The Bad Fat Problem
Why is there a fight for bad fat by the pharmaceutical industry in the development of anti-NASH therapeutics? The answer lies in the evidence that bad fat is a major inducer of hepatic steatosis (i.e. fatty liver) that leads to NASH and also an inducer of metabolic syndrome ((MetS)).
NAFLD is a disease that comprises, non-alcoholic fatty liver (NAFL or simple steatosis) and NASH. NAFL or simple steatosis is typified by benign simple fatty liver that could be resolved by exercise/physical activity and diet modification. If NAFL is unresolved, it progresses to NASH, a chronic disease characterized by hepatic steatosis/fatty liver. This fat is called an ‘inflammatory fat’ that cannot be resolved solely by exercise. Inflammatory fat presumably induces lipotoxic effects that promote and/or sustain the progression of NASH.
The third type of fat is the “visceral adipose fat (VAT). VAT is found in the adipose tissue surrounding gastrointestinal organ systems. VAT is difficult to reduce with diet and exercise alone.
VAT is not currently an area of intense clinical interest in NASH therapeutic development. But, it has been actively researched by the scientific community for years. I strongly believe that VAT research would be the next big push by biopharma for effective therapeutics to resolve VAT that could be contributing to MetS and NASH.
Fat Burners In NASH Therapeutics
To understand the need for clinical development of anti-NASH therapeutics that target inflammatory fat, I first highlight the 2 faces and phases of NASH.
There is an ongoing misunderstanding on the clinical value and rationale for several anti-NASH drug candidates currently in development. NASH is a progressive chronic liver disease with 2 phases and 2 faces:
The first face is the early phase which is typified by inflammation, ballooning of hepatocytes (i.e. early apoptosis) and steatosis (i.e. fatty liver). The second face is the late phase which is characterized by inflammation associated with full activation of apoptotic machinery that leads to fibrosis and consequently cirrhosis. This is the clinical rationale for the existence of 2 main groups of anti-NASH therapeutics currently in clinical development.
There is substantial evidence on the lipotoxic injurious effects of bad fat in the development of early NASH. It is becoming well-established that reduction of hepatic inflammatory fat in early NASH patients leads to histologic response, including NASH resolution. As I alluded to previously, patients with early NASH have inflammatory fat which can only be reduced via decreased fat production and/or increased breakdown of fat (i.e lipolysis).
For this reason, anti-NASH drug candidates such as those by Genfit, Madrigal, NGM, Galmed, are in clinical development for early NASH to induce anti-lipogenesis effects (ie. suppress hepatic fat formation). In contrast, drug candidates by Gilead, Conatus, GALT, and Allergan, are designed to suppress fibrotic events in late NASH. Intercept is targeting both early and late NASH based on its clinical endpoints. This could be the clinical rationale for most combination therapeutic approaches in NASH clinical trial utilizing a fat burner drug candidates in their trials.