Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Clinical Trial
. 2021 Dec;54(11-12):1405-1415.
doi: 10.1111/apt.16664. Epub 2021 Oct 20.

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

Rifaat Safadi  1 , Marius Braun  2 , Adi Francis  3 , Yael Milgrom  1 , Muhammad Massarwa  1 , David Hakimian  1 , Wadi Hazou  1 , Assaf Issachar  2 , Zivit Harpaz  4 , Motti Farbstein  4 , Inbal Itzhak  4 , Naama Lev-Cohain  5 , Avital Bareket-Samish  6 , Michael H Silverman  4 , Pnina Fishman  4
Affiliations
Clinical Trial

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

Rifaat Safadi et al. Aliment Pharmacol Ther. 2021 Dec.

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.

PubMed Disclaimer

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
See this image and copyright information in PMC

Comment in

References

    1. Ratziu V, Bellentani S, Cortez‐Pinto H, et al. A position statement on NAFLD/NASH based on the EASL 2009 special conference. J Hepatol. 2010;53:372‐384. - PubMed
    1. Williams CD, Stengel J, Asike MI, et al. Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle‐aged population utilizing ultrasound and liver biopsy: a prospective study. Gastroenterology. 2011;140:124‐131. - PubMed
    1. Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of non‐alcoholic fatty liver disease: Practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology. 2012;55:2005‐2023. - PubMed
    1. Angulo P, Kleiner DE, Dam‐Larsen S, et al. Liver fibrosis, but no other histologic features, is associated with long‐term outcomes of patients with nonalcoholic fatty liver disease. Gastroenterology. 2015;149:389‐397. - PMC - PubMed
    1. Kabbany MN, Selvakumar PKC, Watt K, et al. Prevalence of nonalcoholic steatohepatitis‐associated cirrhosis in the United States: an analysis of national health and nutrition examination survey data. Am J Gastroenterol. 2017;112:581‐587. - PubMed

Publication types

Associated data