Liver Fibrosis and Nonalcoholic Steatohepatitis (NASH)

NAFLD: NASH and NAFL

Nonalcoholic fatty liver disease (NAFLD) is defined as the accumulation of hepatic fat, as evidenced by imaging or histologic examination, in the absence of coexisting causes of chronic liver disease or secondary cause of steatosis including drugs, significant alcohol consumption, or inherited or acquired metabolic states. The spectrum of NAFLD encompasses 2 subtypes: nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH). Isolated NAFL is characterized by steatosis in at least 5% of hepatocytes, while NASH is defined by a pattern of characteristics including steatosis, lobular and portal inflammation, and liver cell injury in the form of hepatocyte ballooning.1

NASH, Prevalence and Incidence:

Nonalcoholic steatohepatitis (NASH) is strongly associated with being overweight or obese and having metabolic syndrome. Metabolic syndrome includes a cluster of conditions occurring together such as, increased blood pressure, high blood sugar, excess body fat around the waist, and abnormal cholesterol or triglyceride levels. A recent analysis of studies involving more than 8.5 million people from 22 countries showed that more than 80% of patients with nonalcoholic steatohepatitis are overweight or obese, 72% have dyslipidemia, and 44% have received a diagnosis of type 2 diabetes mellitus.2 The prevalence of NAFLD in the US is about 24% to 26%—about 85 million Americans. Up to 20% to 30% of these cases (about 17–25 million Americans) are thought to have NASH. Future projections estimate an exponential rise in NASH expected by 2025, to affect close to 43 million Americans.3 The number of patients awaiting liver transplant due to NASH nearly tripled from 2004 to 2013, and in 2013 NASH became the second leading disease among waitlisted patients for liver transplantation.4 Dynamic Markov modeling predicts that cases of decompensated NASH cirrhosis (i.e., liver failure) will rise by 161%, from about 144,000 to 376,000 cases over the next 15 years.5 These projections predict that NASH will overtake HCV (hepatitis C virus) as the leading cause of chronic liver disease among patients awaiting a liver transplant.

Developmental Stage of Prometic’s Research:

Prometic is currently committed to initiating a randomized, double-blind, placebo-controlled, dose ranging, proof of concept phase-IIa clinical study focused on investigating the potential efficacy and safety of PBI-4050 in the treatment of PBI-4050 in the treatment of NASH. PBI-4050 has demonstrated antifibrotic properties among multiple organ systems both in human and animal models, via G protein receptors, GPR40 and GPR84. The dual modulator PBI-4050 reinforces the involvement of both GPR40 and GPR84 in multiple models of fibrosis. PBI-4050 was well tolerated and demonstrated a good safety profile in two early-phase clinical trials.6