About Non-Alcoholic Steatohepatitis (NASH)
Nonalcoholic fatty liver disease (NAFLD) is a condition in which fat builds up in the liver. Nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH) are types of NAFLD.1 With NASH, which is considered a more severe form of NAFLD, a person has inflammation and liver damage, along with fat in their liver (steatohepatitis).1,2 NASH tends to develop in people who are overweight or obese, or have diabetes, high cholesterol or high triglycerides. However, some people have NASH even if they do not have any risk factors. Most people with NASH are between the ages of 40 and 60 years. It is more common in women than in men. NASH often has no symptoms and people can have NASH for years before symptoms occur.2
NASH is one of the leading causes of cirrhosis in adults in the United States. Up to 25% of adults with NASH may have cirrhosis, which is the replacement of normal liver tissue with non-living scar tissue.2,3
It is estimated that in the United States between 6.5 and 16.3 million people have NASH.4 Worldwide, an estimated 115 million individuals have the disease, and by 2030 it is projected that globally it will affect upward of 350 million people.5 Also, in 2030, NASH is expected to be the most frequent reason for liver transplants in the United States.4
Up to 25% of adults with NASH may have cirrhosis, which is the replacement of normal liver tissue with non-living scar tissue.
It is estimated that in the United States between 6.5 and 16.3 million people have NASH.
Enanta’s NASH Compounds
Enanta has developed two compounds targeting the farnesoid X receptor (FXR), a nuclear hormone receptor that is expressed in the liver, gall bladder, intestine and kidney. Activation of FXR by its natural ligands, namely bile acids, regulates the expression of multiple genes encoding proteins involved in bile acid biosynthesis, transport and metabolism. Beyond the regulation of bile acid homeostasis, FXR agonists exhibit anti-inflammatory and anti-fibrotic activity making it an attractive target for the treatment of NASH.6, 7
EDP-305, An FXR Agonist
EDP-297, A Follow-on FXR Agonist
EDP-305 is a potent FXR agonist and Enanta’s first candidate developed for the treatment of NASH. EDP-305 represents a class of FXR agonists that has been designed to take advantage of increased binding interactions with the receptor. This non-bile acid class contains steroidal and non-steroidal components. It does not contain the carboxylic acid group normally present in other classes of FXR agonists and natural bile acids that can lead to the formation of taurine and glycine conjugates.
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In September 2019, Enanta reported results from ARGON-1, a 12-week, randomized, double-blind, placebo-controlled Phase 2a study evaluating the safety, tolerability, pharmacokinetics and efficacy of EDP-305 in a NASH population. The primary objectives of the study were to evaluate change in ALT levels at week 12 and to evaluate the safety and tolerability of EDP-305. Key secondary objectives included change in liver fat content by MRI-PDFF, change in lipids, and pharmacokinetics and pharmacodynamic parameters, including C4 and FGF19.
The study’s primary endpoint was achieved with a statistically significant ALT reduction of 28 U/L in the EDP-305 2.5mg arm versus 15 U/L in the placebo arm at week 12 (p=0.049). There was a statistically significant reduction in liver fat content with EDP-305 at the 2.5mg dose as measured by MRI-PDFF (p>0.001). A higher numerical reduction compared to placebo in ALT was observed between EDP-305 1 mg and placebo. Forty-five percent (45%) of subjects were MRI-PDFF responders (i.e. ≥30% fat reduction). In both EDP-305 arms combined, MRI-PDFF responders had a higher ALT reduction from baseline compared to no difference in the placebo. EDP-305 also exhibited strong target engagement as shown by increases in FGF-19 and ALP, as well as reductions in C4 at both doses. A robust reduction in GGT was also observed at both doses.
Overall, EDP-305 was generally safe, with the majority of treatment-emergent adverse events (TEAEs) being mild to moderate. The most common (≥5%) TEAEs included pruritus, gastro-intestinal (GI) related symptoms (nausea, vomiting, diarrhea), headache and dizziness. A consistent safety profile has been observed across more than 600 subjects exposed to EDP-305 across all studies to date. As for tolerability of EDP-305 in this 12-week Phase 2a study, pruritus was present in approximately 51% of the subjects in the 2.5 mg arm compared to less than 10% in the 1 mg arm, with the majority being mild or moderate in severity. The incidence of treatment discontinuation due to pruritus was 1.8% for 1 mg and 20.8% for 2.5 mg, with all the discontinuations in the 2.5 mg arm being due to moderate pruritus.
Enanta began evaluating EDP-305 in ARGON-2, a Phase 2 study designed to evaluate doses of 1.5 mg and 2.0 mg with the aim of demonstrating stronger biomarker signals of efficacy than seen at 1.0 mg in the ARGON-1 study and less pruritus than seen at the 2.5 mg dose in that study. The study was designed as a randomized, double-blind, placebo-controlled, 72-week study in approximately 340 subjects with biopsy-proven NASH. The primary endpoint of ARGON-2 was improvement of fibrosis without worsening of NASH and/or NASH resolution without worsening of fibrosis.
After a planned 12-week internal interim analysis of EDP-305 in ARGON-2, which was compared to clinical data from ARGON-1, Enanta identified the 1.0 mg dose of EDP-305 as providing the best balance of efficacy and tolerability to move forward into combination studies with other mechanisms in NASH.
Enanta identified EDP-297 as its follow-on FXR candidate. Preclinical data on EDP-297 reveal a profile that delivers high target-tissue distribution, along with potency greater than that published on any FXR agonist in clinical development today.
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Enanta’s Path to Treating NASH
Enanta believes that the multiple mechanisms in development for NASH today, which reflect the complex pathophysiology of this disease, make it likely that using FXR agonists in a combination regimen will ultimately provide the optimal benefit of these compounds for the treatment of NASH patients. In September 2021, the company ended the 72-week ARGON-2 study early in favor of pursuing combination regimens sooner.
Based on the significant data generated to date, EDP-305, which has been administered in almost 600 patients for up to 12 weeks, and EDP-297, the company’s follow-on candidate, are both well-positioned to be important components of combination therapies to bring a much-needed treatment to patients with NASH. The company is actively seeking to out-license both candidates.
- National Institute of Diabetes and Digestive and Kidney Diseases Fact Sheet
- American Liver Foundation: Nonalcoholic Steatohepatitis (NASH) Information Center
- American Liver Foundation: Cirrhosis of the Liver Facts at a Glance
- American Liver Foundation: NAFLD-NASH Infographic
- Wong, Sui-Weng et al. “Epidemiology of Non-alcoholic Fatty Liver Disease-Related Hepatocellular Carcinoma and its Implications.” JGH Open: An Open Access Journal of Gastroenterology and Hepatology vol. 2,5 235-241. 17 Jul. 2018, doi:10.1002/jgh3.12070
- Claudel, Thierry et al. “The Farnesoid X Receptor: a Molecular Link Between Bile Acid and Lipid and Glucose Metabolism.” Arteriosclerosis, Thrombosis, and Vascular Biology vol. 25,10 (2005): 2020-30. doi:10.1161/01.ATV.0000178994.21828.a7
- Xu, Jiao-Ya et al. “Recent Insights into Farnesoid X Receptor in Non-alcoholic Fatty Liver Disease.” World Journal of Gastroenterology vol. 20,37 (2014): 13493-500. doi:10.3748/wjg.v20.i37.13493