A Clinical Trial to Evaluate the Efficacy and Safety of Two Aramchol Doses Versus Placebo in Patients With NASH

This is a multicenter, Phase IIb, randomized, double blind, placebo-controlled study designed
to evaluate the efficacy and safety of two Aramchol doses in subjects that are 18 to 75 years
of age, with Non-Alcoholic Steatohepatitis (NASH) confirmed by liver biopsy performed in a
period of 6 months before entering the study, with overweight or obesity and who are pre
diabetic or type II diabetic.

Eligible subjects will be enrolled into three treatments arms: Aramchol 400 and 600 mg
tablets and placebo tablets in ratio 2:2:1.

The subjects will be evaluated at study sites for 11 scheduled visits: at screening (visit
1(weeks -4 - 0)), baseline (visit 2 (day 0)), visit 3 (week 2), visit 4 week 4), visit 5
(week 8), visit 6 (week 12), visit 7 (week 24), visit 8 (week 32), visit 9 (week 40) and
visit 10 (week 52 - (End of Treatment/early termination visit)). After completion of the
study treatment period, the subjects will be followed for an additional period of 13 weeks
without study medication (until visit 11 (week 65)).

During the screening period, the severity of the disease will be evaluated with blood tests,
liver biopsy and NMRS.

During the study the following assessments will be performed:

- Vital signs will be measured at each study visit.

- A physical examination will be performed at the screening visit, 24 weeks, End of
Treatment/early termination and week 65 visit.

The following blood tests will be performed: complete blood count (CBC), serum chemistry
(including electrolytes, liver enzymes, direct and total bilirubin, glucose, lipid profile
which include triglyceride, cholesterol, HDL, LDL and VLDL, CPK, creatinine, urea, albumin,
alkaline phosphatase), ESR and urinalysis during the screening visit, baseline, week 2, 4, 8,
24, 40, 52 and 65 (end of follow up) visits. Serology (HBV, HCV and HIV) will be performed
during the screening visit. Coagulation (fibrinogen, PT/INR, aPTT) will be measured in
screening and baseline, week 24, End of Treatment/early termination and week 65 visits.
Insulin (HOMA) will be measured in the screening, week 24 and End of Treatment/early
termination visits. HbA1C will be measured in the screening, week 8, 24, 40 and End of
Treatment/early termination visits. C reactive protein, Leptin, Adiponectin, CK-18 (M30 and
M65), Ferritin, PAI-1, IL-6, TNF-alpha, FGF-19, C4 (7-alpha-hydroxy-4-cholesten-3-one), pool
serum Bile Acids, B-hydroxybutyrate and Free Fatty Acids will be measured in baseline visit
and end of treatment period. The blood samples taken at these visits, will be tested for
possible biomarkers, including, but not limited to, Fetuine A and GDF15. TSH, T3 and T4 will
be measured during the screening visit. beta-hCG in women of childbearing potential will be
performed during the screening visit. A serum sample will be collected and kept frozen until
study end in case special investigation needs to be performed. This sample will be collected
during the screening and visit 10/Early Termination.

- Body weight and waist circumference will be measured in screening, baseline, week 24,
end of treatment and week 65 visits. Height will be measured during the screening visit.

- ECG will be performed during the screening visit, visit 7 (week 24) and end of treatment
visits.

- All subjects will undergo two NMRS scans, at screening and end of treatment visits.

- FibroMax test will be performed only if the investigator thinks it is necessary

- Liver biopsy will be conducted during the screening and end of treatment visit. The
biopsy in the screening visit will be performed only if it was not done within the 6
months prior to this visit.

- Metabolomics blood test will be performed at the screening, visit 7 and the
End-of-Treatment/Early Termination visits. From some consenting patients (about 15) a
sample from the liver biopsy will be taken for analysis.

- Endothelial Function will be conducted in selected sites. The test will be conducted
during the baseline visit before the study treatment will be given and End of
Treatment/early termination visit.

- Blood sample for Aramchol trough level will be collected (pre-dose) from patients in
Israel at baseline (visit 2) week 4 (visit 4), week 12 (visit 6), week 24 (visit 7),
week 40 (visit 9), end of treatment (visit 10) and follow up (visit 11). At selected
sites in Mexico, USA and Hong Kong one blood sample will be collected (pre-dose) on
visit 4 (up to 10 subjects per country) to test for trough Aramchol blood level
differences between populations (e.g., African American, Asian, Hispanic).

- Blood sample for gene analysis will be taken from all consenting patients during the
baseline visit, will be kept frozen and analyzed only at the study end.

- Life style questionnaire will be completed in all visits.

- Adverse events will be monitored throughout the study.

- Concomitant Medications will be monitored throughout the study.

- Telephone contacts will be performed on week 16, 20, 28, 36, 44 and 48. An interim
safety analysis will be conducted as soon as 120 subjects will completed the follow up
period of 24 weeks under study treatment. An independent DSMB will analyze the safety
data and recommend a continued course of action. All patients will continue to be
treated under the study protocol until conclusion of the analysis will be known.

Safety assessment will include frequency and severity of treatment-emergent AEs, clinically
significant laboratory abnormalities, ECG changes and physical examination findings.

Inclusion Criteria:

1. Male or female age 18 to 75 years.

2. BMI between 25kg/m2 to 40kg/m2 or waist circumference between 88 cm to 200 cm for
women, and between 102 cm to 200 cm for men. If there is deviation above the upper
limit, please consult the MRI center, to ensure that the machine is suitable for the
patient.

