JKB-121 for the Treatment of Nonalcoholic Steatohepatitis

Study Overview
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Brief Summary
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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

Detailed Description
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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.

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

Conditions
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Nonalcoholic Steatohepatitis

Intervention / Treatment
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* Drug: JKB-121: 5 mg twice daily
* Drug: JKB-121: 10 mg twice daily
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years Provision of written informed consent Biopsy-proven NASH within 12 months or at screening ALT > 40 U/L for women and > 60 U/L for men at screening and at least once in the previous 12 months. HBA1C of ≤ 9.0 Exclusion Criteria: Any chronic liver disease other than NASH Cirrhosis, as assessed clinically or histologically Presence of vascular liver disease BMI ≤ 25 kg/m2 Excessive alcohol use (> 20 g/day) within the past 2 years AST or ALT > 250 U/L. Type 1 diabetes mellitus Bariatric surgery in the past 5 years. Weight gain of > 5% in past 6 months or > 10% change in past 12 months. Contraindication to MRI Inadequate venous access HIV antibody positive, hepatitis B surface antigen positive (HBsAg), or Hepatitis C virus (HCV) RNA positive. Receiving an elemental diet or parenteral nutrition Chronic pancreatitis or pancreatic insufficiency Any history of complications of cirrhosis 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. Concurrent medications which may treat NASH HbA1C > 9.0% Pregnancy or breastfeeding.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: A<br>JKB 121, 5 mg twice daily | Drug: JKB-121: 5 mg twice daily<br> <br> |
| Active Comparator: B<br>JKB 121, 10 mg twice daily | Drug: JKB-121: 10 mg twice daily<br> <br> |
| Placebo Comparator: C<br>Identical appearing placebo | Drug: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Analysis of MRI-PDFF Change From Baseline to Week 24 (Per Protocol Population) |  | Baseline to week 24 | 
| Analysis of MRI-PDFF Change From Baseline to Week 12 (Per Protocol Population) |  | Baseline to Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Analysis of ALT Change From Baseline to Week 24 (Per Protocol Population) |  | Baseline to week 24 | 
| Analysis of ALT Change From Baseline to Week 12 (Per Protocol Population) |  | Baseline to week 12 | 
| Time to Remission (in Weeks) | Time to remission is the time in weeks from randomization to liver function remission, defined as two consecutive ALT values within normal range (<40 U/L) during the treatment period. | 24 weeks | 
| Change in BMI (Body Mass Index) |  | Baseline, week 24 | 
| Change in Hemoglobin A1C |  | Baseline, week 24 | 
| Change in Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) | HOMA-IR was calculated according to the formula: fasting insulin (microU/L) x fasting glucose (nmol/L)/22.5. Optimal Range: 1.0 (0.5-1.4). Lower values represent a better outcome. | Baseline, week 24 | 
| Percent Change in Cholesterol |  | Baseline, week 24 | 
| Percent Change in Triglycerides |  | Baseline, week 24 | 
| Percent Change in Low Density Lipoprotein (LDL) Cholesterol |  | Baseline, week 24 | 
| Percent Change in High Density Lipoprotein (HDL) |  | Baseline, week 24 | 
| Mean Serum Aspartate Aminotransferase (AST) |  | weeks 4, 8, 12, 16, 20, and 24 | 
| Mean Serum Alanine Aminotransferase (ALT) |  | weeks 4, 8, 12, 16, 20, and 24 | 
| Mean Serum Gamma-glutamyl Transpeptidase (GGT) |  | weeks 4, 8, 12, 16, 20, and 24 | 
| Number of Subjects With ALT in Normal Range at Week 24 | Normal range is <40 U/L | Week 24 | 
| Maximum Observed Concentrations (Cmax) |  | pre-dose and at 0.25, 0.5, 0.75, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, 10, 12, and 24 hours | 
| Minimum Observed Concentration (Cmin) |  | pre-dose and at 0.25, 0.5, 0.75, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, 10, 12, and 24 hours | 
| Area Under Concentration-time (AUC) |  | pre-dose and at 0.25, 0.5, 0.75, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, 10, 12, and 24 hours | 
| Half-life |  | pre-dose and at 0.25, 0.5, 0.75, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, 10, 12, and 24 hours |