Anyone following the next big thing in pharma will likely be familiar with the acronym NASH. But what is this emerging indication that companies are racing to treat? Non-alcoholic steatohepatitis (NASH) is a type of non-alcoholic fatty liver disease (NAFLD), a condition where fat builds up in the liver. If you have NASH, you have inflammation and liver cell damage, along with fat in your liver.
Around 20% of Americans are thought to have NAFLD, and between 3.5% and 5% have NASH. Reports suggest that NASH could soon become the leading cause of liver transplant in the US by 2020 – a result of the increase in obesity and diabetes – and a potential public health crisis in the making.
Current Diagnosis and Treatment
Since NAFLD and NASH can cause few or no symptoms, it can be tricky to diagnose. A blood test looking at liver enzyme levels is the starting point, and ultrasound, CT, or MRI may also be used. However, imaging can show fat in the liver, but it can’t show inflammation or fibrosis, making it a challenge to distinguish between a fatty liver and NASH. NASH clinical trials use biomarkers such as serum lipids and triglycerides and the NAFLD activity scores (NAS) to assess disease severity.
There are currently no approved drugs for NASH. Doctors instead recommend weight loss, which might comprise lifestyle changes, pharmacological weight loss drugs (e.g. orlistat), and gastric band or bypass surgery.
Treatments on the Horizon?
Such is the unmet need for NASH, there are thought to be around 195 treatments in the pipeline. These can be broadly grouped into agents that target metabolic dysfunction driving the disease (insulin resistance and lipogenesis) and those that target the resulting pathological processes, such as apoptosis, inflammation, and fibrosis. They include:
Challenges in Developing Drugs for NASH
Despite the many drugs in development for NASH, many challenges exist. One is that NASH can be difficult to diagnose early; it can take years before patients show any sort of symptoms. It’s also not completely clear how physicians would respond to a NASH drug, if approved. Confirmed diagnosis requires a liver biopsy — a procedure that physicians are reluctant to do without a clear need.
There are also no criteria for identifying which patients with NAFLD will progress to NASH, making it hard for drug developers to provide a clear case for treating those patients now, especially when clinicians are trained to focus on related co-morbidities like diabetes and heart disease.
A further challenge is that drug developers and analysts are figuring out the market segment that will suit each drug. The severity of fibrosis is ranked from F0 to F4, with F0 denoting no fibrosis and F4 marking cirrhosis. Some pharma companies are focusing their efforts on F3 and F4 patients, while others are targeting more moderate populations. However, the earlier stages can resolve on their own with a dietary change and lifestyle change, so the commercial potential might not be as great.
Acknowledging these challenges, the FDA recently produced extensive guidance to help companies develop drugs to treat NASH. It says that companies should focus on developing treatments for non-cirrhotic NASH with liver fibrosis until there are methods for identifying the subset of patients who are at risk of progression. It also encourages sponsors to develop and validate biomarkers for diagnosing and grading NASH and liver fibrosis, as liver biopsy is currently the only reliable method.
The guidance also provides recommendations on trial design and endpoint selection. This includes the use of liver histological improvements as endpoints that are reasonably likely to predict clinical benefit, recognizing that the slow progression of NASH and the time required to evaluate progression to cirrhosis or survival is an impediment to conducting trials for this condition.
The Future Clinical Landscape
No medicines have yet been approved to treat NAFLD and NASH, but that looks set to change. GlobalData forecasts the NASH market will hit $18.3 billion by 2026, but some warn that the mixed data from trials mean that NASH trials have an uncertain future.
According to analysts, there’s room for improvement in the response rates currently being seen, and it’s unlikely that any single emerging NASH drug will be so effective that it will own the market.