Genfit's Advanced Compound Status

GFT505:  A Phase II drug candidate for the treatment of pre-diabetes and diabetes.

GFT505 is the most advanced compound of a new generation of drug candidates stemming directly from GENFIT’s Research, and developed by GENFIT for the treatment of the global cardiometabolic risk associated with pre-diabetes and diabetes.

A mixed PPARa/d agonist, GFT505 originates from GENFIT’s Selective Nuclear Receptor Modulator (SNuRM) platform that was set up to identify innovative drug candidates that are more effective and safer than current therapies. GFT505 simultaneously targets several micro- and macro-vascular risk factors such as hyperglycemia and insulin resistance, dyslipidemia, inflammation, and hepatic steatosis.

After completing all the pre-clinical development steps and demonstrating its excellent safety profile in Phase I studies, GFT505 has proved its therapeutic efficacy in two pilot Phase IIa clinical trials.

In patients with atherogenic dyslipidemia (low HDL-cholesterol, high triglycerides) and abdominal obesity, GFT505 improves plasma lipid levels, diminishes the pro-inflammatory state and improves hepatic function, without inducing adverse side-effects. In pre-diabetic patients with fasting hyperglycemia, glucose intolerance and abdominal obesity, GFT505 significantly reduces global cardiovascular risk. It improves fasting glucose levels and insulin sensitivity, reduces plasma levels of triglyceride and LDL-cholesterol, increases plasma levels of HDL-cholesterol, and lowers inflammatory markers.

GFT505 Clinical trials in detail

Phase I: GFT505-1084 study
GFT505 demonstrated its excellent safety profile in this Phase I double-blind placebo-controlled trial, in which increasing oral doses were administered daily for a period of 14 days. Indeed, up to the strongest dose administered, there were no treatment-related adverse events, and safety markers (hematology, biochemistry) remained normal.
In this study, GFT505 showed strong beneficial effects on plasma lipids: after 14 days of treatment, GFT505 significantly reduced the level of triglycerides. At a dose of 60 mg/day, a reduction of 35% was obtained vs. placebo (p<0.05), and the reduction was 45% vs. placebo (p<0.01) at a dose of 100 mg/day. In parallel, an 11% increase of plasma HDL-cholesterol was observed vs. placebo (p=0.07) in the 100 mg/day group.   

Phase I: GFT505-1095 study
This open label Phase I study conducted in two parallel groups of healthy volunteers examined the potential pharmacokinetic interaction between GFT505 and simvastatin. The results showed that a 14 day treatment with GFT505 (80 mg/day) does not increase the plasma concentration of native simvastatin or of one of its active metabolites (beta-hydroxyacid-simvastatin). Conversely, a 14 day treatment with simvastatin (20 mg/day) did not modify the circulating concentration of GFT505 (80 mg) or of its principal active metabolite, GFT1007. Thus, in contrast to certain of its competitors, GFT505 can be prescribed in conjunction with a statin without a risk of muscular side-effects linked to a pharmacokinetic drug interaction.     

Phase II: GFT505-2083 study
This pilot Phase II study included 97 patients with atherogenic dyslipidemia (plasma triglycerides >150 mg/dL and HDL-cholesterol <40 mg/dL for men or <45 mg/dL for women) as well as abdominal obesity (>102 cm and >88 cm, respectively). The double-blind placebo-controlled study evaluated the safety and efficacy of GFT505 administered orally for 28 days at a dose of 80 mg/day. Efficacy was evaluated by comparing the changes in plasma triglycerides and HDL-cholesterol induced by GFT505 treatment (63 patients) versus placebo treatment (31 patients).   
The results of this clinical trial showed that GFT505 is well tolerated at a dose of 80 mg/day and has a very good safety profile. No specific adverse event was observed in the GFT505 group relative to the placebo group, and the therapeutic efficacy of GFT505 was clearly demonstrated. Compared to the placebo group, the patients treated with GFT505 showed a statistically significant 21% reduction (p=0.0027) in their plasma triglycerides and a 9% increase (p=0.003) in the level of good cholesterol (HDL-C).  These metabolic effects were comparable to those published with the best competitors of GFT505 in the same patient population.
Furthermore, GFT505 showed a remarkable lack of effect on a known cardiovascular risk factor, plasma homocysteine (+5% vs +40 to 50% reported with the competitor). These data suggest an excellent safety profile and superior protective properties for GFT505 in a long-term treatment.
GFT505 also showed significant effects on secondary evaluation criteria related to inflammation. Notably, GFT505 significantly reduced acute phase inflammation markers such as fibrinogen (p=0.045) and haptoglobin (p=0.009). Finally, GFT505 had clear beneficial effects on two hallmarks of fatty-liver dysfunction, alanine amino transferase (ALAT: 15% decrease vs placebo, p=0.02) and gamma glutamyl transpeptidase (gGT: 20% reduction vs placebo, p<0.0001) while it did not affect the activity of aspartate amino transferase (ASAT).

Phase II : GFT505-2094 study
This pilot Phase II study included 47 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). The double-blind placebo-controlled study evaluated the safety and efficacy of GFT505 administered orally for 35 days at a dose of 80 mg/day. Efficacy was assessed by comparing changes in glucose metabolism (fasting plasma glucose, insulin, C-peptide, insulin resistance index…), plasma lipids (triglycerides, HDL-C, LDL-C, apolipoproteins…) and inflammation markers in the GFT505-treated group (n=23) and in the placebo-treated group (n=24).
After one month of treatment with GFT505 (80 mg/day), the main objective of demonstration of compound efficacy on glucose homeostasis was attained. In particular, GFT505 led to a significant reduction in fasting plasma glucose levels in the treated group in comparison to the placebo-treated group (-5% vs placebo, p=0.03). In parallel, significant reductions in fasting plasma insulin (-25% vs placebo, p=0.009) and C-peptide (-11% vs placebo, p=0.03) levels were also obtained. In addition, the ability of GFT505 to increase insulin sensitivity was observed, as assessed by the HOMA insulin-resistance index (HOMA: -31% vs placebo, p=0.0027).
In addition to the effects of GFT505 on glucose homeostasis, the results from the GFT505-2094 study confirm and extend the beneficial effects of the compound on plasma lipids, as previously observed in the GFT505-2083 study. Patients treated with GFT505 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). Finally, treatment with GFT505 also led to a significant reduction in plasmatic markers of inflammation (fibrinogen, -10%, p=0.0128; haptoglobin, -16%, p=0.007).
Taken together, the effects of GFT505 on plasma glucose, lipids, and inflammation, are expected to strongly reduce the risk of macrovascular events and microvascular complications in pre-diabetic patients. The efficacy/safety ratio of GFT505 remains excellent, since no specific side effects were observed between the treated and placebo groups. In particular, the GFT505-2094 study confirmed the absence of effect of GFT505 on the circulating level of homocysteine. 

In conclusion, a clean safety profile and the demonstrated beneficial activity on a range of related cardiometabolic risk factors position GFT505 as an attractive new generation drug candidate for the treatment of pre-diabetic and diabetic patients.