GFT505 IS A NEW GENERATION DRUG CANDIDATE FOR THE MANAGEMENT OF GLOBAL CARDIOMETABOLIC RISK ASSOCIATED WITH PREDIABETES AND DIABETES

GFT505 is the most advanced compound of a group of drug candidates developed by GENFIT. GFT505 targets multiple risk factors of prediabetes and diabetes: hyperglycemia and insulin resistance, atherogenic dyslipidemia (low levels of HDL-cholesterol, elevated triglycerides), and inflammation, as well as certain liver disorders often associated with prediabetic and diabetic states (Non-Alcoholic Fatty Liver Disease or NAFLD, and Non-Alcoholic Steato-Hepatitis or NASH).

Proof of efficacy and safety of GFT505 have been obtained in Phase I and Phase IIa trials as follows:

Improvement of glucose homeostasis in prediabetic and diabetic patients with significant reduction in fasting plasma glucose, fasting insulinemia and improvement of insulin resistance index (HOMA)
Improvement in the insulin sensitivity of the liver and peripheral tissues measured by the glucose clamp technique
Improvement of the two components of atherogenic dyslipidemia with reduction in plasma triglycerides and increase in HDL-cholesterol
Demonstration of anti-inflammatory effects with a significant reduction in plasma fibrinogen and haptoglobin
Demonstration of favorable effects on two indicators of diabetes-associated liver dysfunction with significant reduction in plasma ALAT and γGT
Demonstration of a very good safety profile, with no safety concerns identified in Phase I and II, and no effect on plasma homocysteine and other PPAR related safety 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 I: GFT505-1096 study
The clinical trial (GFT505-1096) demonstrates that GFT505 significantly improves insulin action on the adipose tissues following a meal test. This strong increase in the insulin sensitivity of peripheral tissues is pivotal in the mechanism of action of GFT505 and confirms its anti-diabetic potential.
The study conducted in healthy volunteers demonstrates that after only 14 days of treatment at 100 mg/d, GFT505 potentiates the effect of a meal test on plasma free fatty acids. At the end of the treatment period, the fasting free fatty acid plasma concentration was significantly lowered in the GFT505 group (-14±6%, p=0.012 vs baseline), while it remained unchanged in the placebo group (-1.6%, p=0.655 vs baseline). More importantly, the meal-induced decline in plasma free fatty acids (area under the curve between 0-6 hours after meal) was significantly potentiated in subjects treated with GFT505 (+22%, p<0.001 vs baseline) but not in placebo-treated subjects (+4%, p=0.852 vs baseline). Inter-group comparison confirmed the potentiating effect of GFT505 treatment (p<0.05 vs placebo group).
These effects of GFT505 on the response to the meal test likely result from an increase in the modifying action of insulin on lipolysis in adipose tissues. Indeed, in both groups, the peaks of plasma insulin and c-peptide were not modified by the treatment and were comparable. In addition, after 14 days of treatment, significant decreases in fasting plasma triglycerides (-25%, p<0.001 vs baseline), total cholesterol (-7%, p=0.006 vs baseline) and LDL-Cholesterol (-12%, p=0.006 vs baseline) were observed in the GFT505-treated group but not in the placebo group. The GFT505-induced decrease in plasma triglycerides persisted throughout the duration of the meal test, such that plasma exposure between 0-6 hours after the meal test significantly declined by 20% (p<0.001 vs baseline).

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.

Phase II: GFT505-210-5 study
The GFT505‐210‐5 Phase II trial studied the effect of 12 weeks of GFT505 treatment (80 mg/d) versus placebo in 97 treatment‐naïve diabetic patients, as part of GENFIT’s program for the evaluation of the therapeutic potential of GFT505 in different target populations. The results confirm and reinforce the multifaceted activity of GFT505 on several metabolic parameters: In the GFT505‐treated group, glucose homeostasis was improved. Compared to baseline values, there was a significant reduction in HbA1c levels (‐0.4%, p=0.01), in 2 hour glycemia upon OGTT (‐38 mg/dL ; p<0.001), and in the area under the curve for glycemia upon OGTT (‐39 mg/dL*h ; p<0.001). There was also a reduction in fasting glycemia in the GFT505 group (‐8.01 mg/dL, p=0.08), while this parameter was not altered in the placebo group. A non‐significant improvement observed for the other glycemic parameters in the placebo group limited inter‐group statistical significance.
In addition, GFT505 treatment strongly lowered plasma triglyceride levels (‐34% vs placebo, p<0.0001). It also significantly lowered non‐HDL‐C (‐12%, p<0.001), LDL‐C (‐8%, p<0.05), and total cholesterol (‐8%, p<0.01). The level of HDL‐C was increased by +15% (p<0.0001) compared to baseline values, but a significant effect was also observed in the placebo group (+11%, p<0.01).
Markers of hepatic dysfunction were improved upon GFT505 treatment, with a highly significant reduction in gamma GT levels (‐28% vs placebo, p<0.0001).
Moreover, the excellent safety profile of GFT505 was confirmed over a prolonged period of 3 months. GFT505 had no undesirable effect on arterial pressure or cardiac rhythm, and did not induce weight gain, peripheral edema, or hemodilution.

Phase II: GFT505-210-6 study
The GFT505-210-6 study was based on the gold standard "hyperinsulinemic euglycemic clamp", with two levels of insulin and using a deuterated tracer to measure hepatic glucose production. This single-blind study included a total of 22 insulin-resistant patients (HOMA>3) in a specific crossover design that optimized the statistical power of the study. Each patient underwent two successive 2-month treatment periods (Group 1: GFT505 80 mg/d then Placebo, Group 2: Placebo then GFT505 80 mg/d) with a treatment-free period of 4 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 were compared. Markers of hepatic dysfunction, plasma lipids, and inflammation markers were also measured at the beginning and the end of each treatment period.
Results showed that GFT505 very significantly increased 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 gGT (-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) were particularly marked, while the level of ASAT was unchanged (-1±4% after GFT505 vs +6±4% after placebo, p=0.16).

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 treating NFLD/NASH and preventing cardiovascular events in prediabetic and diabetic patients suffering from NAFLD/NASH.