Lanifibranor in Patients With Type 2 Diabetes & Nonalcoholic Fatty Liver Disease

The study is a two-arm (placebo, lanifibranor 800 mg/day), randomized (1:1), double-blind, placebo-controlled, 24-week treatment study. Thirty four (n=34)patients with T2DM will be randomized, allowing for a 10% drop-out rate. The diagnosis of NAFLD on imaging will be done by measuring IHTG using the gold-standard magnetic resonance and spectroscopy (¹H-MRS) technique. Ten non-diabetic subjects without NAFLD will also serve as a control group for the metabolic and imaging procedures. The study will last 34-36 weeks (~6-8 weeks for run-in, 24 weeks of treatment and 4 weeks post-study follow-up), with an estimated recruitment period of ~9 months. Patients with uncontrolled T2DM and a diagnosis of "fatty liver" per history (elevated AST/ALT and/or liver fat on liver ultrasound or ¹H-MRS and/or other appropriate imaging technique - see below). Participants may be treated by diet only, or be on a stable dose of metformin and/or a sulfonylurea and/or a DPP-IV inhibitor for ≥ 2 months prior to enrollment. If the HbA1c is ≤8.0% on any of these diabetes medications, the dose of these medications will be kept stable throughout the study and baseline studies performed as outlined below. If the HbA1c is > 8.0% but ≤ 9.5%, metformin (minimum dose required: 1,000 mg/day for metformin) and/or a sulfonylurea (minimum dose required: glimepiride 2 mg once daily) will be added, or doses maximized, during the first 2 weeks of the lead-in period. Afterwards, patient's metformin or sulfonylurea dose will be maintained at the new dose stable for 4 weeks before baseline metabolic and study-specific liver imaging.

After patients sign the informed consent and meet eligibility criteria, baseline imaging and metabolic studies will be performed. These will include measurement of IHTG by 1H-MRS, liver fibrosis by VCTE (Fibroscan) and MRE, and additional imaging by T1 MRI mapping. Metabolic testing will be done with the patient being admitted to the CRC (clinical research unit) for an overnight stay. Assessment of insulin sensitivity and DNL will be done with the administration of stable isotopes of glucose (intravenously) and deuterium labeled water (orally) to measure glucose and lipid turnover and substrate oxidation (with indirect calorimetry) during a euglycemic hyperinsulinemic clamp.

After all baseline tests are completed, patients will be asked to take a therapeutic dose of 800 mg lanifibranor (QD), or placebo, for 24 weeks. They will be closely followed by study staff every 4 weeks with visits to the CRC and interim phone calls. At 24 weeks, all baseline tests will be repeated and treatment considered completed. There will be a final, off-drug, safety follow-up visit 4 weeks after treatment at week 28. After this the participant will have completed all study procedures.

Note: The investigators recalculated the sample size for the primary endpoint of change in intrahepatic triglyceride (IHTG) measured by 1H-MRS with lanifibranor (800 mg/day) vs. placebo based on the data from the population with diabetes from the Phase IIb NATIVE (NCT03008070: NAsh Trial to Validate IVA337 Efficacy; liver histology results) and comparing to prior studies by Dr. Cusi et al that had simultaneous liver histology and liver fat measured by 1H-MRS (Belfort et al, NEJM 2006; Cusi et al, Annals Int Med 2016). From this analysis, the required sample size per group calls for 15 patients in each arm (lanifibranor vs. placebo) to complete treatment. Conservatively assuming that 10 % of the randomized patients will not complete the trial (dropouts), the total number of patients to be randomized is 33-34 patients.

Inclusion criteria

• Be able to communicate meaningfully with the investigator and legally competent to provide written informed consent
• Have an age between 21 to 75 years inclusive
• Subjects should be on stable standard of care and background therapy for ongoing chronic conditions, including stable doses of anti-diabetic medications, for at least two (2) months prior to trial entry
• Have uncontrolled diabetes with a fasting plasma glucose (FPG) ≥ 100 mg/dL but ≤ 250 mg/dL and HbA1c ≥ 6.0% but ≤ 9.5%, on diet alone, or on metformin (≥1,000 mg/day), and/or sulfonylurea and/or DPP-IV therapy, SGLT2 inhibitors or GLP1RA. These medicines will be continued at stable doses during the entire study.

