Randomised clinical trial: A phase 2 double-blind study of namodenoson in non-alcoholic fatty liver disease and steatohepatitis

Rifaat Safadi, Marius Braun, Adi Francis, Yael Milgrom, Muhammad Massarwa, David Hakimian, Wadi Hazou, Assaf Issachar, Zivit Harpaz, Motti Farbstein, Inbal Itzhak, Naama Lev-Cohain, Avital Bareket-Samish, Michael H Silverman, Pnina Fishman, Rifaat Safadi, Marius Braun, Adi Francis, Yael Milgrom, Muhammad Massarwa, David Hakimian, Wadi Hazou, Assaf Issachar, Zivit Harpaz, Motti Farbstein, Inbal Itzhak, Naama Lev-Cohain, Avital Bareket-Samish, Michael H Silverman, Pnina Fishman

Abstract

Background: Namodenoson, an A3 adenosine receptor (A3AR) agonist, improved liver function/pathology in non-alcoholic steatohepatitis (NASH) preclinical models.

Aim: To evaluate the efficacy and safety of namodenoson for the treatment of non-alcoholic fatty liver disease (NAFLD) with or without NASH METHODS: This phase 2 study included 60 patients with NAFLD (ALT ≥60 IU/L) who were randomised (1:1:1) to oral namodenoson 12.5 mg b.d. (n = 21), 25 mg b.d. (n = 19), or placebo (n = 20) for 12 weeks (total follow-up: 16 weeks). The main efficacy endpoint involved serum ALT after 12 weeks of treatment.

Results: Serum ALT decreased over time with namodenoson in a dose-dependent manner. The difference between change from baseline (CFB) for ALT in the namodenoson 25 mg b.d. arm vs placebo trended towards significance at 12 weeks (P = 0.066). Serum AST levels also decreased with namodenoson in a dose-dependent manner; at 12 weeks, the CFB for 25 mg b.d. vs placebo was significant (P = 0.03). At Week 12, 31.6% in the namodenoson 25 mg b.d. arm and 20.0% in the placebo arm achieved ALT normalisation (P = 0.405). At week 16, the respective rates were 36.8% and 10.0% (P = 0.038). A3AR expression levels were stable over time across study arms. Both doses of namodenoson were well tolerated with no drug-emergent severe adverse events, drug-drug interactions, hepatotoxicity, or deaths. Three adverse events were considered possibly related to study treatment: myalgia (12.5 mg b.d. arm), muscular weakness (25 mg b.d. arm), and headache (25 mg b.d. arm).

Conclusion: A3AR is a valid target; namodenoson 25 mg b.d. was safe and demonstrated efficacy signals (ClinicalTrials.gov #NCT02927314).

Keywords: clinical trial; fibrosis; liver; non-alcoholic fatty liver disease; non-alcoholic steatohepatitis.

© 2021 Can-Fite BioPharma Ltd. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.

Figures

FIGURE 1
FIGURE 1
Patient disposition
FIGURE 2
FIGURE 2
Changes from baseline (CFB) in inflammation‐related parameters. A, CFB in ALT levels over time. B, The proportion of patients achieving normalisation of ALT levels over time. C, CFB in AST levels over time. D, CFB in adiponectin levels at Week 12. Error bars represent SE P‐values for ALT and AST CFB were derived from ad hoc analyses
FIGURE 3
FIGURE 3
Changes from baseline in liver content and fibrosis‐related parameters. A, CFB in liver fat volume at Week 12. B, The proportion of patients with CAP ≥ 331 at screening and Week 12. C, CFB in FIB‐4 score at Week 12. D, The proportion of patients with NASH (FAST > 0.67) at screening and Week 12. E, CFB in FAST scores at Week 12. Error bars represent SE. Screening data were used as baseline
FIGURE 4
FIGURE 4
CFB in body weight with namodenoson treatment over time. Error bars represent SE P‐values were derived from ad hoc analyses

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