First approved NASH Drug : Complexity Delays More Approvals

USFDA has approved the first noncirrhotic non-alcoholic steatohepatitis (NASH) Madrigal Pharmaceuticals drug Rezdiffra (resmetirom), in the US. Rezdiffra was approved under the accelerated approval pathway for the treatment of adults with NASH with moderate to advanced liver scarring (fibrosis), to be used along with diet and exercise.

Over the past two decades, much effort has been put forth in understanding the pathophysiology of non-alcoholic fatty liver disease/non-alcoholic steatohepatitis (NAFLD/NASH). Although multiple potential targets for drug development exist, the first approval has been received now for therapies for NAFLD/NASH. Apart from Rezdiffra, Obeticholic acid was in the advanced stage and received accelerated approval; however, it was denied for approval by the USFDA until additional clinical outcome data from the regenerate trial were submitted and reviewed.

NASH is a result of the progression of non-alcoholic fatty liver disease, where liver inflammation, over time, can lead to liver scarring and liver dysfunction. NASH is often associated with other health problems, such as high blood pressure and type 2 diabetes. NAFLD/NASH is the most common cause of chronic liver disease worldwide, affecting 25% of the population. It is the leading indication for liver transplant in women and second overall in the US. It is characterised by excess fat deposition in the liver, defined as the presence of steatosis in greater than 5% of hepatocytes without secondary contributing factors such as significant alcohol use, viral infections, or steatogenic drugs.

Overview of trials in NASH

NAFLD/NASH is a complex disease driven by insulin resistance, lipotoxicity, and activation of inflammatory pathways. Moreover, genetics, environmental factors, social determinants of health, and comorbidities converge to lead to variable disease progression. As fibrosis is the most important predictor of clinical outcomes, fibrosis regression or lack of progression is critical to any therapeutic intervention’s success. Given the complexity of the pathophysiology of NAFLD/NASH, multiple potential targets are available for drug development. Metabolic targets lead to improved insulin sensitivity, inhibition of de novo lipogenesis, and enhanced mitochondrial utilization of fatty acids. Targets of the inflammatory pathways result in reduced cell stress and apoptosis. The gut-liver axis is a target for some drugs to alter the gut microbiota and modulate enterohepatic circulation. In contrast, other drugs target fibrosis pathways either by decreasing fibrogenesis or increasing fibrinolysis. Many drugs in development work on multiple pathways to varying degrees.

Following is an overview of drugs that are under trials, along with their presumed primary targets in the pathophysiology of NAFLD/NASH