by Kavitha Gnanasambandan
Outside of the rising aging population, another big public health concern is the increase in metabolic disorders such as obesity, diabetes, and non-alcoholic fatty liver disease (NAFLD). NAFLD represents a histopathological spectrum of liver diseases ranging from fat accumulation in liver (steatosis) to non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and liver failure or liver cancer (hepatocellular carcinoma or HCC). NAFLD is estimated to affect 30% of adults in US. Pathogenesis of NAFLD is closely associated with obesity and diabetes and its prevalence has been rising in parallel with these two disorders. While adopting a healthy lifestyle could reverse NAFLD at the early stages such as steatosis, there is still a major unmet need for effective therapeutics at later stages of disease.
The liver plays an important role in metabolism within our body enabling nutrient storage and processing, bile production, and elimination of waste products. Though the liver has a regenerative capacity, certain insults like virus infection, alcohol, or continuous fat deposition over a long period could cause severe liver injuries that create scar tissue in the liver and prevent regeneration (Figure 1). Liver disease management varies based on the underlying insult. While treatment options are available for liver diseases caused by hepatitis infection or autoimmune diseases, no FDA approved therapeutics are available for NASH. Recent success in HCV treatment and rising NASH prevalence has incited the interest of drug developers in NASH. Big pharma has become particularly active in deal making over the past two years with smaller companies that have promising NASH candidates. However, drug development for NASH has its own uphill battles right from identifying the candidate with an appropriate mechanism of action (MOA) to targeting the right patients and using appropriate end points in clinical trial design. Further, upon approval, availability of non-invasive diagnostics to identify appropriate patients for treatment will be key for both market penetration and successful reimbursement.
A number of companies are currently developing treatments for NASH. Unlike Hepatitis C, where HCV infection is the primary underlying cause of the disease, NASH is a multifactorial disease with a complex pathophysiology. Hence a therapeutic with single MOA may not be sufficient for treatment. Since no benchmarks have yet been established for successful NASH treatment, each company is taking its own approach to develop the best treatment for NASH through internal and external R&D. Pipeline candidates can be characterized as drugs that target the major pathways involved in NASH pathogenesis or drugs with pleiotropic effects that can bind to multiple key targets implicated across several pathways (Figure 2). Ultimately, combination therapies that combine molecules with complementary MOAs may provide the greatest clinical benefit. Intercept Pharmaceuticals and GENFIT carry the most advanced pipeline candidates in phase III. Gilead Sciences could be catching up with its own candidates that target patients with more advanced fibrosis. Several other companies like BMS, Allergan, and J&J are building up their NASH portfolio through deal making.
The next key challenge in NASH is in targeting the right patients and identifying appropriate endpoints for clinical trial design. Many companies are using biopsies as a key tool for including patients in clinical trials. Histologic improvement in NASH resolution is essential to prove a drug’s efficacy and is the endpoint that is currently accepted by FDA. However, upon approval it will be important for physicians to have a more non-invasive and affordable diagnostic tool for identifying patients who will be eligible for treatment. Further, given the chronic nature of the disease, clinical trials can span two to four years or more; biomarker-based diagnostics could help delineate drug effects on disease progression in a shorter timeframe through surrogate endpoints. Governing bodies like AASLD and FDA have conducted workshops to encourage biomarker discovery for NASH. Accordingly, companies that are active in NASH biomarkers (e.g. OWLiver) development and those with noninvasive imaging modalities (e.g. Echosens) have engaged drug developers for parallel development of diagnostic tools in clinical trials. Given the large prevalent population of NASH, diagnostic tools will be critical to identify the appropriate patients who will benefit from treatment and avoid reimbursement barriers that could prevent access. Payers are paying close attention to NASH and are developing their own cost control strategies to avoid significant budget impact.
Despite the challenges, recent interest and efforts in NASH drug development are a sign of hope for patients. Given the growing promise of disease modifying therapies for challenging conditions, companies with NASH portfolios can become successful by addressing the development challenges in a strategic and timely manner.
Kavitha Gnanasambandan is a Senior Analyst at Health Advances.