Namodenoson at the Crossroad of Metabolic Dysfunction-Associated Steatohepatitis and Hepatocellular Carcinoma

Abstract

Namodenoson (CF102) is a small, orally available, anti-inflammatory, and anti-cancer drug candidate currently in phase 2B trial for the treatment of metabolic dysfunction-associated steatohepatitis (MASH; formerly known as non-alcoholic steatohepatitis (NASH)) and in phase 3 pivotal clinical trial for the treatment of hepatocellular carcinoma (HCC). In both MASH and HCC, the mechanism-of-action of namodenoson involves targeting the A3 adenosine receptor (A3AR), resulting in deregulation of downstream signaling pathways and leading to inhibition of inflammatory cytokines (TNF-α, IL-1, IL-6, and IL-8) and stimulation of positive cytokines (G-CSF and adiponectin). Subsequently, inhibition of liver inflammation, steatosis, and fibrosis were documented in MASH experimental models, and inhibition of HCC growth was observed in vitro, in vivo, and in clinical studies. This review discusses the evidence related to the multifaceted mechanism of action of namodenoson, and how this mechanism is reflected in the available clinical data in MASH and HCC.

Lipid Trolling to Optimize A3 Adenosine Receptor-Positive Allosteric Modulators (PAMs)

“…The A 3 AR is a G i protein-coupled receptor (GPCR) that has many reported nucleoside agonists, including those with >10,000-fold selectivity over other AR subtypes that contain a rigid ribose substitution . A 3 AR agonists present therapeutic potential for the treatment of inflammatory and ischemic conditions, cancer, fibrosis, and chronic pain. − Prototypical, directly acting (orthosteric) A 3 AR nucleoside agonists are in advanced clinical trials (Phases 2 and 3) for psoriasis and other inflammatory diseases, liver and pancreatic cancer, and metabolic dysfunction-associated steatohepatitis (MASH, previously known as NASH), and entering Phase 2 studies for ischemic stroke and traumatic brain injury. − …”