Study in Healthy Volunteers to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of GS-9674 (Cilofexor), and the Effect of Food on GS-9674 Pharmacokinetics and Pharmacodynamics

Study Overview
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Brief Summary
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This study will evaluate the safety and tolerability of escalating single- and multiple-oral doses of cilofexor, and characterize the single- and multiple-dose pharmacokinetics (PK) of cilofexor. The study will be conducted in 3 parts (Part A, Part B, and Part C). Participants will receive either cilofexor or cilofexor placebo. Part A will proceed in 4 prespecified staggered cohorts. Within each cohort, the cumulative, blinded safety data will be evaluated for dose escalation from single-dose (Period 1) to multiple-dose (Period 2). Based on the available safety, pharmacokinetics, and/or pharmacodynamics (PD) data from cohorts in Part A and Part C (if applicable), total daily doses and frequency of dosing will be chosen for the cohorts in Part B. Parts B and C will consist of adaptive cohorts and may be initiated in parallel. Part B cohorts may be initiated in parallel with cohorts in Part A if the total dose under evaluation is at or below a dose already evaluated. This study is partially blinded (no one is blinded on Day -1).

Official Title
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A Phase 1 Study in Healthy Volunteers to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of GS-9674, and the Effect of Food on GS-9674 Pharmacokinetics and Pharmacodynamics

Conditions
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Nonalcoholic Steatohepatitis (NASH)

