Drug Development for Nonalcoholic Fatty Liver Disease: Landscape and Challenges

Abstract

Nonalcoholic fatty liver disease (NAFLD) is now the leading cause of chronic liver disease in industrialized economies. With no licensed treatment currently available, together with a growing prevalence that parallels global increases in obesity and type 2 diabetes, NAFLD will dominate the landscape of hepatology for the foreseeable future. A multifaceted etiopathogenesis, paucity of reproducible preclinical models that effectively recreate human NAFLD, and lack of robust surrogate trial endpoints have presented major hurdles in drug discovery and development. Smooth collaboration between bench scientists, biotechnology, pharmaceutical industries, and clinicians will be pivotal to target identification, development of effective therapies, biomarker discovery, and ultimately to bring pipeline drugs to market. This review examines the key challenges remaining in NAFLD drug development, outlines early and late phase clinical trials of candidate treatments, and discusses the journey toward biomarker discovery which may facilitate development of novel endpoints in NAFLD clinical trials, enabling meaningful response to be determined noninvasively.

Keywords: BMI, Body Mass Index; DGAT, Diacyl Glycerol Acyl Transferase; ELF, Extended Liver Fibrosis Panel; FIB-4, Fibrosis 4; FXR, Farnesoid X Receptor; HCC, Hepatocellular Carcinoma; HOMA-IR, Homeostasis Model Assessment of Insulin Resistance; HVPG, Hepatic Venous Pressure Gradient; HbA1C, Hemoglobin A1C; MCD, Methionine-Choline–Deficient Diet; MRE, MR Elastography; MRI, Magnetic Resonance Imaging; MRS, Magnetic Resonance Spectroscopy; NAFLD; NAFLD, Nonalcoholic Fatty Liver Disease; NASH, Nonalcoholic Steatohepatitis; OCA, Obeticholic Acid; OGTT, Oral Glucose Tolerance Test; Pro-C3, Pro-collagen 3; TE, Transient Elastography; endpoints; preclinical models; targets; therapeutics.

Figure 1

Multifactorial etiopathogenesis of NAFLD. Some putative mechanisms, notably insulin resistance, are bidirectional, with growing evidence to suggest that NAFLD is a driver, as well as a consequence, of systemic insulin resistance and the metabolic syndrome. NAFLD, Nonalcoholic fatty liver disease.