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

Abstract

ObjectiveNo 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.Designdouble-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.Results57 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).ConclusionALF-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 RegistrationClinicalTrials.gov NCT01318525

Regenerating islet-derived protein 3α: A promising therapy for diabetes. Preliminary data in rodents and in humans

“…The rcREG3α protein (ALF-5755) has been synthetized by adding one amino-terminal methionine to the sequence of the secreted (i.e., lacking the 26-amino acid signal sequence) form of the human endogenous REG3α (HIP/PAP) (NP_620355). It was produced in Escherichia coli, purified to !99% and released in batches in compliance with the clinical grade manufacturing process by PX'Therapeutics (Grenoble, France) which permitted to achieve a phase 1 then a phase 2a in patients with acute liver disease [12].…”

“…In this study ALF-5755 treatment protected in vitro primary hepatocytes against multiple cell death signals and prevented in vivo death of the mice upon treatment with Fas agonists; this activity was correlated with the scavenger ROS activity and the prevention of extra-and intra-cellular oxidative stress. ALF-5755 was then used in a phase 1 then 2a clinical trial in patients with acute liver failure and led to a significant although moderate clinical benefit in a per-protocol analysis of patients with hepatitis B virus or auto-immune acute or chronic hepatitis [12]. Due to its antioxidant and anti-inflammatory effects, ALF-5755 could also play an important therapeutic role in other pathological situations including metabolic disorders like insulin resistance (IR) and type 2 diabetes (T2D), two conditions characterized by chronic multi-tissular low grade inflammation and oxidative stress, hepatic and pancreatic β cells dysfunctions [13].…”