Intervention / Treatment
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* Drug: Cilofexor
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Healthy male and non-pregnant, non-lactating female volunteers Body mass index (BMI) 19 ≤ BMI ≤ 30 kg/m^2 Normal 12-lead electrocardiogram (ECG) or one with abnormalities that are considered clinically insignificant by the investigator Normal renal function (estimated glomerular filtration rate calculated using the Cockcroft-Gault equation ≥ 80 mL/min) No significant medical history, and in good general health as determined by the investigator at screening evaluation performed no more than 28 days prior to the scheduled first dose. Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1: Cilofexor 10 mg<br>Participants in fasted state will receive cilofexor 10 mg or placebo once on Day 1 followed by a 5-day washout period then receive cilofexor 10 mg or placebo once daily from Day 7 to Day 20. | Drug: Cilofexor<br>* Tablets administered orally<br>* Other names: GS-9674;Drug: Placebo<br>* Tablets administered orally<br>|
| Experimental: Cohort 2: Cilofexor 30 mg<br>Participants in fasted state will receive cilofexor 30 mg or placebo once on Day 1 followed by a 5-day washout period then receive cilofexor 30 mg or placebo once daily from Day 7 to Day 20. | Drug: Cilofexor<br>* Tablets administered orally<br>* Other names: GS-9674;Drug: Placebo<br>* Tablets administered orally<br>|
| Experimental: Cohort 3: Cilofexor 100 mg<br>Participants in fasted state will receive cilofexor 100 mg or placebo once on Day 1 followed by a 5-day washout period then receive cilofexor 100 mg or placebo once daily from Day 7 to Day 20. | Drug: Cilofexor<br>* Tablets administered orally<br>* Other names: GS-9674;Drug: Placebo<br>* Tablets administered orally<br>|
| Experimental: Cohort 4: Cilofexor 300 mg<br>Participants in fasted state will receive cilofexor 300 mg or placebo once on Day 1 followed by a 5-day washout period then receive cilofexor 300 mg or placebo once daily from Day 7 to Day 20. | Drug: Cilofexor<br>* Tablets administered orally<br>* Other names: GS-9674;Drug: Placebo<br>* Tablets administered orally<br>|
| Experimental: Cohort 5: Cilofexor 100 mg<br>Participants in fed state will receive cilofexor 100 mg or placebo once with food on Day 1 followed by a 5-day washout period then receive cilofexor 100 mg or placebo tablet, orally, once daily with food from Day 7 to Day 20. | Drug: Cilofexor<br>* Tablets administered orally<br>* Other names: GS-9674;Drug: Placebo<br>* Tablets administered orally<br>|
| Experimental: Cohort 6: Cilofexor 50 mg<br>Participants in fed state will receive cilofexor 50 mg or placebo twice with food on Day 1 followed by a 5-day washout period then receive cilofexor 50 mg or placebo twice daily from Day 7 to Day 20. | Drug: Cilofexor<br>* Tablets administered orally<br>* Other names: GS-9674;Drug: Placebo<br>* Tablets administered orally<br>|
| Experimental: Cohort 7: Cilofexor 15 mg<br>Participants in fed state will receive cilofexor 15 mg or placebo twice with food on Day 1 followed by a 5-day washout period then receive cilofexor 15 mg or placebo twice daily from Day 7 to Day 20. | Drug: Cilofexor<br>* Tablets administered orally<br>* Other names: GS-9674;Drug: Placebo<br>* Tablets administered orally<br>|
| Experimental: Cohort 8: Cilofexor 10 mg<br>Participants in fed state will receive cilofexor 10 mg or placebo once with food on Day 1 followed by a 5-day washout period then receive cilofexor 10 mg or placebo once daily from Day 7 to Day 20. | Drug: Cilofexor<br>* Tablets administered orally<br>* Other names: GS-9674;Drug: Placebo<br>* Tablets administered orally<br>|
| Experimental: Cohort 9: Cilofexor<br>Participants will receive cilofexor up to 300 mg or placebo once daily in the evening on empty stomach. | Drug: Cilofexor<br>* Tablets administered orally<br>* Other names: GS-9674;Drug: Placebo<br>* Tablets administered orally<br>|
| Experimental: Cohort 10: Cilofexor<br>Participants will receive cilofexor up to 300 mg or placebo once daily in the evening on empty stomach. | Drug: Cilofexor<br>* Tablets administered orally<br>* Other names: GS-9674;Drug: Placebo<br>* Tablets administered orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Single-Dose Pharmacokinetic (PK) Parameter: AUClast of Cilofexor | AUClast is defined as the concentration of drug from time zero to the last quantifiable concentration. | Day 1: -0.5, 0 (pre-dose), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 16, 24, 48, 72, and 96 hours post-dose | 
| Single-Dose PK Parameter: AUCinf of Cilofexor | AUCinf is defined as the concentration of drug extrapolated to infinite time (area under the plasma concentration versus time curve extrapolated to infinite time). | Day 1: -0.5, 0 (pre-dose), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 16, 24, 48, 72, and 96 hours post-dose | 
| Single-Dose PK Parameter: Cmax of Cilofexor | Cmax is defined as the maximum observed concentration of drug in plasma. | Day 1: -0.5, 0 (pre-dose), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 16, 24, 48, 72, and 96 hours post-dose | 
| Multiple-Dose PK Parameter: AUCtau of Cilofexor | AUCtau is the concentration of drug over time (area under the plasma concentration versus time curve over the dosing interval). | Day 20: -0.5, 0 (pre-dose), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 16, 24, 48, 72, and 96 hours post-dose | 
| Multiple-Dose PK Parameter: Cmax of Cilofexor | Cmax is defined as the maximum observed concentration of drug in plasma. | Day 20: -0.5, 0 (pre-dose), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 16, 24, 48, 72, and 96 hours post-dose | 
| Multiple-Dose PK Parameter: Ctau of Cilofexor | Ctau is defined as the observed drug concentration at the end of the dosing interval. | Day 20: -0.5, 0 (pre-dose), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 16, 24, 48, 72, and 96 hours post-dose | 
| Percentage of Participants With at Least One Adverse Event (AE) | An AE is any untoward medical occurrence in a clinical study participant administered a medicinal product, which does not necessarily have a causal relationship with the treatment. An AE can therefore be any unfavorable and/or unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. | First dose date up to last dose date (Maximum: 20 days) plus 30 days | 
| Percentage of Participants With Clinically Significant 12-Lead Electrocardiogram (ECG) Abnormalities | Investigator determined the ECG findings were clinically significant. | First dose date up to last dose date (Maximum: 20 days) plus 30 days | 
| Percentage of Participants With Clinical Laboratory Abnormalities | Treatment-emergent laboratory (Hematology, Chemistry, and Urinalysis) abnormalities were defined as values that increase at least one toxicity grade from baseline. Laboratory Abnormalities are graded by the investigator as Grade 1, 2, 3, or 4 according to the modified Gilead Sciences, Inc (GSI) Grading Scale. The most severe graded abnormality from all tests was counted for each participant. Data is only reported for those Grades reported in 1 or more participants. | First dose date up to last dose date (Maximum: 20 days) plus 30 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacodynamic (PD) Parameter: Fibroblast Growth Factor 19 (FGF19) AUC2-12 Ratio | AUC2-12 is defined as the AUC from time 2 to 12 hours. The ratios calculated were normalized to Day -1. Participants received a single placebo tablet at Day -1 for Baseline. The ratio reported for Day 1 is the AUC2-12 Day 1 /AUC2-12 Day-1. The ratio reported for Day 20 is the AUC2-12 Day 20 /AUC2-12 Day-1. | Day -1: -0.5, 0 (pre-dose), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, and 16 hours post-dose; Days 1, and 20: -0.5, 0 (pre-dose), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 16, 24, 48, 72, and 96 hours post-dose | 
| PD Parameter: FGF19 Cmax Ratio | Cmax is defined as the maximum observed concentration of FGF19 in plasma. The ratios calculated were normalized to Day -1. Participants received a single placebo tablet at Day -1 for Baseline. The ratio reported for Day 1 is the Cmax Day 1 /Cmax Day-1. The ratio reported for Day 20 is the Cmax Day 20 /Cmax Day-1. | Day -1: -0.5, 0 (pre-dose), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, and 16 hours post-dose; Days 1, and 20: -0.5, 0 (pre-dose), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 16, 24, 48, 72, and 96 hours post-dose | 
| PD Parameter: 7alpha-hydroxy-4-cholesten-3-one (C4) AUC2-12 Ratio | AUC2-12 is defined as the AUC from time 2 to 12 hours. The ratios calculated were normalized to Day -1. Participants received a single placebo tablet at Day -1 for Baseline. The ratio reported for Day 1 is the AUC2-12 Day 1 /AUC2-12 Day-1. The ratio reported for Day 20 is the AUC2-12 Day 20 /AUC2-12 Day-1. | Day -1: -0.5, 0 (pre-dose), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, and 16 hours post-dose; Days 1, and 20: -0.5, 0 (pre-dose), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 16, 24, 48, 72, and 96 hours post-dose | 
| PD Parameter: C4 Cmin Ratio | Cmin is defined as the minimum observed concentration of C4 in plasma. The ratios calculated were normalized to Day -1. Participants received a single placebo tablet at Day -1 for Baseline. The ratio reported for Day 1 is the Cmin Day 1 /Cmin Day-1. The ratio reported for Day 20 is the Cmin Day 20 /Cmin Day-1. | Day -1: -0.5, 0 (pre-dose), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, and 16 hours post-dose; Days 1, and 20: -0.5, 0 (pre-dose), 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 16, 24, 48, 72, and 96 hours post-dose |