NASH Definition and Prevalence:

NASH (non-alcoholic steatohepatitis) occurs when there is a build-up of excess fat in the liver that is accompanied by inflammation and fibrosis. Some amount of liver fat is normal, but a higher amount is termed nonalcoholic fatty liver disease (NAFLD).  NASH is a progressive inflammatory disease occurring in fatty liver that leads to severe fibrosis (cirrhosis) and may require liver transplantation.  NASH usually occurs in people with NAFLD who are obese and may have other health problems, such as type 2 diabetes and hyperlipidemia.  NASH has been termed “the next big global epidemic”.  About 30% of the global population has fatty liver, up to 30% of these patients will develop NASH, and up to 25% of patients with NASH will develop cirrhosis within 7 years from diagnosis.


NASH Biology:

Progression from NAFLD to NASH is thought to require “two hits”: the first being accumulation of excess hepatic fat, and the second being initiation of an inflammatory process. While various factors have been proposed as second hits, the generation of reactive oxygen species (ROS) has been tightly linked to inflammation and tissue damage in a variety of diseases, including atherosclerosis and NASH.  ROS-induced lipid peroxidation triggers inflammation and generates cytokines that activate hepatic stellate cells to secrete the collagen that leads to fibrosis.


Relationship of NASH to Uric Acid:

A subgroup of NASH patients (30% to 50%) also have elevated serum uric acid (UA).  In such patients, UA has a dose:effect correlation with NASH: namely, higher risks of NASH development from NAFLD, as well the severity of NASH, are linked to progressively higher serum levels of UA.  This correlation suggested that UA, or underlying factors associated with elevated UA, may actually be causative in NASH, especially since production of UA is well-known to generate ROS.  Recent studies have shown that drugs that reduce UA can inhibit both development of NASH as well as progression of NASH to fibrosis. Reduction of UA solely by increasing UA excretion also appears beneficial. These results have prompted calls for clinical trials of potent hypouricemic drugs in NASH.

Relburn compounds inhibit production of UA and promote its urinary excretion, thus yielding marked reductions of serum UA and presumably reduction of ROS that may promote inflammation in NASH.  The Company proposes to test its drugs in clinical trials of patients afflicted with NASH.