Evolving Role for Pharmacotherapy in NAFLD/NASH

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a highly prevalent, dynamic disease that occurs across the age spectrum and can lead to cirrhosis and hepatocellular carcinoma. There are currently no US Food and Drug Administration (FDA) approved treatments for NAFLD; however, this is a field of active research. This review summarizes emerging pharmacotherapies for the treatment of adult and pediatric NAFLD. Investigated pharmacotherapies predominantly target bile acid signaling, insulin resistance, and lipid handling within the liver. Three drugs have gone on to phase III trials for which results are available. Of those, obeticholic acid is the single agent that demonstrates promise according to the interim analyses of the REGENERATE trial. Obeticholic acid showed reduction of fibrosis in adults with nonalcoholic steatohepatitis (NASH) taking 25 mg daily for 18 months (n = 931, reduction in fibrosis in 25% vs. 12% placebo, P < 0.01). Ongoing phase III trials include REGENERATE and MAESTRO-NASH, which investigates thyroid hormone receptor-β agonist MGL-3196. Outcomes of promising phase II trials in adults with NASH are also available and those have investigated agents, including the fibroblast growth factor (FGF)19 analogue NGM282, the GLP1 agonist liraglutide, the FGF21 analogue Pegbelfermin, the sodium glucose co-transporter 2 inhibitor Empagliflozin, the ketohexokinase inhibitor PF-06835919, the acetyl-coenzyme A carboxylase inhibitor GS-0976, and the chemokine receptor antagonist Cenicriviroc. Completed and ongoing clinical trials emphasize the need for a more nuanced understanding of the phenotypes of subgroups within NAFLD that may respond to an individualized approach to pharmacotherapy.

Figure 1

Tissue specific pathways targeted by the novel pharmacotherapies. Novel therapeutics under investigation for treatment of nonalcoholic fatty liver disease target metabolic pathways in the liver and other tissue. Fructose metabolized in the liver supports de novo lipogenesis. PF‐06835919 targets ketohexokinase (KHK), the rate‐limiting enzyme of fructose metabolism. Conversion of acetyl‐CoA to malonly‐CoA by acetyl‐CoA carboxylase (ACC) is the first committed step in lipogenesis. Malonyl‐CoA is an inhibitor of carnitine palmitoyltransferase 1 alpha, the rate‐limiting enzyme of fatty acid metabolism. GS‐0976 is an inhibitor of ACC, thus it prevents lipogenesis and increases fatty acid oxidation. However, increased acetyl‐CoA pool can serve as a substrate for cholesterol synthesis. Once fat is made in the liver, it can be oxidized in the mitochondria to generate energy. Elafibranor is a peroxisome proliferator‐activated receptors alpha/delta (PPARα/δ) agonist that increases fatty acid oxidation. MGL‐3196 and VK2809 are thyroid hormone receptor beta (THR‐β) agonists that increase the transcription of genes to upregulate mitochondrial fatty acid oxidation. Fibroblast growth factor 19 (FGF19) analogue NGM282 and Pegbelfermin, as well as PEGylated human FGF21, work in the liver and other tissues via fibroblast growth factor receptor 4 (FGFR4) to increase glucose utilization and fatty acid oxidation. Whereas FGF21 is made in the liver, FGF19 is made in the intestine through FXR activation. Obeticholic acid (OCA) is a semisynthetic bile acid that is a highly potent FXR agonist in the liver and the intestine. Activation of FXR in the liver can decrease conversion of cholesterol to bile acids, so a common side effect of OCA is increased serum cholesterol. Lipids made in the liver, but not oxidized, can be excreted from the liver to be utilized or stored in other organs, such as adipose tissue. Thiazolidinediones (TZDs) are PPAR gamma (PPARγ) agonists that increase the storage of fatty acids in adipocytes. As such, they create a sink for excess fat from the liver to be deposited in the adipose tissue; thus, they can also cause weight gain. MSDC‐0602K is a second generation PPARγ agonist that has fewer systemic side effects. Liraglutide is an analogue of the gut‐secreted hormone glucagon‐like peptide 1 (GLP‐1), which increases glucose‐stimulated insulin secretion. It also decreases gastric emptying leading to decreased appetite and weight loss. Empagliflozin is a sodium‐glucose transport protein 2 (SGLT‐2) inhibitor that works on the kidney to prevent glucose reabsorption, leading to calorie loss via glucosuria. Agonists are in GREEN color whereas antagonists are in RED.

Figure 2

Summary of novel medications at the various stages of investigation (active or completed).