The Race Against Nash
A silent epidemic creeping upon the Western world pushed the headline grabbing acquisition of a Phase 1 non-alcoholic steatohepatitis (NASH) drug last week. Boehringer Ingelheim (Ingelheim, Germany) acquired Pharmaxis (Sydney, Autralia) due to the promise of PXS4728A. Several other companies also have NASH drugs in development, such as Intercept, Genfit, Gilead, Galmed, Conatus, Raptor, and Galectin Therapeutics.
With no approved treatment on the market and liver transplant shortages only increasing, the race is on. Let’s take a look at the science behind NASH and profile the three of the contenders vying for a FDA approval.
Easily Confused: NAFLD vs. NASH
Non-alcoholic fatty liver disease (NAFLD) happens when excess fat is deposited in the liver of people who drink very little to no alcohol. NASH is the severe form of NAFLD, and is characterized by liver inflammation and scarring. It is the number one cause of non-alcohol related cirrhosis, potentially leading to liver failure. NASH is the third leading cause of liver transplants in the U.S.
Non-alcoholics with diabetes, obesity, and metabolic syndrome run the risk of getting NAFLD and later on, NASH. It is estimated that approximately 25% of Americans have NAFLD, creating a silent epidemic since symptoms often go unnoticed. Approximately 5% of Americans are currently afflicted by NASH, with the numbers rising.
Like many disease processes, inflammation is a hallmark of NASH. As fat accumulates in the liver and overtaxes the organ, the release of inflammation-inducing signaling molecules (called cytokines) set off a cascade of events. Namely, the infiltration of white blood cells (such as macrophages) to the liver increase the likelihood of cell death and scarring.
Pharmaxis’ investigational therapy, PXS4728A, is a small molecule inhibitor of the vascular adhesion protein 1 (VAP1). Inhibiting VAP1 slows down the infiltration of white blood cells into the liver, thereby limiting inflammatory damage. Boehringer Ingelheim’s investment in PXS4728A comes after encouraging Phase 1 interim results.
Pharmaxis is also considering PXS4728A as a potential treatment for chronic obstructive pulmonary disease (COPD), a disorder also associated with excessive inflammation induced scarring.
Intercept Pharmaceuticals: Obeticholic Acid
Recently granted breakthrough status by the FDA, Intercept Pharmaceutical (San Diego) brings about a promising small molecule drug called obeticholic acid. Based on positive results from Phase 2 clinical studies, Intercept announced last week the preparations to initiate Phase 3 studies are under way.
Obeticholic acid works by binding to a so-called nuclear receptor—a receptor protein that is present inside of cells, rather than on their surface. When activated by the appropriate signaling molecule, the nuclear receptor moves inside the cell’s nucleus, where it binds DNA at a specific location, activating the expression of particular genes. Obeticholic acid specifically binds to and activates the nuclear receptor FXR. FXR then modulates the expression of a variety of genes involved in lipid metabolism and glucose homeostasis that potentially disrupts the progression of NASH.
Yet another nuclear receptor activator is Genfit’s (Loos, France) investigational GFT505, which targets the receptors PPAR α/σ. Activation of these receptors turns on genes that increase the metabolism of fatty acids, resulting in a decrease of liver fat and improvement in lipid profiles—as well as an increase in insulin sensitivity and anti-inflammatory activities. In preclinical models of NASH, the drug performed very well, preventing the onset and even reversing established NASH markers.
Surprisingly, recently reported Phase 2 clinical results failed to demonstrate notable improvement; however, examining data from the more advanced NASH patients showed significant improvement. Genfit has recently announce plans for Phase 3 trials targeting only NASH patients in more severe stages of the disease. With the race to treat NASH only heating up, it remains to be seen which contender will become the first FDA approved treatment.
Emily Burke, PhD has worked in biopharma for 20 years, gaining science writing experience at The Scripps Research Institute and Ionis Pharmaceuticals. As a Ph.D. molecular biologist, she is passionate about advancing the public’s understanding of science. In addition to being a self-proclaimed “science geek,” she is regularly asked to speak at international scientific meetings. When not teaching and writing the WEEKLY for Biotech Primer, Dr. Burke swims with her swim club and performs regularly on the improv circuit in San Diego.