Trial to Examine the Effect of Two Doses of GRI-0621 in Patients With Chronic Liver Disease

A Double-blind, Randomized, Placebo-Controlled Phase 2a Trial of GRI-0621 in Patients With Chronic Liver Disease

Primary objectives:

To evaluate the change in serum alanine transaminase [ALT] levels from Day 0 to Day 28, following daily doses of 4.5 or 6mg of GRI-0621 compared to placebo, in patients with chronic liver disease and elevated serum levels of ALT. Serum ALT level will be used as a marker of liver inflammation.

To assess the safety and tolerability of GRI-0621 at these two doses.

Secondary objectives:

To assess the change in serum aspartate transaminase [AST] levels from baseline to Day 28, following daily doses of 4.5 or 6mg of GRI-0621 or matching placebo, in patients with chronic liver disease and elevated serum levels of AST. Serum AST level will be used as a second marker of liver inflammation.

To evaluate the response to 4.5mg GRI-0621 versus 6mg GRI-0621 in terms of the change in serum ALT levels from baseline measured at the different trial time points.

To assess changes in serum cytokeratin 18 [CK-18] levels from baseline to Day 28, following daily doses of 4.5 or 6mg of GRI-0621 or matching placebo, in patients with chronic liver disease. Serum CK-18 is used as a marker of hepatocyte cell death due to either necrosis or apoptosis.

To measure Natural Killer T lymphocyte [NKT] cell activity at baseline and at Day 28 following daily doses of 4.5 or 6mg of GRI-0621 or matching placebo.

To describe the steady-state pharmacokinetics [PK] of GRI-0621 in patients with chronic liver disease.

Exploratory objectives:

To assess the effect, if any, that the investigational product may have on serum triglyceride levels.

This is a multi- centre, double-blind, randomized, placebo-controlled phase 2a trial in participants aged 18 to 65 years with chronic liver disease. It is designed to assess the safety, tolerability and efficacy of both 4.5mg and 6mg of GRI-0621 when administered once daily for 28 days.

A total of 60 participants will be randomised to received 4.5mg or 6mg of GRI-0621 or matching placebo in a 1:1:1 ratio. The investigational product will be administered orally once daily in the morning for a duration of 28 days. Participants will return to the clinic for follow-up safety and efficacy assessments on Days 7, 14, 21 and 28. Additionally, PK sampling will be performed on Days 7 and 28, and samples for immunological assays to assess the activity of NKT cells will be drawn on Days 0 (baseline) and 28. An end-of-trial follow-up visit will be performed 14 days after the last dose of the investigational product on Day 42.

The primary efficacy objective will be measured by the change from baseline to Day 28 in serum ALT levels. The baseline ALT level will be calculated as the mean of the Day -7 to -1 and Day 0 serum ALT results.

Safety and tolerability will be measured by the incidence and severity of adverse events and changes in physical examination findings, physical measurements, vital signs, ECG findings and standard laboratory safety parameters (including hematology, clinical chemistry, coagulation parameters and urinalysis).

Inclusion Criteria:

A participant will be eligible for participation in the trial if all of the following inclusion criteria are met:

1. Completion of the written informed consent process for trial participation prior to all trial-related procedures, including HIV testing.

2. Male or female participants aged 18 to 65 years.

3. Female participants of child-bearing potential must practice an effective method of birth control from four weeks prior to randomization and agree to continue this until 6 months after the completion of the end-of-trial follow-up visit. Effective birth control must include two methods, one of which must be a barrier method. Female participants are considered not to be of child-bearing potential if they are post-menopausal (12 months of spontaneous amenorrhoea with an appropriate clinical profile, or 6 months of spontaneous amenorrhoea with local laboratory serum follicle-stimulating hormone [FSH] levels in keeping with post-menopause) or surgically sterile (after bilateral oophorectomy, hysterectomy or salpingectomy). For the purpose of this trial any participant who has had a tubal ligation will not be considered surgically sterile due to the teratogenic nature of this class of chemical entities.

4. Female participants of child-bearing potential must have negative serum and urine pregnancy tests at screening and randomization respectively.

5. History of chronic liver disease [CLD] as a result of viral hepatitis, alcoholic steatohepatitis [ASH] or non-alcoholic steatohepatitis [NASH].

