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

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Abstract

Objective

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.

Design

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.

Results

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).

Conclusion

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.

Trial Registration

ClinicalTrials.gov NCT01318525

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Most cited references 17

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Intravenous N-acetylcysteine improves transplant-free survival in early stage non-acetaminophen acute liver failure.

Timothy Davern, Patricia R Robuck, T McCashland … (2009)

N-acetylcysteine (NAC), an antidote for acetaminophen poisoning, might benefit patients with non-acetaminophen-related acute liver failure. In a prospective, double-blind trial, acute liver failure patients without clinical or historical evidence of acetaminophen overdose were stratified by site and coma grade and assigned randomly to groups that were given NAC or placebo (dextrose) infusion for 72 hours. The primary outcome was overall survival at 3 weeks. Secondary outcomes included transplant-free survival and rate of transplantation. A total of 173 patients received NAC (n = 81) or placebo (n = 92). Overall survival at 3 weeks was 70% for patients given NAC and 66% for patients given placebo (1-sided P = .283). Transplant-free survival was significantly better for NAC patients (40%) than for those given placebo (27%; 1-sided P = .043). The benefits of transplant-free survival were confined to the 114 patients with coma grades I-II who received NAC (52% compared with 30% for placebo; 1-sided P = .010); transplant-free survival for the 59 patients with coma grades III-IV was 9% in those given NAC and 22% in those given placebo (1-sided P = .912). The transplantation rate was lower in the NAC group but was not significantly different between groups (32% vs 45%; P = .093). Intravenous NAC generally was well tolerated; only nausea and vomiting occurred significantly more frequently in the NAC group (14% vs 4%; P = .031). Intravenous NAC improves transplant-free survival in patients with early stage non-acetaminophen-related acute liver failure. Patients with advanced coma grades do not benefit from NAC and typically require emergency liver transplantation.

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Acute liver failure: Summary of a workshop.

Edward Doo, L Nyberg, Charles Squires … (2008)

Acute liver failure (ALF) is a rare but challenging clinical syndrome with multiple causes; a specific etiology cannot be identified in 15% of adult and 50% of pediatric cases. The course of ALF is variable and the mortality rate is high. Liver transplantation is the only therapy of proven benefit, but the rapidity of progression and the variable course of ALF limit its use. Currently in the United States, spontaneous survival occurs in approximately 45%, liver transplantation in 25%, and death without transplantation in 30% of adults with ALF. Higher rates of spontaneous recovery (56%) and transplantation (31%) with lower rates of death (13%) occur in children. The outcome of ALF varies by etiology, favorable prognoses being found with acetaminophen overdose, hepatitis A, and ischemia (approximately 60% spontaneous survival), and poor prognoses with drug-induced ALF, hepatitis B, and indeterminate cases (approximately 25% spontaneous survival). Excellent intensive care is critical in management of patients with ALF. Nonspecific therapies are of unproven benefit. Future possible therapeutic approaches include N-acetylcysteine, hypothermia, liver assist devices, and hepatocyte transplantation. Advances in stem cell research may allow provision of cells for bioartificial liver support. ALF presents many challenging opportunities in both clinical and basic research.

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Toward an improved definition of acute-on-chronic liver failure.

Rajiv Jalan, Cihan Yurdaydin, Jasmohan Bajaj … (2014)

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Author and article information

Contributors

Lise Lotte Gluud: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, CA USA )

ISSN (Electronic): 1932-6203

Publication date (Electronic): 16 March 2016

Publication date Collection: 2016

Volume: 11

Issue: 3

Electronic Location Identifier: e0150733

Affiliations

[1 ]Inserm, Département de l’Information Scientifique et de la Communication, Paris, France

[2 ]Centre Hépatobiliaire Paul Brousse and Inserm U 1193, Villejuif, France

[3 ]Hôpital Universitaire Paul Brousse, Villejuif, France

[4 ]Alfact Innovation, Paris, France

[5 ]Service Hépato-gastro-entérologie, Hôpital Saint Antoine, Paris, France

[6 ]Service Hépatologie et de Gastroentérologie, Hôpital La Pitié Salpétrière, Paris, France

[7 ]Service des maladies de l'appareil digestif, Hôpital Claude Huriez, Lille, France

[8 ]Service Hépatologie, Hôpital Beaujon, Clichy, France

[9 ]Gastroenterology and Hepatology Unit, University of Essen, Essen, Germany

[10 ]Gastroenterology and Hepatology Unit, University of Hanover, Hanover, Germany

[11 ]Medizinische Klinik III, University Clinic, RWTH-Aachen, Aachen, Germany

[12 ]Service Hépato-Gastro-Entérologie, Hôpital Saint-Eloi, Montpellier, France

[13 ]Service Hépatologie et Gastro-Entérologie, Hôpital Croix-Rousse, Lyon, France

[14 ]Service d'Hépato-Gastro-Entérologie, Hôpital Henri MondorCréteil, France

[15 ]Département d’Hépato-Gastroentérologie, Hôpital de Grenoble, Grenoble, France

[16 ]Institut Pasteur, Paris, France

Hvidovre Hospital, DENMARK

Author notes

Competing Interests: Paul Amouyal is Chairman of Alfact Innovation. Gilles Amouyal is CEO of Alfact Innovation. Christian Brechot is scientific adviser and share-holder at Alfact Innovation. Bertrand Nalpas and Jamila Faivre are scientific consultant to Alfact Innovation. Laure Jamot was employed to manage and supervise the clinical trial. ALF-5755 patent belongs to Alfact innovation: ( https://www.google.com/patents/US8329661). The funder provided support in the form of salaries for author [LJ] and honorarium for author [BN], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

Conceived and designed the experiments: BN PI LJ JB CB GA PA DS. Performed the experiments: NC MR PM FD GG MM CT DL SR CD VL. Analyzed the data: BN PI LJ JF NM CB GA PA DS. Wrote the paper: BN.

* E-mail: bertrand.nalpas@ 123456inserm.fr

Article

Publisher ID: PONE-D-15-45927

DOI: 10.1371/journal.pone.0150733

PMC ID: 4794150

PubMed ID: 26983031

SO-VID: 73fc8576-7053-42dd-b97c-ce62c5d56717

License:

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 26 October 2015

Date accepted : 17 February 2016

Page count

Figures: 3, Tables: 5, Pages: 14

Funding

Alfact Innovation is an independent French biotech. This work was supported by a grant from the ANR (Agence Nationale de la Recherche) (RIB 2007:HIP/PAP and Hepatitis) and by a grant of the German Research Foundation (DFG: TR 285/10-1). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Data Availability All relevant data are within the paper and its Supporting Information files.

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

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Abstract

Objective

Design

Results

Conclusion

Trial Registration

Related collections

PLOS Climate

Most cited references 17

Intravenous N-acetylcysteine improves transplant-free survival in early stage non-acetaminophen acute liver failure.

Acute liver failure: Summary of a workshop.

Toward an improved definition of acute-on-chronic liver failure.

Author and article information

Contributors

Journal

Affiliations

Author notes

Article

History

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Funding

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