OCA—a bile acid analogue and a first-in-class farnesoid X receptor (FXR) agonist that is thought to modulate inflammation and prevent the formation of fatty acids—has since won breakthrough therapy designation for NASH. Intercept has also already filed the drug for FDA approval in primary biliary cirrhosis.

Joining in Although Intercept is leading the field, the NASH pipeline has exploded in the past 2 years. At least 34 companies are working on NASH drugs, says Kapeller. Candidates target a variety of disease mechanisms. To name a few: Tobira Therapeutics’ Phase IIb cenicriviroc inhibits CC-chemokine receptor 2 (CCR2) and CCR5, which are involved in inflammation and fibrosis; Genfit’s Phase IIb GFT505 agonizes peroxisome proliferator-activated receptor-α (PPARα) and PPARδ to break down fatty acids, block production of fat and glucose and improve inflammation; Galmed Pharmaceuticals’ Phase II aramchol is a synthetic fatty-acid–bile-acid conjugate that boosts liver fat metabolism; Raptor’s Phase II delayed-release cysteamine bitartrate is a cysteine-depleting agent that may have protective anti-oxidant activity; and Nimbus’ Phase I NDI-010976 is an allosteric inhibitor of acetyl‑CoA carboxylase, an orchestrator of fatty-acid synthesis and oxidation. Large companies are joining the fray, too. In May, Boehringer Ingelheim bought Pharmaxis’ Phase I candidate, PXS4728A, which inhibits key aspects of the inflammatory process driven by leukocytes. In January, Gilead Sciences acquired Phenex Pharmaceuticals’ Phase II FXR agonist, NR1H4.(Gilead is also studying its own lysyl oxidase like 2 (LOXL2)-specific antibody simtuzumab, which modulates the cross-linking of collagen fibres, in a Phase IIb trial in people with cirrhosis caused by NASH.) In the next few years,“we’ll get a lot of information about which are the important mechanisms and whether more than one mechanism at a time is essential,” Friedman says.