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MSDC-0602K Shows Potential For Improving Markers Of Liver Disease In Individuals With Nonalcoholic Steatohepatitis (NASH)

ILC 2019: Second-generation thiazolidinedione, MSDC-0602K may significantly improve liver enzymes, fibrosis, and glycaemic markers with minimal adverse events, according to a Phase 2b study

12 April 2019, Vienna, Austria

EASL (EUROPEAN ASSOCIATION FOR THE STUDY OF THE LIVER)

An interim analysis from the ongoing, 12-month, Phase 2b EMMINENCE trial of the novel second-generation thiazolidinedione, MSDC-0602K, has reported significant improvements in liver enzymes and markers of fibrosis after 6 months of treatment in individuals with biopsy-confirmed nonalcoholic steatohepatitis (NASH). The results, which were presented today at The International Liver Congress™ 2019 in Vienna, Austria, represent a promising new approach to management of a disease where there are currently no approved treatment options.

It is estimated that ~25% of the world population has nonalcoholic fatty liver disease (NAFLD), which is frequently associated with metabolic disorders including type-2 diabetes.1 ~59% of individuals with NAFLD are estimated to progress to NASH, which in turn can lead to cirrhosis, liver failure, and hepatocellular carcinoma.1 The prevalence of NAFLD/NASH is increasing worldwide, with one recent model in the USA predicting an increase in NASH cases from 16.5 million to 27.0 million between 2015 and 2030.2 To address this growing health burden, thiazolidinediones are one of several drug classes being investigated for their potential to mitigate disease and reduce liver damage.3

Thiazolidinediones are understood to achieve insulin sensitivity by targeting the peroxisome proliferator-activated receptor-gamma (PPARɣ) transcription factor but their use has been limited by PPARɣ-related side effects.4 More recently, thiazolidinedione binding sites have been identified on the mitochondrial pyruvate carrier (MPC),5 inhibition of which has been shown in animal models to protect against liver damage.6 MSDC-0602K is a second-generation thiazolidinediones that has been formulated to limit PPARɣ binding while maintaining efficacy through MPC inhibition.7,8

In the EMMINENCE trial, 402 participants with a NAFLD Activity Score of ≥4 including ballooning and inflammation ≥1 and F1–3 fibrosis were randomized 1:1:1:1 to receive MSDC-0602K 62.5 mg, 125 mg, or 250 mg, or placebo, daily. Over 50% of participants also had type-2 diabetes, and >60% had baseline fibrosis ≥F2. The interim analysis presented today was conducted in the first 328 participants to complete 6 months of therapy.

According to Principal Investigator, Dr Stephen Harrison from the University of Oxford, UK, MSDC-0602K 125 mg demonstrated improvements in most disease markers at 6 months, with statistically significant placebo-corrected reductions in alanine aminotransferase (ALT; 27.0%; p<0.001) and aspartate aminotransferase (21.3%; p=0.012). Improvements in ALT were also seen in the MSDC-0602K 250 mg group (20.1%; p=0.004). The MSDC-0602K 125 mg dose also demonstrated statistically significant reductions in bilirubin, alkaline phosphatase, and gamma-glutamyl transferase, as well as improvements in several fibrosis markers including APRI Score and Fibro Test (both p<0.05). In participants with type-2 diabetes, all doses of MSDC-0602K were associated with significant improvements in HbA1c, a marker of glycaemic control. The adverse event profile of MSDC-0602K was similar to that of placebo, with a modest dose-dependent, placebo-corrected weight increase of ≤2%, which was statistically significant in the MSDC-0602K 125 mg and 250 mg groups.  Importantly, unlike pioglitazone, no difference from placebo for any dose was seen in the frequency of peripheral edema by physical exam.

‘This is the largest Phase 2b study in NASH to include paired biopsies, and even in this interim analysis, MSDC-0602K has demonstrated significant effects on multiple markers of liver disease,’ said Dr Harrison. ‘MSDC-0602K validates the strategy to develop novel thiazolidinediones to target the MPC, and may have the potential to ameliorate NASH and fibrosis and, in patients with type 2 diabetes, to improve glycaemic control.’

Prof Philip Newsome (Vice-Secretary, EASL) said, “This study is very exciting, with early data suggesting that MSDC-0602K shows promise in reducing markers of liver injury and fibrosis, in the absence of any significant adverse events. We look forward to seeing the results of liver biopsy analysis.”

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About The International Liver Congress™

This annual congress is the biggest event in the EASL calendar, attracting scientific and medical experts from around the world to learn about the latest in liver research. 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 expected to attract approximately 10,000 delegates from all corners of the globe. The International Liver Congress™ 2019 will take place from 10­–14 April 2019 at the Reed Messe Wien Congress and Exhibition Center, Vienna, Austria.

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 4,000 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

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Onsite location reference

Session title: ‘NAFLD – Clinical Therapy’

Time, date and location of session: 17:30–17:45, 12 April 2019, Main plenary

Presenter: Stephen Harrison, UK

Abstract: Six month interim results of MSDC-0602K in a large phase 2b NASH study demonstrate significant improvement in liver enzymes and glycemic control (NCT02784444) (PS-111)

Author disclosures

Dr Harrison has received consulting fees from Cirius Therapeutics

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. Estes C, et al. Modeling the epidemic of nonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease. 2018;67(1):123–33.
  3. McCommis, KS. Treating hepatic steatosis and fibrosis by modulating mitochondrial pyruvate metabolism. Cell Mol Gastroenterol Hepatol. 2018;7(2):275–84.
  4. Colca JR, Kletzien RF. What has prevented the expansion of insulin sensitisers? Expert Opin Investig Drugs. 2006;15(3):205–10.
  5. Colca JR, et al. Identification of a mitochondrial target of thiazolidinedione insulin sensitizers (mTOT)–relationship to newly identified mitochondrial pyruvate carrier proteins. PloS One. 2013;8(5):e61551.
  6. Rauckhorst AJ, et al. The mitochondrial pyruvate carrier mediates high fat diet-induced increases in hepatic TCA cycle capacity. Mol Metab. 2017;6(11):1468–79.
  7. Divakaruni AS, et al. Thiazolidinediones are acute, specific inhibitors of the mitochondrial pyruvate carrier. Proc Natl Acad Sci USA. 2013;110(14):5422–7.
  8. McCommis, KS. Targeting the mitochondrial pyruvate carrier attenuates fibrosis in a mouse model of nonalcoholic steatohepatitis. 2017;65(5):1543–56.