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. Sixty four 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.

Inclusion Criteria:

1. Be able to communicate meaningfully with the investigator and legally competent to
provide written informed consent

2. Have an age between 21 to 75 years inclusive.

3. 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. These medicines will be
continued at stable doses during the entire study.

4. Presence of hepatic steatosis (Intrahepatic Triglycerides IHTG) > 10 % determined by
Nuclear Magnetic Resonance Techniques.

5. Have no new symptoms associated with decompensated diabetes in the previous 3 months.

6. Have been on a stable dose of allowed chronic medications for two months prior to
entering the double-blind treatment period.

7. Compensated liver disease with the following hematologic and biochemical criteria on
entry into protocol:

- ALT and AST ≤ 3.5xULN

- 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

- Platelets > 100 K/µL

- Total bilirubin < 35µmol/L. Patients with bilirubin > 35µmol/L can be included if
non-conjugated bilirubin in the setting of a Gilbert's syndrome.

- Albumin > 36 g/L

- Serum creatinine < 1.3 mg/dL (males) or < 1.1 mg/dL (females) or estimated
glomerular filtration rate ≥ 60 mL/min/1.73m2

8. No other causes of chronic liver disease (autoimmune, primary biliary cholangitis,
HBV, HCV, Wilson's, α-1-antitrypsin deficiency, hemochromatosis, other).

9. 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:

1. Evidence of another form of liver disease.

2. 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.

3. Unstable metabolic condition: Weight change > 5 kg in the last three months, 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.

4. 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.

5. Subjects on sulfonylureas, metformin or DPP-IV unless the dose has been stable for at
least 2 months prior to study entry.

6. Patients on insulin, pioglitazone (or prior use in the past 12 months), GLP-1RA (or
prior use in the past 3 months), or SGLT2 inhibitor (or prior use in the past 3
months)

7. 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.

8. Patients with history of myopathies or evidence of active muscle diseases

9. Unstable cardiovascular disease, including 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

10. History of (within prior 3 months) or current unstable cardiac dysrhythmias

11. Uncontrolled hypertension (systolic blood pressure > 160 mmHg and/or diastolic blood
pressure > 100 mmHg.

12. Stroke or transient ischemic attack within the prior 6 months

13. History of malignancy in the past 5 years and/or active neoplasm with the exception of
resolved superficial nonmelanoma skin cancer

14. History of bladder disease and/or hematuria or has current hematuria unless due to a
urinary tract infection

15. Any of the following laboratory values:

16. 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.

17. Serum ALT > 3X ULN

18. INR > 1.2

19. Platelets < 150,000 per microliter of blood.

20. Renal impairment as demonstrated by estimated glomerular filtration rate (eGFR) < 60
mL/min/1.73m2

21. Total creatinine kinase > 1.5 X ULN

22. Lipase > ULN

23. Hemoglobin A1c > 9.5%

24. 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.

25. 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.

26. Pregnancy/lactation or inability to adhere to adequate contraception in women of
child-bearing potential.

27. Any other condition which, in the opinion of the investigator would impede competence
or compliance or possibly hinder completion of the study.

28. Body mass index (BMI) > 45 kg/m2.

29. Type 1 diabetes and type 2 diabetic patient on insulin.

30. Diabetic ketoacidosis.

31. Fasting plasma triglycerides > 500 mg/dL.

32. Hemostasis disorders or current treatment with anticoagulants.

33. Participation in any other investigational drug study within the previous 3 months.

34. 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.

35. Be possibly dependent on the Investigator (e.g., including, but not limited to,
affiliated employee).

36. 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.

37. Claustrophobia to a degree that prevents tolerance of MRI scanning procedure. Sedation
is permitted at discretion of investigator.

38. 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..