Health & Medical stomach,intestine & Digestive disease

What's on the Horizon for Treating NASH?

What's on the Horizon for Treating NASH?

PPAR Agonists

PPARs are nuclear receptors that play key roles in the regulation of hepatic metabolism and inflammation. Novel selective PPAR modulators and dual PPAR agonists may have important roles in the treatment of cardiometabolic disorders in view of their lipid-modifying, insulin-sensitizing, and anti-inflammatory properties.

GFT505, a dual agonist of the PPAR-alpha and PPAR-delta isoforms, improves lipid and glucose metabolism in patients with type 2 diabetes and exerts hepatoprotective effects in mouse models of NAFLD. GFT505 also reduces plasma triglyceride levels, increases HDL cholesterol concentrations, and improves insulin sensitivity. The beneficial effects of GFT505 are complemented by preclinical findings that demonstrated liver-protective effects (reduction of hepatic fat accumulation, inflammation, and fibrosis), making it a promising candidate for the treatment of NAFLD/NASH. Furthermore, GFT505 improved liver dysfunction markers, reduced hepatic lipid accumulation, and inhibited proinflammatory and profibrotic gene expression.

In a clinical trial, GFT505 was administered to more than 600 patients and healthy volunteers as an oral, once-daily (short-term; 4-8 weeks) potential treatment for NASH. GFT505 administration led to an improvement in markers of liver dysfunction, including ALT, aspartate aminotransferase, gamma glutamyl transferase, and alkaline phosphatase levels, with documented improvement in insulin sensitivity and glucose homeostasis. There was also a favorable effect on plasma lipids, including a reduction in plasma triglycerides and LDL cholesterol and an increase in HDL cholesterol levels. Hyperinsulinemic-euglycemic clamp studies demonstrated an insulin-sensitizing effect of GFT505, with a strong effect on the liver, and a significant plasma liver enzymes-lowering effect. The safety profile is reassuring, without any signs of PPAR-gamma–related side effects. The combination of its insulin sensitizing and hepatoprotective effects makes GFT505 a promising drug candidate for the treatment of NASH.

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