Translational Research for Basic and Clinical Research: The World’s First NASH to Liver Cancer model—STAM™—and Its Clinical Relevancy.

Our mission here at SMC Laboratories, Inc. is to facilitate the development of new drug options for patients whose needs are not currently being met by the treatments available in the market today, and above all, to increase their quality of life. In order to accomplish this, we offer preclinical drug efficacy studies specifically targeting inflammation and fibrosis. Although the pharmaceutical industry has spent countless hours attempting to develop a treatment for every kind of illness, the number of presently incurable diseases is still extremely high and many seemingly promising drug candidates are found to be unsuccessful during clinical testing. According to a paper published by Nature Reviews Drug Discovery^1, the number one reason that drug candidates are dropped is due to a lack of efficacy (see fig. 1) and the reasons remain largely unchanged today. This is often a problem that occurs when a model with low clinical correlation is used at the preclinical stage. In an article entitled “Make mouse studies work”, published in a 2010 issue of Nature^2, Steve Perrin identified the ability that high-quality preclinical models (i.e., those with high clinical relevancy) have in predicting whether a drug candidate will be successful at the clinical stage (see fig. 2). The gap that occurs in translational medicine between basic research and clinical research is called the “Valley of death”. Our goal at SMC is to bridge this gap by recommending models and study designs that have a high clinical correlation, thereby increasing the number of new drug candidates that successfully enter the market. In this blog post, we will introduce our proprietary STAM™ model as one example of a model that has a high clinical correlation.

The Creation of the STAM™ Model

Non-alcoholic fatty liver disease (NAFLD) is a pathological condition that is diagnosed via histopathology and/or imaging, and is separate from alcoholic liver disease. While non-alcoholic fatty liver (NAFL) often does not progress and will simply remain as NAFL, it can also lead to non-alcoholic steatohepatitis (NASH), liver fibrosis, cirrhosis, and even cancer. NASH differs from NAFL in that it has a type 2 diabetic (T2D) background and can progress to cirrhosis and liver cancer. Owing to the fact that there are currently no available treatments for NASH, it has become one of the biggest problems facing the medical world today. One of the reasons for the lack of available treatments is a lack of animal models that replicate human NASH. While there are many models that use transgenic mice (ob/ob, db/db, etc.) as well as diet-induced models (MCD, DIO, etc.), they often do not develop fibrosis or cancer and lack important pathologies such as a diabetic background and sever weight loss. This lack of relevant models is what lead us to create the world’s first NASH model that progresses from fibrosis to hepatocellular carcinoma (HCC) and has a T2D background.

The Clinical Relevancy of the STAM™ Model

The STAM™ model, as mentioned previously, has a T2D background and progresses from steatohepatitis to NASH to fibrosis, and finally, to HCC. This is the same disease progression that we see in humans, and it takes just 20 weeks for 100% of the mice to develop HCC. While these qualities alone make it stand apart from all the other models that are currently available on the market, another impressive aspect of this model is its ability to replicate many of the pathologies seen in human NASH. Below are six specific pathologies that can be observed in the model, as STAM™ well as in humans:

1. Ballooning hepatocytes in the liver
2. Burnt out NASH, in which lipid droplets decrease as fibrosis progresses, occurs
3. Fibrosis develops around the central vein
4. Mild elevation in the liver damage marker ALT
5. A significant increase in the NASH related biomarker CK-18
6. Increases in human HCC markers such as glutamine synthase, glypican-3, and AFP

As described above, the STAM™ model is the only model that reproduces many of the pathological conditions of human NASH. For this reason, the value of this model has been recognized all of the world and patents have been obtained in Japan, the United States, Europe, and South Korea.

The STAM™ Models Clinical Relevancy in the Drug Discovery Process

NASH in the STAM™ model exhibits a similar pathology to human NASH. For example, the NAFLD activity score, which was set as the primary end point in clinical trials by the FDA, can be used to evaluate NASH in the STAM™ model as well, which we have been doing here at SMC for over 10 years. On top of that, more than 800 test substances have been evaluated for efficacy in this model (see Fig. 3), and more than 15 test substances have entered into the clinical stage, including Cenicriviroc, which is currently in Phase 3. Presently, of the drug candidates that have been tested in the STAM™ model and entered into clinical trials, 35.48% of them were found to have data that correlated with the results received during clinical trials, 29.03% were not correlated, and 35.49% are currently unknown as the studies are ongoing (see Fig. 4, Clinical relevancy is about 50% when considering only those whose results have been clarified). When compared to the PDX model, which is generally thought to have a high clinical predictive value of 30%, the STAM™ model boasts an even higher clinical relevancy in comparison.

Here at SMC laboratories, we hope to continue to supporting the development of drug candidates for diseases that currently have no treatments by providing study designs and models that have a high clinically relevancy, like the STAM™ model.

About SMC Laboratories
SMC Laboratories, Inc. is a global specialty CRO focusing on non-clinical trials, with expertise in the area of inflammatory and fibrosis diseases. We have been delivering non-clinical study services to more than 800 clients in 30 countries, such as global pharmaceuticals, biotech, and National Institutes around the world. We have supported our partners with our strategic solutions based on our knowledge and experience. Please let me know if you have any interest in our models, any publications using our model data.
For more information: SMC Laboratories, Inc.

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References

1. Richard K. Harrison, Phase II and phase III failures:2013-2015, 15, 817-818, 2016, Nature Reviews Drug Discovery
2. Steve Perrin, Preclinical research: Make mouse studies work, 507, 423-425, 2014, Nature