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Digital ILC 2020: As new data highlight the increasing prevalence of NAFLD, two new treatments have demonstrated reductions in ALT, hepatic fat and other indicators of liver disease, including in patients with type 2 diabetes

EUROPEAN ASSOCIATION FOR THE STUDY OF THE LIVER (EASL)

27 August 2020: Improvements in multiple biomarkers of non-alcoholic steatohepatitis (NASH) progression, reported in clinical studies across two drug classes, were presented today at The Digital International Liver Congress™ (DILC) 2020. The studies, which evaluated safety, biochemical signs of liver damage, and hepatic fat, represent further progress in an emerging strategy for the treatment of fatty liver disease: the targeting of lipid metabolism. The potential for such treatments to address type 2 diabetes mellitus (T2DM) and obesity, as well as liver disease, makes them a focus for current research.

Non-alcoholic fatty liver disease (NAFLD) is estimated to affect approximately 25% of the global population and is the fastest growing liver disease globally,1 with NASH putting patients at risk for complications such as hepatocellular carcinoma and cirrhosis. The reported prevalence of NASH varies widely, but estimates suggest that 1.5–6.5% of the general population has NASH and about one in five of these cases can progress to cirrhosis.2 New epidemiological data also presented at DILC 2020 by Dr Zobair Younossi, President of Inova Medicine and Chairman of the Department of Medicine at Inova Fairfax Medical Campus, Falls Church VA, USA reported that NAFLD is now the second most common cause of liver-related deaths in the USA (26.3%), closely behind alcoholic liver disease (27.9%). Among individuals who died with NAFLD, the leading causes of death were liver-related (53.1%), cardiovascular disease (12.2%), and non-liver cancer (6.6%). In fact, cancer deaths were related to liver cancer (42.6%), lung cancer (8.5%), colorectal cancer (6.9%), pancreatic cancer (5.5%), and breast cancer (4.2%).

While there are currently no approved pharmacological options indicated for NASH, research has been focused on a wide range of mechanisms that underlie processes common to multiple pathologies, including lipid metabolism.3 As NASH is estimated to be present in 37.3% of patients with T2DM,4 receptors influencing lipid metabolism and inflammation have been a key area of focus. These include the farnesoid X receptor (FXR), which negatively regulates hepatic gluconeogenesis,5 lipogenesis, and steatosis,6 and the glucagon-like peptide-1 (GLP-1) receptor, which improves glucose control and reduces body weight by decreasing appetite, influencing hepatic lipid content and inflammation.7

Results on a novel FXR agonist, designated EDP-305, were presented at DILC 2020. In the Phase 2a ARGON-1 study, patients with fibrotic NASH without cirrhosis were randomized to placebo (n=24), EDP-305 1 mg (n=55), and EDP-305 2.5 mg (n=53) groups and treated for 12 weeks. The higher-dose EDP-305 group exhibited significant reductions vs placebo in ALT (-27.9 U/L; p=0.0495), fat percentage (-7.1%; p=0.0009; measured by magnetic resonance imaging-proton density fat fraction), gamma-glutamyl transferase (-49.4 U/L; p<0.0001), and C4 as a pharmacodynamic marker (-72%; p<0.001). High-density lipoprotein was also significantly reduced (-0.21 mmol/L; p<0.0001). Pruritus was the most common treatment-emergent AE, present in <5%, <10%, and 51% of subjects in the placebo, EDP-305 1 mg, and EDP-305 2.5 mg groups, respectively. This led to discontinuation in 1.8% and 20.8% of the EDP-305 1 mg and EDP-305 2.5 mg groups, respectively.

“This trial confirms that FXR agonism is a valuable therapeutic target in NASH with strong antisteatotic effects and the potential to reduce inflammatory injury to the liver”, said presenter Dr Vlad Ratziu, Professor of Hepatology at Sorbonne University and Pitié Salpêtrière Hospital, Paris, France. “This highlights the need to conduct large and longer-term trials to show histological benefit at the dose that will minimize the side-effects of this class of drugs”.

The second study examined the first-in-class GLP-1/glucagon dual-receptor agonist, cotadutide. This Phase 2b study enrolled 834 overweight or obese patients with T2DM over 54 weeks of treatment; it was designed to assess the holistic metabolic effects of cotadutide and included an exploratory analysis of liver biomarkers. Patients were randomized to placebo, open-label once-daily liraglutide 1.8 mg, or once-daily subcutaneous cotadutide (100 µg, 200 µg, or 300 µg) for 54 weeks. At the end of treatment, significant reductions in body weight were observed at all cotadutide doses vs placebo (p<0.001) and cotadutide 300 µg vs liraglutide (p=0.009). Corresponding significant decreases in ALT were also observed for cotadutide 200 µg (-12 U/L; p=0.009) and 300 µg (-14.1; p=0.003) vs placebo, and cotadutide 300 µg vs liraglutide (p=0.023). Improvements in NAFLD fibrosis score (NFS) (p=0.01) and FIB-4 (p=0.004) with cotadutide 300 µg vs placebo further confirmed these results.