• Subjects with an HbA1c > 8.0% but ≤ 9.5% will have their metformin (minimum dose required: 1,000 mg/day) maximized to 1,000 mg BID and/or glimepiride 2 mg once daily added during the first 2 weeks of the run-in period. The baseline visit to initiate lanifibranor (V4; Time 0 or randomization visit) will be not sooner than 8 weeks from diabetes medication titration and the patient should have an HbA1c ≤9.0% to proceed to randomization (V4).
• In addition, if both metformin and glimepiride (or another sulfonylurea) are already maximized at study entry (or the patient is intolerant to either) and the HbA1c ≥ 9.0% but ≤9.5%, we will add sitagliptin 100 mg daily (or an equivalent dose of another DPP-IV inhibitor) to reach an HbA1c ≤9.0% to proceed to randomization (V4).
• Presence of hepatic steatosis (Intrahepatic Triglycerides IHTG) > 10 % determined by Magnetic Resonance and Spectroscopy (1H-MRS).
• Have no new symptoms associated with decompensated diabetes in the previous 3 months.
• Compensated liver disease with the following hematologic and biochemical criteria on entry into protocol:

• Hemoglobin > 11 g/dL for females and > 12 g/dL for males
• White blood cell (WBC) > 2.5 K/µL
• Neutrophil count > 1.5 K/µL
• Total bilirubin ≤ 1.3 mg/dL (≤ 22.2 µmol/L). Patients with bilirubin ≤ 1.3 mg/dL can be included if non-conjugated bilirubin in the setting of a Gilbert's syndrome.
• Albumin > 36 g/L
• No other causes of chronic liver disease (autoimmune, primary biliary cholangitis, HBV, HCV, Wilson's, α-1-antitrypsin deficiency, hemochromatosis, other).
• Negative pregnancy test or at least two-year post-menopausal. Women with childbearing potential (i.e. fertile, following menarche and until becoming post- menopausal unless permanently sterile) must be using a highly effective method of contraception (i.e. combined (estrogen and progesterone containing) hormonal/ progesterone-only hormonal contraception associated with inhibition of ovulation, intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomized partner). The contraceptive method will have to be followed for at least one menstruation cycle after the end of the study.

Exclusion criteria

• Evidence of liver disease other than NAFLD.
• History of excessive alcohol intake, defined by ≥ 21 units of alcohol per week in males and ≥14 units of alcohol per week in females for two years prior to enrollment, where a "unit" of alcohol is equivalent to 12-ounce beer, 4-ounce glass of wine, or 1 ounce shot of hard liquor.
• Unstable metabolic condition: Weight change > 5 kg in the 3 months prior to enrollment, diabetes with poor glycemic control (HgbA1c > 9.5% or FPG > 250 mg/dl), introduction of an anti-obesity drug/malabsorptive or restrictive bariatric (weight loss) surgery in the past 6 months prior to screening.
• History of gastrointestinal malabsorptive bariatric surgery within less than 5 years or ingestion of drugs known to produce hepatic steatosis including corticosteroids, high-dose estrogens, methotrexate, tetracycline or amiodarone in the previous 6 months.
• Subjects on sulfonylureas, metformin, GLP-1RA or DPP-IV unless the dose and body weight (within 5%) have been stable for at least two (2) months prior to study entry.
• Patients on insulin, pioglitazone (or prior use in the past 12 months).
• Patients on any of the following medications unless the patient has been on stable doses of such agents for the past two (2) months before entry into the study: thiazide or furosemide diuretics, beta- blockers, or other chronic medications with known adverse effects on glucose tolerance levels. Patients may be taking stable doses of estrogens or other hormonal replacement therapy if the patient has been on these agents for the prior two (2) months. Patients taking systemic glucocorticoids will be excluded.

