Targeted Therapeutics for Liver Disease - Project Abstract
The blossoming diabetes, obesity and metabolic syndrome epidemics have taken a toll on the North
American liver. The incidence and prevalence of non-alcoholic fatty liver disease (NAFLD), whose
genesis is in simple steatosis, and non-alcoholic steatohepatitis (NASH), are staggering. Left
untreated, NASH can progress to NASH with increasing levels of fibrosis, cirrhosis and hepatocellular
carcinoma (HCC). This disease continues to present a challenge to the gastroenterologist who has
few, if any, combat-ready tools at his/her disposal. While a number of promising agents are in clinical
trials in NASH, none has met approval. Liver disease is a chronic indication that will necessitate a
long course of therapy, which brings with it the attendant risk of drug related side effects. The
proposed program seeks to advance a highly targeted therapeutic, that is both, potentially effective,
and potentially safe, for the treatment of NASH. This program is based on new information on the
biology governing liver fibrosis, viz. the Rho-associated coiled-coil kinase (ROCK)2-hepatic stellate
cell (HSC)-fibrosis (ROCK2-HSC-fibrosis) axis and the synthesis of ANG4201, a proprietary, orally
bioavailable, small molecule inhibitor that can potentially interrupt this cascade. Under the aegis of
this SBIR Phase I application, we will first obtain a profile of ANG4201 pharmacokinetics (PK), and its
exposure-IC50 relationship (Specific Aim # 1). In Specific Aim # 2, we will use these data to evaluate
the efficacy of ANG4201 in two etiologically distinct models of liver disease. Unlike the first generation
of dual ROCK (1 &2) inhibitors, it is anticipated that a selective ROCK2 inhibitor will not only prove
efficacious in mitigating fibrosis but will also carry a lower risk of any side effects associated with
chronic dosing.
