Elafibranor Clinical Overview
Elafibranor (GFT505) has been orally administered to over 800 patients or healthy volunteers to date. Elafibranor is currently being evaluated in the Phase 3 study RESOLVE-IT.
Phase 1 program
A Phase 1 program to assess the safety and tolerability as well as the pharmacokinetic profile of Elafibranor has been conducted through 8 clinical trials.
A total of 280 healthy subjects, 60 overweight/obese subjects, and 12 subjects with Type 2 diabetes were randomized in these studies performed in Phase 1 centers.
Elafibranor has shown a good safety profile at all doses tested under fed or fasting conditions, either in unique (up to 300 mg) or repeated administration (up to 240 mg) for 14 days. It does not show any drug-drug interaction with sitagliptin, simvastatin or warfarin and thus could be safely prescribed with other drugs frequently used in patients suffering from cardiometabolic disorders, including statin.
Phase 2 program
A Phase 2 program has been performed to assess the safety and efficacy profile of Elafibranor (80mg) in patients suffering from cardiometabolic disorders. To date, five Phase 2a trials have been completed in which 297 patients were randomized.
An activity profile beneficial for NASH patients has been consistently found in all the trials.
Elafibranor consistently reduces markers of liver injury along with inflammation markers.
For example, in the GFT505-2106 Phase 2a trial, that included insulin-resistant patients (HOMA>3) in a specific crossover design with two successive 2-month treatment periods, the observed reductions in circulating levels of γGT (-30.5% vs. placebo, p<0.01), ALP (-19.3% vs. placebo, p<0.001) and ALAT (-20.5% vs. placebo, p<0.01) were particularly marked.
Similarly, Elafibranor reduced inflammation markers consistently in all the trials ; for example, in the GFT505‐2105 Phase 2a trial that studied the effect of 12 weeks of Elafibranor treatment versus placebo in treatment‐naïve diabetic patients, GFT505 induced a significant decrease in haptoglobin levels (effect size -26.1%, p<0.0001) and in hsCRP (effect size -74.0% p=0.052) ; fibrinogen levels were also decreased (effect size -7.1% p=0.10).
Elafibranor shows beneficial effects on glucose control and an ability to improve insulin sensitivity both in the liver and in peripheral tissues.
The beneficial effects on glucose homeostasis were shown notably in the GFT505‐2105 Phase 2a trial where Elafibranor significantly reduced 2h glycemia (-37.82±10.11mg/dL versus baseline (p=0.0003), while no significant decrease was observed in the placebo group), AUC (Area Under the Curve) for glycemia (-34.96±12.07 mg*h/dL, p=0.0011), insulinemia (-11.00±6.08 UI/L*h, p=0.0086) and Free Fatty Acids (-5.07mmol*h/dL, p<0.0001) upon OGTT (Oral Glucose Tolerance Test).
The improvement of insulin sensitivity was demonstrated in the GFT505-2106 study that was based on the gold standard sequential “hyperinsulinemic euglycemic clamp”. At the end of the treatment period, the decrease in hepatic glucose production (HGP) induced by insulin was -49.2% after Elafibranor vs -34.3% % after placebo (p=0.0016). The insulin sensitivity of the muscles and other peripheral tissues was also increased by 28% with a significant effect on the glucose infusion rate (GIR, 3.7±0.3 mg/kg/min after Elafibranor vs 3.2±0.3 mg/kg/min after placebo, p=<0.05).
Elafibranor consistently has positive effects on lipid parameters which result in a beneficial profile between pro and anti-atherogenic markers
For example, in the GFT505-2094 Phase 2a, a 35 day-treatment study that included pre-diabetic patients with modest hyperglycemia (fasting plasma glucose between 110 and 126 mg/dL), impaired glucose tolerance (2-hour plasma glucose between 140 and 200 mg/dL following OGTT), and abdominal obesity (waist circumference >94 cm for men and >80 cm for women), patients treated with Elafibranor showed a significant reduction of bad cholesterol (LDL-C, -11% vs placebo, p=0.0049) in parallel with a reduction in triglycerides (-25%, p=0.0003) and an increase in good cholesterol (HDL-C, +9% vs placebo, p=0.003). These effects correlated with a reduction in pro-atherogenic apolipoproteins, including ApoB (-14%, p<0.0001) and an increase in ApoA2 anti-atherogenic HDL particles (+18%, p<0.0001).
B. Cariou et al., Diabetes Care, 2011 – B. Cariou et al., Diabetes Care, 2013
A pivotal phase 2b trial
A pivotal phase 2b trial has been completed to evaluate the efficacy and safety of Elafibranor (GFT505) 80 mg and 120 mg on steatohepatitis in patients with non-alcoholic steatohepatitis (NASH).
GFT505-2127 Phase 2b study recruited diabetic and non-diabetic patients with a histological diagnosis of NASH by liver biopsy in Europe and the US in 56 clinical investigation centers. In March 2015, Genfit announced topline results from the GOLDEN-505 trial in NASH:
- Elafibranor demonstrated dose-dependent efficacy on the primary endpoint, after controlling for baseline severity and heterogeneity (p=0.027)
- Treatment with gft505 lead to significant cardio-metabolic benefits
- Elafibranor was safe and well tolerated in this 1-year trial
Link to the press release
Last update: September 2015