Nonalcoholic steatohepatitis (NASH)
We are committed to ensuring that our drug candidate elafibranor (GFT505) becomes a first-in-line medicine in its field, thus bringing a therapeutic solution to patients who currently have no treatment options.
The most severe form of Nonalcoholic Fatty Liver Disease (NAFLD)
NAFLD is an umbrella term that encompasses a spectrum of conditions characterized by the buildup of fat in the liver, called “hepatic steatosis” that is not caused by alcohol consumption. Although experts are still studying the multiple possible causes, it is generally accepted that NASH is a consequence of unbalanced diets (high-sugar, high-fat and insufficient physical exercise), leading to an accumulation of fat in the liver. As the disease progresses, liver cells can experience inflammation and damage (manifested as liver cell ‘‘ballooning’’). A patient has NASH when the three components—steatosis, inflammation and ballooning—are all present.
As the global epidemic of obesity fuels NAFLD prevalence, NASH has become one of the most common liver disorders. In the absence of approved therapies, NASH remains widely untreated, and has become a critical public health concern with high unmet medical needs.
A progressive liver disease with alarming consequences on health
Without therapeutic intervention, NASH can cause the development of fibrosis, which is the accumulation of non-functional scar tissue, as the body tries to heal itself.
Because this build-up leads to tissue remodeling, development of fibrosis leads to progressive loss of liver function which may ultimately progress to life-threatening conditions such as cirrhosis, liver cancer and ultimately liver failure, a stage where patients have no other choice than undergoing a liver transplantation.
NASH is today the second leading indication for liver transplantation in the United States behind hepatitis C, and is expected to become the primary cause by 2020.
Progression of a normal liver through the development
of NASH and its consequences1
Cardiovascular diseases: leading cause of death among NASH patients
In addition to its deleterious effects on the liver, NASH multiplies the risk of a patient developing cardiovascular problems:
- myocardial infarction,
- peripheral vascular accident.
This contributes to higher mortality rates in NASH patients, and cardiovascular disease is the leading cause of death in NASH patients2.
A study published in the Journal of Hepatology estimates that there were approximately 17.3 million adults with NASH in the United States in 2016 and projects that this number will grow to approximately 27.0 million by 2030; in five major European countries, (France, Germany, Italy, Spain and the United Kingdom) these numbers were estimated to be 12.6 million in 2016 and 18.3 million by 20303.
A silent disease widely under-diagnosed
Like most liver conditions, NASH is a silent disease, meaning patients generally have no symptoms until the first signs of its complications, and is notably under-diagnosed.
Indeed, today, the clinical standard to formally diagnose NASH and stage fibrosis in a patient suspected of having NASH is the liver biopsy. However, the liver biopsy remains an invasive procedure for the patient, which presents a number of limitations including pain and discomfort. In addition, there are a limited number of specialists who are able to perform and interpret liver biopsies when considering the anticipated increase in clinical cases over the next 10 years. In addition to its limitations for patients and healthcare professionals, liver biopsy is a very costly procedure. It indeed represents a financial burden for the healthcare systems, as its cost will hinder the large scale NASH diagnosis that is likely to be needed in the future.
As such there is a clear unmet need recognized by both FDA and EMA, for the development of non-invasive blood-based diagnostics in NASH that would enable patient identification on a large-scale and thus improve patient clinical management4.
A multifaceted disease with high unmet medical needs
NAFLD and NASH are closely associated with metabolic disorders. Patients suffering from NASH usually suffer from one or several co-morbidities, such as:
- type-2 diabetes,
- high triglycerides levels,
- high LDL cholesterol levels,
- low HDL cholesterol levels.
Therefore, as the double obesity and type-2 diabetes pandemic have increased, so too has the number of NASH cases worldwide.
Similarly to many metabolic conditions NASH is a multifactorial disease with numerous components. These include:
- insulin resistance,
- oxidative stress,
- increased liver fat,
A therapeutic solution that has the ability to address multiple NASH components would provide optimal clinical benefit and would have the best probability to attain the histological endpoints required for drug registration for the treatment of NASH patients.
Existing drugs have been tested off-label for assessing potential efficacy on NASH and liver fibrosis but have failed because of lack of efficacy, unacceptable side effects or both.
Elafibranor for the treatment of NASH
Our proprietary compound, elafibranor showed positive results in its international Phase 2b clinical trial in treating NASH patients, and we are currently evaluating the drug candidate for the treatment of NASH in a global randomized, double-blind, placebo-controlled Phase 3 clinical trial named “RESOLVE-IT”.
Regulatory agencies recognize the emergency of making therapies available for patients suffering from NASH. In the light of elafibranor’s positive effects on the 2 key markers of the disease (inflammation + ballooning), while maintaining a favorable safety and tolerability, elafibranor has received fast-track designation from the U.S. FDA, for the treatment of NASH.
The clinical trial began in the first quarter of 2016 and has already completed recruitment of the cohort needed for the interim analysis. We expect to report top line data by the end of 2019. These results, if positive, would support the accelerated approval from the FDA, and conditional approval from the European Medicines Agency, or EMA, as early as 2020.
We believe elafibranor’s unique mechanism of action has the potential to modulate many of the key hallmarks of NASH, thereby making it well-positioned as a first-line treatment as a monotherapy and the backbone of combination regimens.
1Matteoni, Gastroenterology 1999 – Adams, Gastroenterology 2005 – Ekstedt, Hepatology 2006 – Ong, J Hepatol 2008 – Dunn, AJG 2008 – Sorderberg, Hepatology 2010 – Targher, NEJM 2010 – Williams, Gastroenterology 2011 – Chalasani, Gastroenterology 2012 – Torres, Clin Gastroenterol Hepatol 2012 – Wree, Nat Rev Gastroenterol Hepatol 2013 – Rinella, JAMA 2015 – Bazick, Diabetes Care 2015
2Angulo, Gastroenterology 2015
3Estes, C. et al., Modeling the epidemic of nonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease. Hepatology, 2018. 67(1): p. 123-133.
4Noncirrhotic Nonalcoholic Steatohepatitis with Liver Fibrosis: Developing Drugs for Treatment; Guidance for Industry; FDA 2018