HRS-1 treated with terlipressin in the REVERSE and OT-0401 trials, which both showed that terlipressin improved renal function when administered concomitantly with albumin compared with placebo plus albumin in patients with HRS-1 and cirrhosis. Low MAP was defined as < 65mmHg.

Study Methods : Data from the two Phase III studies, REVERSE and OT-0401 of 307 patients with HRS-1 were pooled and analyzed. In both studies, patients received terlipressin or placebo plus albumin intravenously every six hours for up to 14 days. This pooled analysis compared terlipressin and placebo in two groups of patients: one with MAP <65 mm hg and a second group with map greater than 65 mm hg. the analysis included an assessment of overall survival transplant-free survival hrs reversal defined as serum creatinine scr value of less than 1.5 mg dl and change in scr from baseline through end of treatment.>

Key Findings : The pooled analysis of REVERSE and OT0401 clinical data showed: Overall survival at 90 days in the MAP <65 mm hg group was significantly higher among patients receiving terlipressin 17 25 68.0 versus placebo 6 25 24.0: survival estimate was 0.680 versus 0.209 respectively p=".005." no difference in overall survival at 90 days was observed between terlipressin 66 128 51.6 and placebo 72 129 55.8 in the map greater than 65 mm hg group: survival estimate was: 0.515 versus 0.554 respectively p=".429." transplant-free survival at 90 days in the map><65 mm hg group was significantly higher among patients receiving terlipressin 17 25 68.0 versus placebo 7 25 28.0: transplant-free survival estimate was: 0.618 versus 0.083 respectively p=".015." in the map greater than 65 mm hg group no difference in transplant-free survival at 90 days was observed between terlipressin 67 128 52.3 and placebo 76 129 58.9: transplant-free survival estimate was: 0.404 versus 0.444 respectively p=".291." rates of hrs reversal among patients receiving terlipressin were similar between the map><65 mm hg and greater than 65 mm hg groups the proportion of patients with hrs reversal in the map greater than 65 mm hg group was significantly higher among patients receiving terlipressin than among those receiving placebo. improvement in scr from baseline to end of treatment was significantly greater with terlipressin than with placebo in both map groups however the degree of improvement was lower in the map greater than 65 mm hg group.>

Study Limitations : This study is a post-hoc pooled analysis of completed clinical trials. Results were based on a statistical model that was not specified before the data were seen. Appropriately designed randomized, prospective studies are needed to determine the efficacy of terlipressin in this patient population, such as the company's ongoing Phase III study of terlipressin in HRS-1, known as The CONFIRM Study. Details on The CONFIRM Study can be found on clinicaltrials.gov.