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INSIGHTS

Great news! The first NASH treatment Resmetirom was approved by FDA on March 14.

Nonalcoholic steatohepatitis (NASH) is a dangerously progressive form of nonalcoholic fatty liver disease (NAFLD) in which patients have inflammation of the liver and liver damage, in addition to excess fat. NAFLD is estimated to afflict one billion individuals globally and may be present in approximately 25% of the world population1. It is estimated that 20% of individuals with NAFLD will develop into NASH, conferring a sizable risk of cirrhosis and hepatocellular carcinoma (HCC)2.

One approved NASH new drug can’t meet the huge patient needs. Let’s collaborate and work together to transform new and meaningful solutions to benefit more people living with NASH.

With focus on studying immunology, inflammation and metabolic disease models for more than 16 years, John Liu, Head of Pharmacology and Lin Teng, VP of Integrated Biology, BioDuro-Sundia share their insights on the industry challenges and how a highly clinically translatable NASH model can help.


Complimentary Download: A New Obesogenic NASH Mouse Model. In this exclusive 23-page NASH Guide you will learn about:

• Prevalence and Progression of NASH

• Multifactorial NASH Pathogenesis – Challenges to Develop Effective Treatments & Animal Models

• Mechanisms of action of the main candidate drugs for NASH

• Types of Animal Models for NAFLD/NASH

• Validation of the New NASH Model with Reference Drugs

• A New HFC + Fructose Diet Induced NASH Model in Hamsters

• Target-specific biology assays

• In vitro disease models

• Disease phenotypic readouts

• And more…

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What are the technical difficulties and industry pain points of this area at present?

Due to the complex pathogenetic mechanism and considerable heterogeneity of NASH, multiple phase II/III NASH studies failed with monotherapy. A few candidate drugs show good efficacy but with low patient response rate.

Histological evaluation based on liver biopsy is of great value but needs to be improved due to potential risk of invasive injury, sampling variability, insufficient evaluation of dynamic changes in fibrosis and inadequate identification of the complex heterogeneity.

Reliable preclinical evaluation of compounds in animal NASH models with high clinical translatability is of tremendous value to accelerate the development of effective NASH treatments.

What can NASH models at BioDuro-Sundia help new drug discovery?

Our novel NASH model exhibits hallmarks of NASH and the modified High Fat Diet plus Fructose induces hepato-steatosis and fibrosis with increased insulin, glucose, cholesterol, triglyceride and free fatty acid. With respect to histopathological results, the liver has increased steatosis, lobular inflammation, ballooning, Mallory body and robust fibrosis. The phenotype is consistent to human metabolic syndrome/Nash-Fibrosis.

Our NASH model has also shown superior clinical translatability. We have evaluated GFT505, Semaglutide, OCA and Resmetirom in this model to assess the correlation of readouts from our NASH model with the clinical trial outcomes of these compounds. These four reference drugs are chosen because they act on 4 different classes of prominent therapeutic targets for NASH, respectively. The data of these four reference drugs derived from BioDuro-Sundia’s NASH model is fully consistent with the results from their clinical trial studies.

In parallel, BioDuro-Sundia has developed in vitro phenotypic models ranging from steatosis to NASH utilizing primary human hepatocytes (PHH) and HepG2 cells. These models reflect the rising of inflammatory chemokines and fibrosis markers. Furthermore, the effects to inhibit lipid accumulation and anti-inflammatory properties of Resmetirom have been confirmed.

What are the highlights of the studies on NASH and other Metabolic Diseases models at BioDuro-Sundia?

BioDuro-Sundia has established a novel NAFLD/NASH model, which mimics the pathogenesis of clinical NASH patients and exhibits hallmarks of NASH, including steatosis, lobular inflammation, ballooning and fibrosis in 12 - 16 weeks of dieting with total experiment duration almost half of other HFD induced NASH models, saving valuable time and cost for the preclinical study of NASH. BioDuro-Sundia now are keeping mice on our NASH diet so clients don’t need to wait for model induction and can start treatment once the compounds are ready.

BioDuro-Sundia also establishes target-specific in vitro assays for the NASH targets, including nuclear receptors (NR) such as THRs, PPARs and FXR, as well as G protein coupled receptors (GPCRs) like GLP-1R and GIPR, ASK-1 and Caspase 1/3.

With more than 16 years’ experiences in immunology, inflammation and metabolic disease models, we have a deep understanding of the disease mechanisms and different targets and we are committed to providing novel and high-quality solutions to our partners of new drug discovery.

Reference:

1 Zobair Younossi, Frank Tacke, et al. Global Perspectives on Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis. Hepatology (2019) 69(6):2672-2682. doi: 10.1002/hep.30251.

2 Loomba R, Friedman SL, Shulman GI. Mechanisms and Disease Consequences of Nonalcoholic Fatty Liver Disease. Cell (2021) 184(10):2537–64. doi: 10.1016/j.cell.2021.04.015

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