3. Known type II Diabetes Mellitus or pre-Diabetes according to American Diabetes
Association. One of the following 3 criteria is needed for pre-Diabetes: Fasting
Plasma Glucose > 100mg/dl (5.5 mmol/l) or 2hPG following 75g OGTT > 140 (7.8 mmol/l)
mg/dl or HbA1c > 5.7%. HbA1c can be repeated at Investigator's discretion.

4. Histologically proven Steatohepatitis on a diagnostic liver biopsy performed either
during screening or within 6 months before screening visit, confirmed by central
laboratory reading of the slides.(Steatosis ≥1 + inflammation ≥1 + ballooning
≥1).Total activity NAS score of 4 or more.

5. Liver fat concentration in the liver of 5.5% or more as measured by NMRS.

6. Biopsies with an activity NAS score of 4 or more.

7. Normal synthetic liver function (serum albumin >3.2g/dl, INR 0.8-1.2, conjugated
bilirubin < 35 µmol/L).

8. Understanding the nature of the study and signature of the written informed consent.

9. Negative pregnancy test at study entry for females of child bearing potential.

10. Females of child bearing potential practicing reliable contraception throughout the
study period (including oral contraceptives) as well as negative pregnancy test at
study entry.

11. Hypertensive patients must be well controlled by stable dose of anti-hypertensive
medication for at least 2 months prior to screening.

12. Patients previously treated with vitamin E (>400IU/day), Polyunsaturated fatty acid
(>2g/day) or Ursodeoxycholic acid or fish oil can be included if stopped or at least
maintained on stable dose at least 3 months prior to diagnostic liver biopsy (and are
not started during the trial). These treatments-dosages are allowed if they were
stable for at least 12 months prior to biopsy and can remain stable throughout the
study. (Dosages less than the amounts stated above are allowed without washout- or
stable-period restrictions).

13. For patients with type II Diabetes, glycaemia must be controlled (Glycosylated
Hemoglobin A1c ≤9%) while any HbA1c change should not exceed 1.5% during 6 months
prior to enrolment). Treatments with anti-diabetic medications (except for those
mentioned in Exclusion 16) are permitted if glycaemia is self-monitored by the
patient. HbA1c can be repeated at Investigator's discretion.

Exclusion Criteria:

1. Patients with other active (acute or chronic) liver disease other than NASH (e.g.
viral hepatitis, unless eradicated at least 3 years prior to screening; genetic
hemochromatosis; Wilson disease; alpha 1antitripsin deficiency; alcohol liver disease;
drug-induced liver disease) at the time of randomization.

2. Patients with clinically or histologically documented liver cirrhosis

3. Known alcohol and/or any other drug abuse or dependence in the last five years.

4. Known history or presence of clinically significant cardiovascular, gastrointestinal,
metabolic other than Diabetes Mellitus, neurologic, pulmonary, endocrine, psychiatric,
neoplastic disorder or nephrotic syndrome, that in the opinion of the Investigator
warrant exclusion from the study.

5. Patients with familial (i.e., genetic) hypertriglyceridemia and familial (i.e.,
genetic) hypercholesterolemia.

6. History or presence of any disease or condition known to interfere with the absorption
distribution, metabolism or excretion of drugs including bile salt metabolites (e.g.
inflammatory bowel disease (IBD)), previous intestinal (ileal or colonic) operation,
chronic pancreatitis, celiac disease or previous vagotomy. Ongoing Chronic
constipation

7. Patients with heart or brain pacemaker (i.e., implantable neurological devices).

8. Surgery during the last three month before screening which involved stent implantation
of metal devices (e.g. knee, hip etc.)

9. Weight loss of more than 5% within 6 months prior to randomization.

10. History of bariatric surgery within 5 years of liver biopsy.

11. Uncontrolled arterial hypertension.

12. Women who are pregnant and breast feeding.

13. Diabetes Mellitus other than type II (type I, endocrinopathy, genetic syndromes etc.).

14. Patients with HIV infection.

15. Daily alcohol intake >20 g/day for women and >30 g/day for men (on average per day) as
per medical history.

16. Treatment with other anti-diabetic medications:

GLP-1 receptor agonists and Thiazolidinediones (TZDs), unless started at least 12
months prior to biopsy and on stable dose for 6 months. In case of GLP-1 receptor
agonists stopped, it should be at least 6 months before biopsy as per medical history.

17. SGLT-2 Inhibitors, Metformin, fibrates, statins, insulin, DPP-4 inhibitors and
sulfonylurea unless prescribed dose has been stable for the last 6 months prior to the
biopsy.

18. Treatment with Valproic acid, Tamoxifen, Methotrexate, Amiodarone or chronic treatment
with anti-cholinergic agents, corticosteroids, high dose estrogen and tetracycline
within 12 months prior to the screening visit.

19. Chronic treatment with antibiotics (e.g. Rifaximin).

20. Homeopathic and/or alternative treatments. Any treatment should be stopped during the
screening period at least 48 hours before randomization.

21. 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.

22. Patients with renal dysfunction eGFR< 40.

23. Unexplained serum creatine phosphokinase (CPK) >3X the upper limit of normal (UNL).
Patients with a reason for CPK elevation may have the measurement repeated prior to
randomization; a CPK retest > 3X ULN leads to exclusion.

24. Patients with condition(s) that makes them unsuitable to perform the NMRS (as
determined by the PI or the MRI facility).

25. Hypersensitivity to Aramchol or to any of the excipients in the tablets

26. Hypersensitivity to cholic acid or bile acid sequestrants