A Phase ll Study of IMM-124E for Patients With Non-alcoholic Steatohepatitis

A Phase ll, Randomized, Double-blind, Placebo-controlled Study of IMM-124E for Patients With Non-alcoholic Steatohepatitis.

This study will evaluate the safety and preliminary efficacy of two dose levels of IMM-124E in reducing liver fat and/or serum alanine aminotransaminase (ALT) compared with placebo.

Subjects who provide voluntary written informed consent will be screened for eligibility. Subjects meeting all of the inclusion and none of the exclusion criteria will be eligible to participate.

Eligible subjects will be randomized at the Baseline visit to receive one of the three study treatments three times daily for a period of 24 weeks. Each subject will return to the study clinic for assessment and required study procedures on Day 7, 14 and 28 and every 4 weeks thereafter until Week 24.

Inclusion Criteria:

1. Age ≥ 18 years.

2. Provision of written informed consent.

3. Diagnosis of NASH, histologically proven within 12 months of Screening with

   • NASH activity score (NAS) of 4 or more
   • cytologic ballooning score of at least 1;
   • 10% or more macrovescicular steatosis.
   • Hematoxylin & Eosin (H&E) stained slides and/or paraffin block available for independent assessment.

4. HBA1C of <9.0

5. Agree to the use of effective contraceptive measures if either male or female of child bearing potential.

Exclusion Criteria:

1. Presence of vascular liver disease or cirrhosis;

2. Presence of liver disease with other cause (autoimmune, metabolic, medication induced);

3. BMI <25 kg/m^2;

4. Alcohol use >30 g/day;

5. Type 1 diabetes;

6. 6. History of major bariatric surgery (not including balloon / sleeve gastrectomy);

7. Weight loss or gain of 5kg or more in the past 6 months or >10% change in bodyweight in the past 12 months;

8. Contraindication for MRI;

9. Inadequate venous access;

10. Lactating/breastfeeding/pregnant at Screening or Baseline;

11. HIV antibody positive, hepatitis B surface antigen positive (HBsAg) or Hepatitis C virus (HCV)-RNA positive;

12. Receiving an elemental diet or parenteral nutrition;

13. Concurrent conditions

    • Inflammatory bowel disease;
    • Unstable angina, myocardial infarction, transient ischemic events, or stroke within 24 weeks of Screening;
    • Ongoing infectious, ongoing multi-systemic immune-mediated and/or concurrent or past malignant disease;
    • Any other concurrent condition which, in the opinion of the investigator, could impact adversely on the subject participating or on the interpretation of the study data;

14. Concurrent medications including:

    • anti-NASH therapy(s) taken for more than 10 continuous days in the last 3 months. These include S-adenosyl methionine (SAM-e), betaine, milk thistle, probiotic supplements (other than yoghurt), vitamin E and gemfibrozil.

      • NB: If vitamin E or gemfibrozil are used, the dose must be stable and liver biopsy confirming diagnosis of NASH subsequent to commencing treatment; commencing treatment;
      • Wash out for any of the anti-NASH therapies is as follows: under 10 days no washout required, more than 10 days and up to 3 months treatment requires 6 weeks washout. Any treatment of over 3 months would require to re-biopsy to ensure histological eligibility

    • thiazolidinediones (glitazones), dipeptidyl peptidase 4 inhibitors (gliptins) or glucagon-like peptide-1 analogs in the last 6 months. If treatment commenced and is stable for more than 6 month prior to the determinant biopsy and the dose is still stable at time of study entry, subjects will be eligible for recruitment.

    • Allowable anti-diabetic treatment includes metformin and/or sulfonylureas administered at constant dose for at least 2 months prior to study entry.

    • Subjects treated with Insulin are eligible if clinically stable on insulin treatment (i.e. no recurrent acute hypo-/hyperglycemic episodes diagnosed clinically and by Glucose serum levels of <50 mg/dL and >200 mg/dL respectively) for at least 2 months prior to study entry.

    • immune modulatory agents including

      • In the last 3 months:
      • systemic steroids for more than 7 days.
      • daily treatment with multiple non-steroidal anti-inflammatory drugs (such as aspirin >100mg/day, ibuprofen, naproxen, meloxicam, celecoxib) for more than 1 month within 3 months prior to study entry;
      • In the last 12 months:
      • azathioprine, 6-mercaptopurine, methotrexate, cyclosporin, anti-TNFα therapies (infliximab, adalimumab, etanercept) or anti-integrin therapies (namixilab) ;

    • more than 10 consecutive days oral or parenteral antibiotics within 4 weeks prior to study entry (Note: such subjects would not be included in the stool and PBMC analysis).

    • variable dose of antilipidemic agents (3-hydroxy-3-methyl-glutaryl (HMG)-Co-A reductase inhibitors - "statins") in the 3 months prior to study entry.

15. The following laboratory abnormalities:

    • Neutrophil count ≤1.0 x 10^9/L
    • Platelets <100 x 10^9/L
    • Hemoglobin <10 g/dL
    • Albumin <3.5 g/dL
    • International Normalized Ratio (INR) >1.5
    • Total bilirubin >1.5 x upper limit of reference range (unless Gilbert's syndrome or extrahepatic source as denoted by increased indirect bilirubin fraction)
    • Either creatinine clearance ≤60 mL/minute calculated by Cockroft Gault or creatinine >1.5x upper limit of reference range.

16. Known substance abuse, including inhaled or injected drugs in the year prior to Screening.

17. Cow milk allergy, lactose intolerance or any known or suspected hypersensitivity to study products.