Treatment with strong inducers or inhibitors of CYP2C8, or treatment with substrates of CYP2B6 or CYP2C8. When administered chronically, they should be replaced 2 months before trial entry (See Inclusion criterion #3). If not administered chronically, they should be stopped at least 7 days before first dosing.

-Patients with:

• History of myopathies or evidence of active muscle diseases
• Unstable cardiovascular disease, including:

i. Unstable angina (i.e., new or worsening symptoms of coronary heart disease within the past 3 months), acute coronary syndrome within the past 6 months, acute myocardial infarction in the past 3 months or heart failure of New York Heart Association class (III-IV) or worsening congestive heart failure, or coronary artery intervention, within the past 6 months ii. History of (within prior 3 months) or current unstable cardiac dysrhythmias iii. Uncontrolled hypertension (systolic blood pressure > 160 mmHg and/or diastolic blood pressure > 100 mmHg.

iv. Stroke or transient ischemic attack within the prior 6 months c. History of malignancy in the past 5 years and/or active neoplasm with the exception of resolved superficial nonmelanoma skin cancer d. History of bladder disease and/or hematuria or has current hematuria unless due to a urinary tract infection e. Any of the following laboratory values: ii. Serum bilirubin > 1.3 mg/dL (or > 22.2 µmol/L). Patients with bilirubin >1.3 mg/dL can be included if non-conjugated bilirubin in the setting of a Gilbert's syndrome.

iii. Serum ALT > 3X ULN iv. INR > 1.2 v. Platelets < 150,000 per microliter of blood vi. Renal impairment as demonstrated by estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73m2 vii. Total creatinine kinase > 1.5 X ULN viii. Lipase > 1.3X ULN or >2.0X ULN if on a DPP-IV inhibitor. *(if abnormal values are confirmed when repeated within 3 weeks) ix. Hemoglobin A1c > 9.5%

• Significant systemic or major illnesses other than liver disease, including those listed in exclusion criteria #8 and pulmonary disease, organ transplantation, serious psychiatric disease, that, in the opinion of the investigator, would preclude treatment with lanifibranor and/or adequate follow up.
• HB antigen > 0, HCV > 0 (patients with a history of HCV infection can be included if HCV PCR is negative since more than 3 years), prior history of HIV infection.
• Pregnancy/lactation or inability to adhere to adequate contraception in women of child-bearing potential.
• Any other condition which, in the opinion of the investigator would impede competence or compliance or possibly hinder completion of the study.
• Body mass index (BMI) > 45 kg/m2.
• Type 1 diabetes and type 2 diabetic patient on insulin.
• Diabetic ketoacidosis.
• Fasting plasma triglycerides > 500 mg/dL.
• Hemostasis disorders or current treatment with anticoagulants.
• Participation in any other investigational drug study within the previous 3 months.
• Have a known hypersensitivity to any of the ingredients or excipients of the IMP including: Lactose monohydrate, hypromellose, sodium lauryl sulphate, sodium starch glycolate, magnesium stearate, Opadry™ II 85F18422, DSS Granular, cellulose microcrystalline, maize starch.
• Be possibly dependent on the Investigator (e.g., including, but not limited to, affiliated employee).
• Osteopenia or any other well documented bone disease. Patient without well documented osteopenia treated with vitamin D and/or calcium based supplements for preventive reasons can be included.
• Claustrophobia to a degree that prevents tolerance of MRI scanning procedure. Sedation is permitted at discretion of investigator.
• Metallic implant of any sort that prevents MRI examination including, but not limited to: aneurysm clips, metallic foreign body, vascular grafts or cardiac implants, neural stimulator, metallic contraceptive device, tattoo, body piercing that cannot be removed, cochlear implant; or any other contraindication to MRI examination.