A liver-targeting pleiotropic drug candidate targeting multiple types and stages of liver disease
CRV431 is Hepion’s clinical phase, lead oral drug candidate for nonalcoholic steatohepatitis (NASH) and viral hepatitis-induced liver disease. CRV431 meets all of Hepion’s criteria for an effective and unique pleiotropic liver disease drug. As a novel molecule chemically derived from a pharmacological class of therapeutic drugs used clinically for over 35 years, CRV431 has thus far demonstrated an excellent safety profile in all animal and clinical studies to date. Thanks to multiple, diverse mechanisms of action and its accumulation in the liver (5-times higher concentrations than in the blood), CRV431 has demonstrated efficacy in two distinct animal models of NASH and HBV replication. These findings are consistent with in vitro studies documenting mechanisms of action as an antiviral agent (HBV, HCV, HDV ), protection from cellular stress and death, anti-steatotic, anti-inflammatory, anti-fibrotic, and anti-cancer activities. Thus, CRV431 is positioned to become a highly versatile therapeutic drug for the most prominent liver diseases of our time. No other marketed drugs or NASH drug candidates in development address all these mechanisms.
Candidate CRV431 Mechanisms of Action in Chronic Liver Disease (NASH and Viral Hepatitis)
CRV431 specifically binds cyclophilin isomerase enzymes and inhibits cyclophilin function with the highest known potency of any reported cyclophilin inhibitor (Ki= 1 nM). The pleiotropic actions of CRV431 are due to the fact that multiple cyclophilin isoforms exist in the body and participate in many biological processes. Cyclophilins assume especially prominent roles in disease processes such as cell death, fibrosis, and cancer cell growth and metastasis. Many viruses have evolved to recruit cyclophilins into their life cycles to assist in viral replication and evade the immune system. By blocking the participation of cyclophilins in these processes, CRV431 displays a variety of therapeutic activities.
CRV431 Binds to Cylophilin A
CRV431 Blocks the Action of Cylophilin B
CRV431 Binds to Cylophilin D
Mechanism of Action
|A||Viral Infection||Block virus entry, replication, and other activities that trigger liver injury|
|D||Cellular Injury||Decrease mitochondrial stress, ER stress, cell death|
|D||Steatosis||Decrease lipogenesis by lowering transcription of sterol regulatory element–binding protein-1c|
|A||Inflammation||Decrease infiltration and activation of inflammatory cells by blocking extracellular cyclophilin A-CD147 interaction|
|B||Fibrosis||Decrease collagen synthesis and pro-fibrotic activation of hepatic stellate cells|
|B||Fibrosis||Decrease collagen hydroxylation and crosslinking|
|A||Cancer||Decrease cancer cell adaptations to hypoxia|
|A||Cancer||Suppress metastasis-related gene expression|
|A||Cancer||Suppress signaling pathways regulating cancer cell proliferation|
CRV431 consistently decreased NASH-associated fibrosis in several studies, and multiple cyclophilin-mediated mechanisms may have contributed to the effect. Anti-fibrotic activity is an important advantage of CRV431 because many NASH drugs in development instead primarily target mechanisms regulating steatosis during the early phase of NASH. Fibrosis often is well established by the time that patients are diagnosed with NASH, and furthermore, fibrosis is the strongest predictor of adverse clinical outcomes in fatty liver disease, including liver-related death. Consequently, the FDA in a recently amended guidance for drug developers has highlighted noncirrhotic NASH with liver fibrosis as the area of greatest need and potential effect on health (Noncirrhotic Nonalcoholic Steatohepatitis With Liver Fibrosis: Developing Drugs for Treatment, Guidance for Industry, December 2018).
Inflammation, fibrosis, and carcinogenesis are as prevalent in viral hepatitis-induced liver disease as they are in NASH. The additional capacity of CRV431 to inhibit the life cycle of multiple hepatitis viruses means that CRV431 can simultaneously target the driving force of virus-induced liver disease as well the pathological activities that manifest in damaged livers. Antiviral activities of CRV431 apply to hepatitis B, C, and D viruses as well as other, non-liver-tropic viruses such as human immunodeficiency virus-1, and these activities occur through a variety of mechanisms (Gallay et al., 2015, PLoS One 10(8):e0134707). For example, CRV431 decreases HBV levels by blocking virus uptake into cells as well as blocking post-entry stages of the replication cycle. Experimental data has thus indicated reductions in HBV DNA, HBsAg, HBeAg, and pgRNA. In the case of HCV infection, CRV431 blocks the interaction between cyclophilin and the viral protein, NS5A, which is important for HCV replication.