Journal Article

A Proof of Concept, Phase II Randomized European Trial, on the Efficacy of ALF-5755, a Novel Extracellular Matrix-Targeted Antioxidant in Patients with Acute Liver Diseases

Ichaï, Philippe, Mathurin, Philippe, Jamot, Laure, Rudler, Marika, Samuel, Didier, Leroy, Vincent, Amouyal, Paul, Faivre, Jamila, Bréchot, Christian, Bernuau, Jacques, Durand, François, Duvoux, Christophe, Carbonell, Nicolas, Moniaux, Nicolas, Nalpas, Bertrand, Gerken, Guido, Larrey, Dominique, Radenne, Sylvie, Trautwein, Christian, Amouyal, Gilles, Manns, Michael

2016

Overview

No efficient medical treatment is available for severe acute hepatitis (SAH) except N-acetylcysteine for acetaminophen-induced acute liver failure. The human C-type lectin Reg3α, referred to as ALF-5755, improved survival in an animal model of acute liver failure and was well tolerated in a phase 1 trial in humans. We performed a phase 2a trial of ALF5755 in non-acetaminophen induced SAH. double-blind, randomized, placebo-controlled study. The primary end-point was the improvement in the coagulation protein synthesis assessed by the change of Prothrombin (PR) during the 72 hours following treatment initiation calculated as PRH0 minus PRH72 divided by 72 (PR slope H0H72). Intention to treat (ITT) and per-protocol (PP) analysis of the entire group and the Hepatitis B virus (HBV)/AIH (auto-immune hepatitis) sub-group were done separately. 57 patients were included. Twenty-eight received ALF-5755, 29 the placebo. Etiologies were: Hepatitis A (n = 10), HBV (n = 13), AIH (n = 9), drug-induced (n = 8), other (n = 17). On the whole group, nor the PR slope H0H72 (0.18±0.31 vs 0.25±0.32), nor the transplant-free survival rate at day 21 (75 vs 86%) differed between groups. Conversely, in the HBV-AIH subgroup, in which ALF was more severe, PR slope H0-H72 was higher in the ALF-5755 arm, the difference being significant in PP analysis (0.048±0.066 vs -0.040±0.099, p = 0.04); the median length of hospitalization was lower in the ALF-5755 group (8 vs 14 days, p = 0.02). ALF-5755 was not efficient in a ITT analysis performed on the whole sample; however it led to a significant, although moderate, clinical benefit in a PP analysis of the sub-group of patients with HBV or AIH related SAH. As HBV is the major cause of SAH in Asia and Africa and AIH a growing cause, this study emphasizes the need to pursuit the evaluation of this novel medical treatment of SAH. ClinicalTrials.gov NCT01318525.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Acetaminophen / Acetylcysteine / Acute Disease / Adult / Analgesics / Analysis / Animal models / Antigens, Neoplasm - adverse effects / Antigens, Neoplasm - pharmacology / Antigens, Neoplasm - therapeutic use / Antioxidants / Antioxidants - pharmacokinetics / Antioxidants - pharmacology / Antioxidants - therapeutic use / Apoptosis / Area Under Curve / Biology and Life Sciences / Biomarkers, Tumor - adverse effects / Biomarkers, Tumor - pharmacokinetics / Biomarkers, Tumor - pharmacology / Biomarkers, Tumor - therapeutic use / Care and treatment / Clinical trials / Coagulation / Double-Blind Method / Drug overdose / Etiology / Extracellular matrix / Extracellular Matrix - drug effects / Female / Gastroenterology / Hepatitis / Hepatitis A / Hepatitis A virus / Hepatitis B / Hepatitis B virus / Hepatology / Human health and pathology / Humans / Hépatology and Gastroenterology / Lectins, C-Type - therapeutic use / Life Sciences / Liver / Liver diseases / Liver Diseases - drug therapy / Liver transplants / Male / Medical treatment / Medicine and Health Sciences / Middle Aged / Motivation / Oxidative stress / Pancreas / Pancreatitis / Pancreatitis-Associated Proteins / Patients / Placebo effect / Placebos / Poisoning / Prognosis / Protein biosynthesis / Protein synthesis / Proteins / Prothrombin / Randomization / Recombinant Proteins - adverse effects / Recombinant Proteins - pharmacokinetics / Recombinant Proteins - pharmacology / Recombinant Proteins - therapeutic use / Research and Analysis Methods / Slopes / Survival / Transplants & implants / Tumor necrosis factor-TNF / Viruses