Non-alcoholic steatohepatitis, or NASH, has had an explosion of interest due to the growing impact on world health. In the United States alone the number of patients with NASH is projected to expand from ~16 million in 2015 to ~27 million in 2030. Due to the progression of NASH to cirrhosis, end-stage liver disease and hepatocellular carcinoma this increase will be accompanied with a rise in liver transplantation and economic burden.
With no approved therapies NASH is a disease of high-unmet therapeutic need and therefore is currently the focus of a huge amount of drug development effort. The market size is predicted to grow from $138m in 2016 to more than $18bn in 2026, according to analysts GlobalData – a compound annual growth rate of more than 60%.
However, pharma companies are currently struggling with a lack of non-invasive endpoints for their clinical trials. There is still a reliance on histological tests, which means patients have to undergo invasive, painful liver biopsies which puts the consistency of the results in question. With a requirement for biopsies at the start and end of the study and, ideally, another at the trial mid-point, patient drop-out rates are high.
There is a real drive towards finding a non-invasive test. Several have potential, including the enhanced liver fibrosis, or ELF, test, plus Fibroscan, FIB-4 and NAFLD fibrosis score. Only ELF is really suitable for in vivo studies, with issues such as age, BMI and technical issues surrounding scanning rodent livers precluding the rest.
In a clinical setting, Siemens already have a patented ELF test that can be used in clinical trials. Combining, the measurement of three separate circulating biomarkers– tissue inhibitor of metalloproteinase 1 (TIMP-1), hyaluronic acid and procollagen III amino terminal peptide (PIIINP) an ELF score is calculated. NICE guidelines suggest diagnosing patients with advanced fibrosis using the ELF test prior to referral to a hepatologist.
In preclinical development, in vivo models that translate well into the clinic are essential for assessing potential drugs before moving to Phase 1/2. Having a suitable biomarker to track progression throughout the study phase, which can also be used in subsequent clinical trials is ideal and demonstrates translatability.
Liver enzyme biomarkers correlate to hepatitis rather than NASH, and thus are of limited use. Now, Renasci has demonstrated in vivo biomarker tests that correlate directly with the ELF tests used in the clinic. It’s early days, but we have had good results thus far. Blood samples can be taken at various time points, allowing the course of the disease to be tracked, and improvements resulting from treatment to be monitored. It will also allow the disease state of the animals to be assessed before treatment starts, allowing a direct tracking of the therapeutic intervention.
There is a real desire to move away from biopsies in a clinical setting, and the ELF test may be the answer. While FDA guidelines still recommend biopsies to assess patients who may have NASH, NICE guidelines now recommend the ELF test. Being able to correlate preclinical studies more directly with measurements made in clinical trials is going to make a huge difference to companies researching treatments for diseases such as NASH, and the prospects of new, effective drug treatments becoming available for patients.
At RenaSci we’re preclinical experts in NASH and a range of other therapeutic areas. If you would like to discuss preclinical challenges, or how RenaSci can help your project towards the clinic we’d be happy to have a chat. You can get in touch using our contact form or by emailing firstname.lastname@example.org
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