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  The Liver Meeting
Digital Experience
November 13 - 16 - 2020
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A phase 2, randomized, double-blind, placebo-controlled dose-finding study of the efficacy and safety of namodenoson (CF102), an A3 adenosine receptor (A3AR) agonist, in treating non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). - A3AR Agonist Improves NAFLD-Related Variables in Phase 2 Trial
  Can-Fite's liver drug, Namodenoson, is headed into a Phase III trial for hepatocellular carcinoma (HCC), the most common form of liver cancer, and successfully achieved its primary endpoint in a Phase II trial for the treatment of non-alcoholic steatohepatitis (NASH). Namodenoson has been granted Orphan Drug Designation in the U.S. and Europe and Fast Track Designation as a second line treatment for HCC by the U.S. Food and Drug Administration. Namodenoson has also shown proof of concept to potentially treat other cancers including colon, prostate, and melanoma.
Can-Fite's Phase II NAFLD/NASH study achieved its efficacy and safety endpoints in a dose dependent and statistically significant manner.
PETACH TIKVA, Israel--(BUSINESS WIRE)--Can-Fite BioPharma Ltd. (NYSE American:CANF) (TASE:CFBI), a biotechnology company advancing a pipeline of proprietary small molecule drugs that address inflammatory, cancer and liver diseases, today announced the Scientific Program Committee of the American Association for the Study of Liver Diseases (AASLD) has selected Can-Fite's late-breaking abstract for oral presentation at The Liver Meeting Digital Experience™ 2020. The presentation titled, "A Phase 2, Randomized, Double-Blind, Placebo-Controlled Dose-Finding Study Of The Efficacy And Safety Of Namodenoson (CF102), An A3 Adenosine Receptor (A3AR) Agonist, In Treating Non-Alcoholic Fatty Liver Disease (NAFLD) And Non-Alcoholic Steatohepatitis (NASH)" will be delivered on Sunday, November 15, 2020, by the Principal Investigator of the Phase II study, Dr. Rifaat Safadi, Head of the Liver Unit, Gastroenterology and Liver Diseases, Division of Medicine at Hadassah Medical Center, Professor of Internal Medicine, Bowel, Liver Disease, and Metabolic Syndrome at Hebrew University in Israel. The AASLD's The Liver Meeting® will be held virtually on November 13 through 16, 2020.
Preclinical Pharmacology
Namodenoson has potent anti-cancer effect, particularly against hepatocellular carcinoma, and anti-inflammatory activity demonstrated in pre-clinical animal models of liver inflammation.
Mechanism of Action
Namodenoson mechanism of action is mediated via de-regulation of the NF-κB and the Wnt signal transduction pathways, resulting in apoptosis of tumor cells. The protective effect of Namodenoson is mediated via down-regulation of the NF-kB signal transduction pathway and preventing apoptosis.
A3AR Agonist Improves NAFLD-Related Variables in Phase 2 Trial
AASLD The Liver Meeting Digital Experience, November 13-16, 2020
Mark Mascolini
Namodenoson, an A3 adenosine receptor (A3AR) agonist, lowered liver fat and eased fibrosis and liver inflammation in a 12-week phase 2 double-blind trial [1].
A nucleoside derivative with a 12-hour half-life, this highly selective A3AR agonist is orally available and minimally metabolized in the liver [2]. The agent may have use in treating nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), and hepatocellular carcinoma. Researchers at Hadassah Hebrew University and colleagues in other groups who presented the phase 2 study listed its potential activities (based on studies in experimental models) as antiinflammatory (lowers NAFLD activity score), antisteatotic (decreases steatosis, ballooning, lobular inflammation), and antifibrotic. In lowers alanine aminotransferase (ALT) and triglycerides and protects the liver from ischemia and reperfusion injury.
This dose-finding study recruited people 18 or older with a NAFLD diagnosis, with "acceptable" hepatic metabolic and synthetic function, and with 2 or more of the following comorbidities: obesity, type 2 diabetes, controlled hypertension, hypertriglyceridemia, and reduced HDL cholesterol. The study excluded people with cirrhosis, other acute or chronic liver diseases, type 1 diabetes, and heavy alcohol use.
This double-blind multicenter trial randomized 60 participants equally to 1 of 3 arms: 12.5 or 25 mg of namodenoson twice daily or placebo for 12 weeks with follow-up until week 16. Across the three treatment arms age averaged about 44 years, about three quarters of participants were men, and almost everyone was white. About one quarter of participants had diabetes. Median NAFLD duration stood at 65 months in the 12.5-mg group, 20 months in the 25-mg group, and 48 months in the placebo group. Respective NASH durations were 4, 64, and 67 months.
At 12 weeks ALT fell by an average 10.4 U/L in the 12.5-mg group, 15.4 U/L in the 25-mg group (P = 0.066 vs placebo), and 1.7 U/L in the placebo group. Respective percent changes from baseline were 8.2%, 22% (P = 0.079 vs placebo), and 3%. By week 16 about 37% taking 25 mg of namodenoson had reached a normal ALT (P = 0.038 vs placebo).
At 12 weeks aspartate aminotransferase fell an average 7.4 U/L with 12.5 mg of namodenoson, fell 8.1 U/L with 25 mg (P = 0.03 vs placebo), and rose 0.3 U/L with placebo. Respective percent changes from baseline was 8.1%, 17.9% (P = 0.05 vs placebo), and 1.3% with placebo.
Adiponectin rose significantly in the 12.5-mg group (P = 0.03 vs placebo), by 539 ng/mL, indicating antiinflammatory and antifibrotic activity. But the adiponectin jump with 25 mg of namodenoson (220 ng/mL) did not differ significantly from placebo. Liver fat volume fell about twice as much with 25 mg of namodenoson as with placebo (P = 0.03), but fell less with 12.5 mg of the drug than with placebo.
After 12 weeks of treatment the FIB-4 score fell significantly more with 25 mg of namodenoson than with placebo (P = 0.01), but the drop with 12.5 mg was not significantly greater than with placebo. Through 12 weeks the proportion of participants with a CAP score at or above 331, indicating steatosis progression, dropped from about 42% to about 15% in the 25-mg group and from about 50% to about 30% in the 12.5-mg group. But the proportion with a high CAP score rose with placebo. The proportion of people with a FAST score above 0.67, signaling fibrosis progression, dropped from about 28% to 0% through 12 weeks in the 25-mg group, while falling less in the 12.5-mg group and staying near 0% in the placebo group.
Proportions of participants with at least 1 treatment-emergent adverse events were 52% in the 25-mg arm, 37% in the 12.5-mg arm, and 20% in the placebo arm. But only 2 such adverse events in the 12.5-mg arm (muscular weakness and headache), 1 in the 25-mg arm (myalgia), and 1 in the placebo arm (indigestion) were considered possibly related to treatment. There were no serious drug-related adverse events and none that led to withdrawal from the trial. No evidence of liver toxicity emerged during the study.
Expression of A3AR remained stable throughout 12 weeks of treatment in all study arms.
The researchers concluded that 25 mg of namodenoson is both safe and the more effective dose. The developer plans to pursue study of namodenoson in larger trials.
1. Safadi R, Braun M, Milgrom Y, et al. A phase 2, randomized, double-blind, placebo-controlled dose-finding study of the efficacy and safety of namodenoson (CF102), an A3 adenosine receptor (A3AR) agonist, in treating non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). AASLD The Liver Meeting Digital Experience, November 13-16, 2020. Late-breaker.
2. Can-Fite BioPharma Ltd. Namodenoson (CF102). http://www.canfite.com/?KPageId=20