A Study to Assess the Safety, Tolerability, Pharmacokinetics and Efficacy of CS0159 in Subjects With NASH

Study Overview
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Brief Summary
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A randomized, double-blind study to assess the safety, tolerability, PK and efficacy of CS0159 in subjects with Non-Alcoholic Steatohepatitis (NASH)

Detailed Description
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This will be a multicenter, double-blind, randomized, placebo-controlled, dose-ranging study to evaluate the safety, tolerability, PKs, and efficacy of CS0159 in the treatment of patients with NASH over 12 weeks.

Official Title
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A Phase II, Randomized, Double-blind, Placebo-controlled Multicenter Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Efficacy of CS0159 in the Treatment of Patients With Nonalcoholic Steatohepatitis (NASH)

Conditions
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Nonalcoholic Steatohepatitis (NASH)

Intervention / Treatment
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* Drug: CS0159 (Linafexor)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients who meet the diagnosis of NASH. Evidence of metabolic syndrome, except for those patients with biopsy-proven NASH. Body mass index (BMI) >25 kg/m2, NOTE: for Asian-Americans BMI >23 kg/m2. Stable use of other antidiabetic, weight loss, or lipid-modifying medications for at least 12 weeks prior to randomization. Exclusion Criteria: Use of other investigational drugs within 5 half-lives of enrollment, or within 30 days, whichever is longer. Previous exposure to farnesoid X receptor (FXR) agonists 3 months prior to the first dosing. Current or within 6 months of screening use of drugs associated with steatosis, including but not limited to eg, methotrexate, amiodarone, high-dose estrogen, tamoxifen, long term systemic steroids, anabolic steroids, valproic acid. Prothrombin time international normalized ratio >1.3, unless due to therapeutic anticoagulation. Total bilirubin >upper limit of normal (ULN; except for patients with Gilbert's syndrome with a normal direct bilirubin value and normal reticulocyte count). Platelet count <140 000/mm³, absolute neutrophil count <1500 cells/mm3, or total white blood cells <3000 cells/mm3. Alanine aminotransferase and aspartate aminotransferase (AST) >5 × ULN, or alkaline phosphatase (ALP) >1.5 × ULN. Weight changes >10% in 6 months prior to screening, or weight changes >5% from the screening MRI-PDFF to randomization or from the time of the diagnostic liver biopsy to randomization, whichever is longer. Poorly controlled hypertension (systolic >160 mm Hg, or diastolic blood pressure >100 mm Hg - mean of 3 measurements). Uncontrolled diabetes mellitus (hemoglobin A1c >10.0% during screening).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1.4mg CS0159<br>One tablet daily for 12 weeks | Drug: CS0159 (Linafexor)<br>* Oral QD<br>* Other names: placebo;|
| Experimental: 2mg CS0159<br>One tablet daily for 12 weeks | Drug: CS0159 (Linafexor)<br>* Oral QD<br>* Other names: placebo;|
| Placebo Comparator: PLACEBO<br>One tablet daily for 12 weeks | Drug: CS0159 (Linafexor)<br>* Oral QD<br>* Other names: placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MRI-PDFF | To assess the changes in liver steatosis through magnetic resonance imaging (MRI) proton density fat fraction (PDFF) from baseline to Week 12 | Week 12 | 
| Adverse events | To evaluate the safety and tolerability of CS0159 in patients with NASH treated over 12 weeks | Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax | maximum concentration (Cmax) from baseline to Week 12 | week 6, week 12 | 
| tmax | time to maximum plasma concentration (tmax) from baseline to Week 12 | week 6, week 12 | 
| t1/2 | half-life (t1/2) from baseline to Week 12 | week 6, week 12 | 
| AUC | accumulation ratio of area under the concentration-time curve (AUC) in plasma from baseline to Week 12 | week 6, week 12 | 
| Pharmacodynamics (PD) | Plasma concentrations and PD parameters of the biomarkers of FXR target engagement fibroblast growth factor 19 and 7α-hydroxy-4-cholesten-3-one (C4) from baseline to Week 12 | week 6, week 12 |