incretins and obeticholic-acid

This review discusses completed phase II randomized clinical trials with high-quality published results for compounds that demonstrate effects on nonalcoholic steatohepatitis histology (obeticholic acid, elafibranor, and liraglutide). The authors also review the available preliminary data on cenicriviroc and selonsertib, with or without simtuzumab's phase II studies. Finally, the authors briefly discuss compounds that have been tested but did not achieve the primary end point of histologic improvement and appeared in high-quality published articles (cysteamine bitartrate and long-chain polyunsaturated fatty acids).

Topics: Antibodies, Monoclonal, Humanized; CCR5 Receptor Antagonists; Chalcones; Chenodeoxycholic Acid; Clinical Trials, Phase II as Topic; Cysteamine; Cystine Depleting Agents; Humans; Imidazoles; Incretins; Liraglutide; Non-alcoholic Fatty Liver Disease; Propionates; Protein Kinase Inhibitors; Randomized Controlled Trials as Topic; Sulfoxides

Given the high prevalence and rising incidence of non-alcoholic fatty liver disease (NAFLD), the absence of approved therapies is striking. Although the mainstay of treatment of NAFLD is weight loss, it is hard to maintain, prompting the need for pharmacotherapy as well. A greater understanding of disease pathogenesis in recent years was followed by development of new classes of medications, as well as potential repurposing of currently available agents. NAFLD therapies target four main pathways. The dominant approach is targeting hepatic fat accumulation and the resultant metabolic stress. Medications in this group include peroxisome proliferator-activator receptor agonists (eg, pioglitazone, elafibranor, saroglitazar), medications targeting the bile acid-farnesoid X receptor axis (obeticholic acid), inhibitors of de novo lipogenesis (aramchol, NDI-010976), incretins (liraglutide) and fibroblast growth factor (FGF)-21 or FGF-19 analogues. A second approach is targeting the oxidative stress, inflammation and injury that follow the metabolic stress. Medications from this group include antioxidants (vitamin E), medications with a target in the tumour necrosis factor α pathway (emricasan, pentoxifylline) and immune modulators (amlexanox, cenicriviroc). A third group has a target in the gut, including antiobesity agents such as orlistat or gut microbiome modulators (IMM-124e, faecal microbial transplant, solithromycin). Finally, as the ongoing injury leads to fibrosis, the harbinger of liver-related morbidity and mortality, antifibrotics (simtuzumab and GR-MD-02) will be an important element of therapy. It is very likely that in the next few years several medications will be available to clinicians treating patients with NAFLD across the entire spectrum of disease.

Topics: Anti-Obesity Agents; Antioxidants; Chenodeoxycholic Acid; Dipeptidyl-Peptidase IV Inhibitors; Drug Discovery; Drug Repositioning; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Immunologic Factors; Incretins; Lipogenesis; Molecular Targeted Therapy; Non-alcoholic Fatty Liver Disease; Peroxisome Proliferator-Activated Receptors; Receptors, Cytoplasmic and Nuclear; Tumor Necrosis Factor-alpha

Nonalcoholic fatty liver disease is the most common cause of liver disease in the United States. There are no drug therapies approved for the treatment of nonalcoholic steatohepatitis (NASH). Multiple different pathways are involved in the pathogenesis and each can be the target of the therapy. It is possible that more than 1 target is involved in disease development and progression. Multiple clinical trials with promising agents are underway. Because NASH is a slowly progressive disease and treatment likely to be of prolonged duration, acceptance and approval of any agent will require information on long-term clinical benefits and safety.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Anti-Inflammatory Agents; Antibodies, Monoclonal, Humanized; Antioxidants; Caspase Inhibitors; Chenodeoxycholic Acid; Cholic Acids; Fatty Acids, Omega-3; Humans; Incretins; Insulin Resistance; Liraglutide; Liver X Receptors; Non-alcoholic Fatty Liver Disease; Pectins; Peroxisome Proliferator-Activated Receptors; Receptors, Cytoplasmic and Nuclear; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors