William F. Balistreri, MD

Disclosures

April 05, 2016

In This Article

Novel Approaches

GFT505 in NASH

The peroxisome proliferator-activated receptor alpha/delta dual agonist GFT505 is a promising therapy for NASH, given that it has been shown to improve hepatic insulin sensitivity, glucose homeostasis, lipid metabolism, and inflammation.

In a randomized, controlled, phase 2 trial (56 European and US centers), 274 patients with histologically defined noncirrhotic NASH received GFT505 (80 or 120 mg daily) or placebo for 1 year.[13,14] Compared with placebo, more patients receiving GFT505 120 mg had resolution of steatohepatitis (22% vs 13% of placebo recipients) and a decrease in the NAS owing to reduced ballooning (45% vs 23%; P = .02), inflammation (55% vs 33%; P = .05), and steatosis (36% vs 18%). There was documented resolution of NASH, with resultant significant histologic improvement in fibrosis. Cardiometabolic risk markers, such as serum levels of triglycerides, LDL cholesterol, and HDL cholesterol, as well as A1c and free fatty acids in diabetic patients, improved significantly in patients receiving GFT505 120 mg compared with those receiving placebo. The excellent safety and tolerability, as well as the improvement in cardiometabolic risk profile, suggest that GFT505 is a candidate agent to be tested in phase 3 trials.

Inhibition of Autophagy and Promotion of Apoptosis

Tanaka and colleagues[15] investigated the role of autophagy in regulating hepatocyte apoptosis, a characteristic feature of NAFLD. They documented that enhanced expression of Rubicon inhibits autophagy and promotes apoptosis by increasing endoplasmic reticulum stress in patients with NAFLD. Expression levels of Rubicon in steatotic livers were higher than those in nonsteatotic livers. Increased expression of Rubicon induced by palmitic acid and a high-fat diet suppressed autophagic flux and promoted hepatocyte apoptosis by increasing endoplasmic reticulum stress. There was a significant reduction of liver volume to approximately normal size, which was accompanied by significant and substantial reduction of the triglyceride content in the liver. Enhancement of autophagy by inhibiting Rubicon may therefore be a new approach to the treatment of patients with NAFLD.

Cysteamine Bitartrate Delayed-Release Tablets

In a multicenter, double-masked, randomized, placebo-controlled, phase 2b clinical trial conducted by the NASH CRN, children with an NAS ≥ 4 were randomly assigned to receive twice-daily oral cysteamine bitartrate (CyB) (300 mg if their body weight was ≤ 65 kg, 375 mg if > 65-80 kg, or 450 mg if > 80 kg) or matching placebo for 52 weeks.[16] Compared with placebo, 1 year of treatment with CyB was safe, although there was no significant difference in the rates of histologic improvement in children with NAFLD who received CyB (28% with CyB vs 22% with placebo).

A New Botanical Treatment for Reducing Hepatic Fat

Magnolia officinalis is a traditional herbal medicine that has been used to treat various liver diseases in Korea.

Kim and colleagues[17] evaluated the effect and safety of the HL tablet, a new botanical drug extracted from M officinalis, in the treatment of patients with NAFLD. In a placebo-controlled, parallel, multicenter, randomized, double-masked, phase 2 clinical trial, patients received either HL tablets (100 or 300 mg) or placebo twice daily for 12 weeks. Despite the short-term treatment, compared with placebo, HL significantly reduced the mean hepatic fat content, as assessed by proton-magnetic resonance spectroscopy, in a dose-dependent manner. Serum ALT levels decreased somewhat; however, serum cholesterol, triglyceride, FFA, HOMA-IR, and BMI values were not affected by HL treatment. No drug-related safety issues occurred during the study.

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