Entering the NASH Race: Tips for Early Clinical Development

Nonalcoholic steatohepatitis (NASH) is a chronic liver disease that affects over 17 million Americans and this number is growing. NASH can lead to cirrhosis, end-stage liver disease, liver transplant and even hepatocellular carcinoma.  Therefore, the need for treatment for this devastating, progressive disease is dire. That said, the NASH drug development landscape is robust. With over 100 compounds in discovery, nearly 80 drugs in clinical trials in which 4 have made it to Phase III; it is anticipated that a NASH drug will be available within the next few years and there will be several drug categories to boot.  Potential drug classes include those that target metabolic pathways such as de novo lipogenesis, those that have anti-inflammatory or anti-apoptotic properties and anti-fibrotic compounds. Similar to the diabetes indication, polypharmacy may be one strategy to tackle this progressive, chronic disease.

Although the NASH pipeline is abundant, with no FDA approved treatment as of yet, there is still time to enter the race. For sponsors considering stepping into the ring, here’s a list of suggestions to navigate the course.

  1. Develop the right plan for your drug.

Demonstrating safety and tolerability in early clinical studies is a must to advance a program forward, but so much more can be captured in these early trials. Pharmacodynamic signals of drug efficacy can be examined in Phase I development through innovative and adaptive study designs which include a patient arm or tailored proof-of-mechanisms studies, like interrogating the de novo lipogenesis pathway for an anti-steatosis drug.

  1. Identify the right participants for your study.

Participant pre-screening efforts can save sponsors time and money. A clinical research organization with a rich database of well characterized participants can expedite study recruitment and reduce screen failures. The FibroScan® is a fast, painless, non-invasive ultrasound-like device that measures liver stiffness (fibrosis) and hepatic steatosis (fat); both measures are key markers for NASH clinical trials. FibroScan® pre-screening can assist with participant selection for more sophisticated and expensive inclusion criteria such as magnetic resonance imaging (MRI) or elastography (MRE).  In addition, the Liver Forum, a consortium of academic leaders, industry and regulators, has recently recommended using the FibroScan® as part of the inclusion criteria for early phase NASH clinical studies.

  1. Do more with less.

The FibroScan® is not only a valuable tool for study inclusion criteria, this technique has served as a key primary or secondary study endpoints in many NASH clinical studies. Additionally, soluble biomarker panels such as FIB4 and NAFLD Fibrosis Score calculated from clinical chemistries such as AST and ALT, are also inexpensive ways to identify potential participants for clinical studies and monitor drug efficacy.

  1. Look towards the future.

Current NASH standards of care and management strategies include vitamin E or pioglitazone treatment as these therapies have been shown to be effective in improving the histological features of NASH. Drug-drug interaction studies may be necessary before moving into later phase studies to accommodate patients on standards of care treatment and allowing for a great patient population base to pull from, if safe to do so.

The NASH race to market is well underway; however latecomers entering the NASH indication do not need to fall by the wayside. A strategic early phase drug development plan may help foster the next blockbuster treatment.

Links:

De novo lipogenesis: https://www.celerion.com/wp-content/uploads/2016/09/Celerion_Clinical-assessement-of-hepatic-DNL-in-NAFLD-review_092716-1.pdf

FibroScan: http://www.fibroscan.com/en/

Liver Forum: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5906171/

Management strategies: https://doi.org/10.1002/hep.29367

Drug-drug interaction: https://www.celerion.com/service/pharmacokineticspharmacodynamics-pkpd