What is non-alcoholic steatohepatitis (NASH) and how does it differ from simple fatty liver (steatosis)?
The progressive form of Non-Alcoholic Fatty Liver Disease (NAFLD) is Non-Alcoholic Steatohepatitis (NASH), which defines a subgroup of NAFLD where liver steatosis co-exists with cell injury (hepatocyte ballooning) and inflammation with or without fibrosis at histological examination.
How many people with steatosis develop NASH and what is known about the reasons for this progression?
In the United States and Europe the prevalence of fatty liver (NAFLD) in the general population is about 30% (Browning, Szczepaniak et al. 2004; Williams, Stengel et al. 2011; Lazo, Hernaez et al. 2013), whilst epidemiological data estimate a prevalence of NASH between 12%-18% (Ryan, Johnson et al. 2002; Browning, Szczepaniak et al. 2004; Tran, Changsri et al. 2006; Williams, Stengel et al. 2011), with the highest rates in Hispanics (19%) and diabetics (22%) (Williams, Stengel et al. 2011). Thus, 40-50% of the NAFLD population has NASH.
How is NASH diagnosed?
Currently, NASH is diagnosed by the histological examination of a liver biopsy showing steatosis with concomitant inflammation and hepatocyte injury (hepatocyte ballooning).
Tremendous efforts are being devoted to the discovery and validation of non-invasive diagnostic biomarkers and/or imaging techniques.
What percentage of NASH patients go on to develop fibrosis and cirrhosis?
Patients with NASH develop progressive fibrosis in 25%-50% of individuals over 4-6 years, while 15-25% of individuals with NASH can progress to cirrhosis (Musso, Gambino et al. 2011).
In another study, 13 % of NASH patients with mild to moderate fibrosis (stage 1-2) and 50% of patients with fibrosis stage 3 developed cirrhosis (Ekstedt, Franzen et al. 2006).
Why is there a high unmet need for NASH treatments?
NASH prevalence is increasing due to its close association with the worldwide epidemic of obesity, and there is abundant evidence of an increased risk of liver-related events in very large cohorts of obese or diabetic individuals.
A recent publication showed that the proportion of patients with NASH amongst those undergoing liver transplantation has steadily increased over the past decades, reaching 10-13% in 2009. It is currently the third most common cause of liver transplantation and is expected to be the first by 2020.
In addition, individuals with NASH have a much higher risk of hepatocellular carcinoma (HCC) than individuals with simple steatosis, and NASH with fibrosis has been shown to increase the risk of HCC 25-fold. Finally, compared to simple steatosis, NASH is associated with a 6-fold increase in liver-related mortality.
Clearly, NASH is a serious evolving chronic disease whose prevalence is rapidly rising in the US and Europe. Although the natural history and the pathophysiological pathways deserve to be better understood, it is considered that necro-inflammation (hepatocyte ballooning + inflammation) initiates and drives the fibrogenic process, ultimately leading to cirrhosis, liver failure, HCC, liver transplantation and liver-related death (Argo, Northup et al. 2009).
Furthermore, NASH is a risk factor for Type 2 diabetes and cardiovascular disease (CVD), both of which have their own morbidity and mortality. Thus, NASH is viewed as a high public health burden which still has no approved treatment.
What do you think the future holds for NASH treatments?
All the pre-clinical and clinical data position our dual PPARa/d agonist, GFT505, as an ideal “first in line” candidate for treating NASH.
A large body of pre-clinical data in disease models of NASH and liver fibrosis clearly show beneficial effects of GFT505 treatment on steatosis, but more importantly on necro-inflammation and liver fibrosis.
In addition, Phase 1 and Phase 2a clinical studies have provided data that supports the therapeutic potential of GFT505 in NAFLD/NASH, acting notably on insulin resistance, plasma lipids and inflammatory markers, and showing beneficial effects on markers of liver dysfunction. Importantly, these studies have not raised any safety concerns associated with GFT505 treatment, thus providing a very favorable efficacy/safety profile for our candidate.
Besides GFT505, the most advanced candidate is obeticholic acid (OCA) from Intercept, currently in Phase 2b. Recently, the FLINT trial of OCA was stopped prematurely after an interim analysis showed good efficacy on histological NASH, but at the expense of an increase in LDL-cholesterol. This latter effect might be a concern for the cardiometabolic population to be treated. The complete data set should be available by the end of 2014.
Behind GFT505 and OCA, Raptor is conducting a Phase 2b trial with RP103 (cysteamine) in children with histological NALFD, while Conatus are planning to launch a phase 2 trial in NASH with their caspase inhibitor Emricasan.
A complementary approach to GFT505 and OCA is being developed by Gilead (Simtuzumab, GS-6624, currently in phase 2) and Galectin (GR-MD-02, currently in Phase 1), with the objective to directly attack bridging fibrosis and cirrhosis in patients with advanced NASH.
What are Genfit’s plans for the future?
GFT505 efficacy is currently being assessed in an international Phase 2b trial of 270 patients with biopsy-proven NASH. The recruitment phase is now completed and the results should be communicated at the end of 2014. The recently-granted FDA “Fast Track” designation will certainly speed up our discussions with the Agencies to prepare for Phase 3 and set up the most appropriate development plan to get approval.
Where can readers find more information?
The pre-clinical results in animal models of NASH and liver fibrosis have been published in Hepatology, and the results of three different Phase 2a trials at 80 mg/d GFT505 have been published in Diabetes Care.
About Jean-François Mouney
Jean-François Mouney holds Business and Health Economics Degrees from the ESCP-Europe Business School in Paris. From 1979, the entrepreneur founded and managed several successful and innovative companies in the aeronautical industry, and since 1992 in the biopharmaceutical field.
Mr. Mouney is co-founder of GENFIT, created in 1999, and has been Chairman & CEO of the Company since its inception; he is President of its US subsidiary, GENFIT Corp., created in Cambridge (MA) in 2003. In 2001 he also founded NATURALPHA, specialized in Nutrition Research and Development.
Mr. Mouney is co-founder and Vice-President of one of the largest Biopharma clusters in Europe (EURASANTE – NSL). He is also advisor to the Banque de France, since 2008.
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