Clinical Trials

Date: 2012-02-03

Type of information: Results

phase: 2

Announcement: results

Company: Genfit (France)

Product: GFT505

Action mechanism: PPAR agonist. Elafibranor (GFT505) is an oral once-daily treatment, and a first-in-class drug acting via dual peroxisome proliferator-activated alpha/delta pathways to treat nonalcoholic steatohepatitis (NASH).

Disease: NAFLD (non-alcoholic fatty liver disease) - NASH (non-alcoholic steatohepatitis)

Therapeutic area: Metabolic diseases - Liver diseases

Country:

Trial details: The GFT505-210-6 study is based on the gold standard "hyperinsulinemic euglycemic clamp", with two levels of insulin and using a deuterated tracer to measure hepatic glucose production. The two principal parameters measured by this method are: - The insulin sensitivity of the liver (the decrease in hepatic glucose production, HGP, induced by the first insulin level). - The insulin sensitivity of the muscles and other peripheral tissues (measure of the glucose infusion rate, GIR, at the end of the second insulin level). The single-blind GFT505-210-6 study included a total of 22 insulin-resistant patients in a specific crossover design that optimizes the statistical power of the study. Each patient underwent two successive 2-month treatment periods (Group 1: Placebo then GFT505 80 mg/d, Group 2: GFT505 80 mg/d then Placebo) with a treatment-free period of 6 weeks between treatments. The “clamp” procedure was performed on all patients at the end of each treatment period, and the data obtained after GFT505 and after placebo are compared. Markers of hepatic dysfunction, plasma lipids, and inflammation markers are also measured at the beginning and the end of each treatment period.

Latest news:

• • On February 3, 2012, Genfit has announced that the GFT505-210-6** Phase II clinical study has reached all its primary and secondary efficacy objectives with no adverse side-effects. Statistical analysis shows that GFT505 improves insulin sensitivity in the liver and peripheral tissues, improves dyslipidemia, and lowers markers of liver dysfunction and inflammation in insulin-resistant patients with abdominal obesity (BMI = 30±3 kg/m2). The primary objective of the GFT505-210-6 pharmaco-clinical trial was to evaluate the effect of 8 weeks of GFT505 treatment (80 mg/day) on the insulin sensitivity of the liver and peripheral tissues by the gold standard hyperinsulinemic euglycemic clamp technique. The decrease in hepatic glucose production (HGP) induced by insulin was -0.86 ± 0.07 mg/kg/min after GFT505 vs -0.63 ± 0.07 mg/kg/min after placebo (p=0.006), equivalent to an improvement in the liver insulin response of 37%. Similarly, the insulin sensitivity of the peripheral tissues was significantly increased by GFT505 treatment (glucose infusion rate GIR, 3.8 ± 0.3 mg/kg/min after GFT505 vs 3.2 ± 0.3 mg/kg/min after placebo, p=0.019).
• Liver function markers: In this study, GFT505 strongly lowered markers of liver dysfunction associated with non-alcoholic steatohepatitis (NAFLD/NASH*), with a decrease in circulating levels of GT (-30.4 ± 8.9% vs placebo, p=0.003), ALAT (-20.5 ± 6% vs placebo, p=0.004) and ASAT (-6.7 ± 4.7% vs placebo, p=0.18). Moreover, a significant improvement in plasma levels of alkaline phosphatase was also observed (-19 ± 3% vs placebo, p<0.0001).
• Plasma lipids: In parallel, GFT505 treatment improved all the plasma lipid parameters. GFT505 significantly lowered the levels of plasma triglycerides (-21 ± 6% vs placebo, p=0.0033), total cholesterol (-9.2 ± 2.8% vs placebo, p=0.004), LDL-cholesterol (-13 ± 3% vs placebo, p=0.0006), and non-HDL-cholesterol (-12.7 ± 3.4% vs placebo, p=0.001), while the level of HDL-cholesterol increased by +4.4 ± 3.1% (p=0.17). These effects correlated with a significant decrease in the pro-atherogenic apolipoprotein, ApoB (-14 ± 3% vs placebo, p=0.0003).
• Inflammatory markers: GFT505 treatment also lowered inflammatory markers such as fibrinogen (-15.0 ± 6.9% vs placebo, p=0.04) and haptoglobin (-10.1 ± 4.1% vs placebo, p=0.03).
• Safety of use: No secondary effect attributed to GFT505 treatment was reported by the investigators. Moreover, the safety markers analyzed during the study were not altered.
• • On October 19, 2011, Genfit has published partial results for a pharmaco-clinical study that demonstrate a hepatic mechanism of action for GFT505 in insulin-resistant patients. Partial results for 19 of the 22 patients included in the study (3 patients are still being treated) already show that GFT505 very significantly increases the response of the liver to insulin action. At the end of the treatment period, the decrease in hepatic glucose production (HGP) induced by insulin was -51±5% after GFT505 vs -34±4% % after placebo (p=0.0014). The insulin sensitivity of the muscles and other peripheral tissues was also increased by 30% with a significant effect on the glucose infusion rate (GIR, 3.71±0.3 mg/kg/min after GFT505 vs 3.2±0.3 mg/kg/min after placebo, p=0.025). The beneficial effects of GFT505 on the liver confirm the findings of previous studies conducted by Genfit, with a very significant decrease in hepatic dysfunction markers. The observed reductions in circulating levels of GT (-35±4% after GFT505 vs +3±4% after placebo, p<0.001) and ALAT (-17±5% after GFT505 vs +7±6% after placebo, p<0.001) are particularly marked, while the level of ASAT is unchanged (-1±4% after GFT505 vs +6±4% after placebo, p=0.16). Genfit is now proceeding with the initiation of an international multi-center Phase IIb study for which the first patient should be recruited at the beginning of the second trimester of 2012.

Is general: Yes