Phase IIb Study to Evaluate the Efficacy and Safety of GFT505 Versus Placebo in Patients With Non-Alcoholic Steatohepatitis (NASH)

A Multicentre, Randomized, Double Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of GFT505 Once Daily on Steatohepatitis in Patients With Non-Alcoholic Steatohepatitis (NASH).

Abdominal obesity and type-2 Diabetes are associated with chronic liver disorders resulting from the accumulation of fat in the liver (steatosis), which may progress towards hepatitis and possibly lead to cirrhosis and liver cancer. NAFLD (Non Alcoholic Fatty Liver Disease) is considered as the most common form of chronic liver disease in adults in the United States, Australia, Asia and Europe. In the USA, the estimated prevalence of NAFLD is 20-30% of the adult population.

Non-alcoholic Steatohepatitis (NASH) is a progressing form of NAFLD, which corresponds to hepatic steatosis associated with inflammation and liver cell injury upon microscopic examination of a liver biopsy. This condition may lead to advanced fibrosis and cirrhosis and deserves serious medical management. Up to now, there is no effective drug which has clearly demonstrated therapeutic efficacy which may help lifestyle and dietary recommendations in the resolution of NASH.

In this context, GENFIT is developing a new liver targeted drug candidate, GFT505, for the treatment of NASH and the reduction of multiple cardiometabolic risk factors associated with the metabolic syndrome and type 2 Diabetes.

This phase IIb study will evaluate the efficacy and safety of GFT505 80mg and 120mg once daily for 52 weeks on the reversal of NASH without worsening of fibrosis, based on liver biopsy assessments.

The study duration per patient will be 80 weeks. A screening period (from 4 to 16 weeks) will precede a 52-week double-blind treatment period and a 3 months follow-up period.

The study will be conducted in 270 patients (90 patients in the placebo arm, 90 patients in the GFT505 80mg arm, and 90 patients in the GFT505 120mg arm).

Enrollment will be performed in two phases: during the first phase, the patients will receive either GFT505 at a dose of 80 mg either the placebo. An independent expert committee will review the safety data when 45 patients receiving the dose at 80 mg will have been treated for 6 months. The committee approval will be necessary to start the second phase, while the patients will receive either GFT505 at a dose of 80 mg, or GFT505 at a dose of 120 mg or the placebo.

Inclusion Criteria:

• Males or females (females must be either of non-child bearing potential or using an efficient double contraception). For male participants, contraceptive measures must be taken during the study, either by the male participant or his female partner.
• Body Mass Index ≤ 45 kg/m².
• Patients agree to have one liver biopsy during the screening period for diagnostic purpose (if no historical biopsy within 6 months before randomization is available) and one at the end of the treatment period for assessment of the treatment effects.
• For hypertensive patients, hypertension must be controlled by stable dose of anti-hypertensive medication for at least 2 months prior to screening (and the stable dose can be maintained throughout the study).
• Patients treated with vitamin E (>400IU/d), or Polyunsaturated fatty acids (>2g/day)or Ursodeoxycholic acid can be included if drugs are stopped at least 3 months prior to diagnostic liver biopsy and up to the end of the study.
• Histological confirmation of steatohepatitis on a diagnostic liver biopsy. Histological diagnostic is confirmed by central reading of the slides (steatosis > 5% + lobular inflammation, any grade + ballooning, any amount).
• For patients with Type 2 Diabetes, glycemia must be controlled (Glycosylated Haemoglobin A1c ≤8.5%). If glycemia is controlled by anti-diabetic drugs, qualitative change is not permitted within 6 months prior to randomization and should be avoided during the study. Treatments with metformin, Dipeptidyl Peptidase 4 inhibitors, Glucagon-like peptide-1 agonists, sulfamides, insulin are authorized. Sulfamides and insulin are permitted if glycemia is self-monitored by the patient.

Exclusion Criteria:

• Known heart failure (Grade I to IV of New York Heart Association classification).
• Weight loss of more than 5% within 6 months prior to randomization.
• History of bariatric surgery.
• Uncontrolled Blood Pressure.
• Type 1 diabetes patients.
• Patients who had an acute cardiovascular episode within the 6 months prior to screening, or with a history of coronary angioplasty, history of stroke, Transient Ischemic Attack, Coronary Heart Disease.
• Compensated and uncompensated cirrhosis. Notably, NASH patients with fibrosis stage = 4 according to the NASH CRN fibrosis staging system are excluded.
• Known alcohol and/or any other drug abuse or dependence in the last five years.
• Pregnant or lactating females.
• Other well documented causes of chronic liver disease
• Known intolerance or contra-indication to the list of excipients of GFT505.
• Evidence of any other unstable or, untreated clinically significant immunological, neoplastic, endocrine, haematological, gastrointestinal, neurological or psychiatric disorder.
• Positive HBsAg (Hepatitis B Surface Antigen), Positive anti-HIV, positive HCV-RNA (Hepatitis C Virus).
• Uncontrolled hypothyroidism defined as Thyroid Stimulating Hormone > 2X the upper limit of normal (ULN). Thyroid dysfunction controlled for at least 6 months prior to screening is permitted.
• Significant renal disease, including nephritic syndrome, chronic renal failure (defined as creatinine clearance < 60 mL/mn and serum creatinine >180 μmol/L).
• Unexplained serum creatine phosphokinase (CPK) > 3X the upper limit of normal (ULN). Patients with a reason for CPK elevation may have the measurement repeated prior to randomization; a CPK retest > 3X ULN leads to exclusion.