“We have demonstrated that cotadutide yielded greater reductions in ALT with similar weight loss to the GLP-1 receptor mono agonist liraglutide at 200 µg, and greater weight loss and ALT reductions at 300 µg in patients with T2DM”, said Dr Philip Ambery, Global Clinical Leader, Late CVRM at AstraZeneca, Gothenburg, Sweden, who presented the study. “The improvements seen in the NFS and FIB-4 are encouraging, and support the need for prospective clinical trials with cotadutide in patients with NASH. ”

“The epidemiological data confirm that NAFLD associated with dysmetabolism is becoming a major cause of liver disease, highlighting the importance of finding effective treatments for this condition”, said Professor Luca Valenti, an EASL Scientific Committee member from the University of Milan, Italy. “These clinical studies show that targeting FXR, GLP-1 and gastrointestinal hormone receptors are promising approaches for the treatment of NASH, which are worth to be further evaluated”.

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About The International Liver Congress™

This annual congress is EASL’s flagship event, attracting scientific and medical experts from around the world to learn about the latest in liver research and exchange clinical experience. Attending specialists present, share, debate and conclude on the latest science and research in hepatology, working to enhance the treatment and management of liver disease in clinical practice. This year, the congress is being held entirely digitally due to the global health situation. The Digital International Liver Congress™ 2020 will take place from 27–29 August 2020. For more information on attendance and registration, please visit https://ilc-congress.eu/.

About The European Association for the Study of the Liver (EASL)

Since its foundation in 1966, this not-for-profit organization has grown to over 4,500 members from all over the world, including many of the leading hepatologists in Europe and beyond. EASL is the leading liver association in Europe, having evolved into a major European association with international influence, and with an impressive track record in promoting research in liver disease, supporting wider education, and promoting changes in European liver policy.

Contact

For more information or to speak to an expert, please contact Sean Deans in the ILC Press Office at:

Session details

Session title: NAFLD – Clinical except therapy
Date and time of session: Thursday 27 August 2020, 15.45–16.00
Presenter: Zobair Younossi
Abstract: Causes of death in patients with nonalcoholic fatty liver disease (NAFLD): data from national vital statistics system (NVSS)

Session title: NAFLD – Pharmacological therapy
Date and time of session: Friday 28 August 2020, 11.45–12.00
Presenter: Philip Ambery
Abstract: Effects of cotadutide on biomarkers of nonalcoholic steatohepatitis in overweight or obese subjects with type 2 diabetes mellitus: a 54-week analysis of a randomized phase 2b study

Author disclosures

Zobair Younossi is a consultant to AbbVie, BMS, Genfit, Gilead, Intercept, Madrigal, Merck, Novo Nordisk, Quest Diagnostics, Siemens, Tern Pharmaceuticals, and Viking.

Philip Ambery is an employee and shareholder of AstraZeneca. He is also a Consultant Physician in Acute Medicine with Cambridge University Hospitals Trust, UK.

Vlad Ratziu is a consultant for Enanta and Intercept.

References

  1. Younossi ZM, et al. Global epidemiology of non-alcoholic fatty liver disease – Meta-analytic assessment of prevalence, incidence, and outcomes. 2016;64(1):73–84.
  2. Spengler EK, Loomba R. Recommendations for diagnosis, referral for liver biopsy, and treatment of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Mayo Clinic Proceedings. 2015;90(9):1233–46.
  3. Oseini AM, Sanyal AJ. Therapies in non-alcoholic steatohepatitis (NASH). Liver Int. 2017;37(Suppl 1):97–103.
  4. Younossi ZM, et al.The global epidemiology of NAFLD and NASH in patients with type 2 diabetes: A systematic review and meta-analysis. J Hepatol. 2019;71(4):793–801.
  5. Hou Y, et al. Farnesoid X receptor: An important factor in blood glucose regulation. Clin Chim Acta. 2019;495:29–34.
  6. Chávez-Talavera O, et al. Bile Acid Control of Metabolism and Inflammation in Obesity, Type 2 Diabetes, Dyslipidemia, and Nonalcoholic Fatty Liver Disease. 2017;152(7):1679–94.
  7. Petit JM, Vergès B. GLP-1 receptor agonists in NAFLD. Diabetes Metab. 2017;43(Suppl 1):2S28–33.
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