JKB-121 for the Treatment of Nonalcoholic Steatohepatitis

A Randomized, Double-Blind, Placebo Controlled, Parallel-Group, Phase II Trial of JKB-121 for the Treatment of Nonalcoholic Steatohepatitis (NASH)

To evaluate the safety and potential efficacy of two dose levels of JKB-121 (5 mg twice daily and 10 mg twice daily) in reducing liver fat and/or liver biochemistry compared to placebo in patients with biopsy-proven nonalcoholic steatohepatitis

JKB-121 is a long-acting small molecule that is efficacious as a weak antagonist at the TLR-4 receptor. It is a non-selective opioid antagonist which has been shown to prevent the lipopolysaccharide (LPS) induced inflammatory liver injury in a methionine/choline deficient diet fed rat model of nonalcoholic fatty liver disease. In vitro, JKB-121 neutralized or reduced the LPS-induced release of inflammatory cytokines, deactivated hepatic stellate cells, inhibited hepatic stellate cell proliferation, and collagen expression. Inhibition of the TLR4 signaling pathway may provide an effective therapy in the prevention of inflammatory hepatic injury and hepatic fibrosis in patients with nonalcoholic steatohepatitis. This study will evaluate the safety and potential efficacy of two dose levels of JKB-121 (5 mg twice daily and 10 mg twice daily) in reducing liver fat and/or liver biochemistry compared to placebo in patients with biopsy-proven nonalcoholic steatohepatitis.

Inclusion Criteria:

1. Age ≥ 18 years
2. Provision of written informed consent
3. Biopsy-proven NASH within 12 months or at screening
4. ALT > 40 U/L for women and > 60 U/L for men at screening and at least once in the previous 12 months.
5. HBA1C of ≤ 9.0

Exclusion Criteria:

1. Any chronic liver disease other than NASH

2. Cirrhosis, as assessed clinically or histologically

3. Presence of vascular liver disease

4. BMI ≤ 25 kg/m2

5. Excessive alcohol use (> 20 g/day) within the past 2 years

6. AST or ALT > 250 U/L.

7. Type 1 diabetes mellitus

8. Bariatric surgery in the past 5 years.

9. Weight gain of > 5% in past 6 months or > 10% change in past 12 months.

10. Contraindication to MRI

11. Inadequate venous access

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

13. Receiving an elemental diet or parenteral nutrition

14. Chronic pancreatitis or pancreatic insufficiency

15. Any history of complications of cirrhosis

16. Concurrent conditions:

    • Inflammatory bowel disease
    • Significant cardiac disease
    • chronic infection or immune mediated disease
    • Any malignant disease
    • Prior solid organ transplant
    • Any other concurrent condition which, in the opinion of the investigator, could impact adversely on the subject participating or the interpretation of the study data.

17. Concurrent medications which may treat NASH

18. HbA1C > 9.0%

19. Pregnancy or breastfeeding.