6. Evidence of viral hepatitis, ASH or NASH as described beneath:

   • Viral Hepatitis:

     • Hepatitis C virus [HCV] infection as confirmed by the presence of HCV RNA (determined by PCR) and no other cause of liver disease or
     • Hepatitis B virus [HBV] infection as confirmed by the presence of HBV DNA > 104 copies/ml (determined by the Roche COBA TaqMan HBV DNA assay) and no other cause for liver disease or
     • Hepatitis C and B co-infection (as defined above) OR

   • ASH:

     • Findings and history consistent with the diagnosis of ASH in the opinion of the investigator OR

   • NASH:

     • Absence of viral hepatitis and
     • A history of no or minimal alcohol use and
     • Findings and history consistent with the diagnosis of NASH in the opinion of the investigator

7. Body Mass Index (BMI) of 18 to 39kg/m2.

8. Weight ≥ 45kg

9. ALT > 1.5 x ULN but less than 10 x ULN on two occasions during the screening period (Day -28 to Day -1). The second occasion must be between Day -7 and Day -1.

10. An ability to communicate well with the investigator and to understand and comply with the requirements of the trial.

11. Agree to stay in contact with the trial site for the duration of the trial, provide updated contact information as necessary.

Exclusion Criteria:

A participant will not be eligible for trial participation if any of the following exclusion criteria are met:

1. Use of any other investigational drug within 30 days or five half-lives (whichever is longer) of the first dose of GRI-0621.

2. Current pregnancy or lactation.

3. A history of anaphylaxis or severe hypersensitivity to any drugs.

4. A known hypersensitivity to any component of the investigational product or to any other retinoids.

5. ALT or AST > 10 x ULN on any occasion during the screening period (Day -28 to Day -1)

6. ALT or AST known to have been > 10 X ULN on any occasion during the 2 months prior to screening.

7. Any of the following laboratory abnormalities at screening:

   • Serum creatinine > 1.5 x ULN
   • Hemoglobin < 10.0 g/L
   • Platelets < 75 x 109/L
   • White cell count < 3.0 x 109/L.

8. Known hypothyroidism requiring treatment or laboratory results suggestive of hypothyroidism at screening (thyroxine [T4] < LLN and thyroid-stimulating hormone [TSH] > ULN).

9. Any clinically significant ECG abnormalities.

10. Current or recent (during the 3 months prior to screening) or required treatment for tuberculosis infection.

11. A history of any malignancy (other than treated localized basal cell carcinoma of the skin) in the last 5 years.

12. A history or known presence of osteoporosis.

13. A history of arthritic conditions requiring treatment with symptom- or disease-modifying drugs for > 4 weeks.

14. A history of atopic dermatitis.

15. History or presence of decompensated liver disease

16. Previous histological evidence of hepatic fibrosis stage > 3.

17. The presence of any acute disorder that could further compromise the hepato-biliary system including but not limited to acute infectious or alcoholic hepatitis, acute pancreatitis, biliary obstruction and cholecystitis.

18. History or presence of hepatocellular carcinoma, hepatic abscess, biliary obstruction or portal vein thrombosis as confirmed by ultrasound, CT or MRI scans.

19. A history of severe gastro-intestinal bleeding requiring blood transfusion therapy (packed cells or whole blood).

20. Any surgical or medical condition other than CLD which might significantly alter the absorption, distribution, metabolism, or excretion of drugs, or which may jeopardize the safety of the participant or the objectives of the trial including but not limited to inflammatory bowel disease, major gastro-intestinal surgery (e.g. gastrectomy, gastroenterostomy or bowel resection) or pancreatic injury.

21. A history of hemachromatosis, Wilson's disease, alpha-1-antitrypsin deficiency or celiac disease.

22. Previous organ or hematopoietic transplantation.

23. HIV infection confirmed by a positive HIV test result.

24. Any other medical condition which, in the opinion of the investigator, could affect the participant's health during trial participation or could compromise his/her ability to participate in the trial. This includes but is not limited to significant cardiovascular, respiratory, renal, neurological, hematological, immunological, endocrinological or metabolic disorders.

25. Any psychiatric or mental disorder which could limit the validity of the informed consent or the participant's ability to comply with the protocol requirements.

26. A history of drug abuse during the 12 months prior to screening, or evidence of such abuse as indicated by urine testing for drugs of abuse at screening that, in the opinion of the investigator, may be indicative of potential participant adherence issues during the course of the trial.

27. In the opinion of the investigator, the participant is not reliable to participate in the trial.