Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of GS-248

Study Overview
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Brief Summary
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This is a First in Human (FIH), double-blinded, parallel-group, randomised, placebo-controlled study designed to evaluate the safety, tolerability, PK and PD of single and multiple ascending oral doses of GS-248 in healthy subjects.

Detailed Description
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Part I (SAD); In the SAD part of the study, single oral doses of GS-248 will be administered in 6 sequential cohorts, each consisting of 8 subjects randomised to receive either GS 248 or placebo in a 3:1 ratio. The first 2 subjects in each cohort will be dosed in a sentinel fashion; 1 subject will receive GS-248 and the other will receive placebo as randomised. The subjects will be carefully monitored by clinical staff during and after dosing. Vital signs, safety laboratory and ECG will be checked at regular intervals. Part II (MAD); The MAD part of the study will explore multiple ascending dosing of GS-248 administered for 10 days. The proposed starting dose is 25 mg/day. However, the starting dose as well as subsequent dose levels may be adjusted based on safety and PK evaluation in previous cohorts. GS-248 will be administered in 4 sequential cohorts, each of 8 subjects randomised to receive either GS 248 or placebo in a 3:1 ratio. The subjects will be carefully monitored by clinical staff during and after dosing. Vital signs, safety laboratory and ECG will be checked at regular intervals.

Official Title
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A Phase I, Placebo-controlled, Double-blind, First-in-human Study to Investigate Safety, Tolerability, Pharmacokinetics (PK) and Pharmacodynamics (PD) of GS-248 Solution in Healthy Subjects and Patients With Systemic Sclerosis (SSc)

Conditions
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Healthy

Intervention / Treatment
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* Drug: GS-248
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Willing and able to give written informed consent for participation in the study. Male and female healthy subjects aged 18-70 years inclusive (Part I [SAD]) and 40-75 years inclusive (Part II [MAD]) Women of child bearing potential must practice abstinence or must agree to use a highly effective method of contraception with a failure rate of < 1% to prevent pregnancy from at least 4 weeks prior to dose to 4 weeks after last dose. Their male partner must agree to use a condom during the same time frame. Women of non-childbearing potential are defined as pre-menopausal females who are sterilised or post-menopausal defined as 12 months of amenorrhea. Male subjects must be willing to use condom or be vasectomised or practice sexual abstinence. Their female partner of child-bearing potential must use contraceptive methods with a failure rate of < 1% to prevent pregnancy (see above). Body mass index (BMI) ≥ 19 and ≤ 30 kg/m2. Subjects must be in good health as determined by medical history, physical examination, vital signs, 12-lead ECG and clinical laboratory assessments at the time of screening, as judged by the Investigator. Exclusion Criteria: Known allergy to any components of the GS-248 formulation. Females who are breast feeding or plan to be pregnant. Positive serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) at screening and within 24 h prior to the first administration of Investigational Medicinal Product (IMP). Use of corticosteroids (inhaled and systemic), NSAIDs (including e.g. coxibs and aspirin), antacids, Proton pump inhibitors (PPIs) or any medication that changes gastric pH within 2 weeks prior to the (first) administration of IMP. Regular use of any prescribed or non-prescribed medication including analgesics, herbal remedies, vitamins and minerals within 2 weeks prior to the (first) administration of IMP, except hormonal contraception and occasional intake of paracetamol (maximum 2000 mg/day; and not exceeding 3000 mg/week) and nasal decongestants without cortisone, antihistamine or anticholinergics for a maximum of 10 days, at the discretion of the Investigator. Inherited or acquired disorders of platelet function, bleeding or coagulation. Presence of any clinically relevant acute or chronic disease that could interfere with the subject's safety during the clinical study or expose the subject to undue risk. After 10 minutes supine rest at the time of screening, any vital signs values outside the following ranges: Systolic blood pressure <90 or >140 mmHg, or Diastolic blood pressure <50 or >90 mmHg, or Pulse <40 or >90 bpm Any positive result on screening for serum hepatitis B surface antigen (HBsAg), hepatitis C virus antibodies (HCVAb) or human immunodeficiency virus (HIV) 1 and/or 2 antibodies at screening. Presence or history of drug and/or alcohol abuse and/or excessive intake of alcohol and/or history, or current use, of anabolic steroids, as judged by the Investigator. Any positive result for drug abuse and/or alcohol at screening or on admission to the unit prior to administration of the IMP. Participation in another clinical study with an experimental drug within 3 months before the administration of IMP. Consumption of grapefruit or grapefruit juice within 14 days of study drug administration. Any clinically significant illness, medical/surgical procedure or trauma within 4 weeks of the first administration of IMP. Malignancy within the past 5 years with the exception of in situ removal of basal cell carcinoma or resected benign colonic polyps. Any planned major surgery within the duration of the study. Prolonged QTcF (>450 ms), cardiac arrhythmias or any clinically significant abnormalities in the resting ECG at the time of screening, as judged by the Investigator. Current smokers or users of nicotine products. Irregular use of nicotine (e.g. smoking, snuffing, chewing tobacco) less than 3 times per week is allowed before screening visit. Regular excessive caffeine consumption defined by a daily intake of >5 cups of caffeine containing beverages. Intake of xanthine and/or taurine containing energy drinks within 2 days prior to screening. Plasma donation within one month of screening or blood donation (or corresponding blood loss) during the three months prior to screening. Investigator considers the subject unlikely to comply with study procedures, restrictions and requirements.

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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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
Interventional Model Description: Part I (SAD) Within each cohort, subjects will be randomised in a 3:1 ratio to receive either GS 248 (n=6) or placebo (n=2) in a blinded fashion. Part II (MAD) Within each cohort, subjects will be randomised in a 3:1 ratio to receive GS-248 (n=6) or placebo (n=2) in a blinded fashion.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GS-248<br>Part I (SAD): Single doses of 1 mg, 5 mg, 25 mg, 75 mg, 225 mg and 450 mg (planned doses) Part II (MAD): Multiple ascending doses for 10 days in four cohorts with planned doses of 25 mg, 75 mg, 225 mg and 450 mg. The doses will be finally selected based on results from Part I. | Drug: GS-248<br>* GS-248 oral solution<br>|
| Placebo Comparator: Placebo<br>Matching placebo oral solution | Drug: Placebo<br>* Placebo oral solution with the same composition to match active drug<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Treatment Related Adverse Events | AEs were assessed as 'unlikely', 'possibly' or 'probably' related to the IMP. 'Possibly' and 'probably' were categorized as treatment related. | AEs were collected from the start of IMP administration until the end-of-study visit of each part, an average of 10 days in Part 1 (SAD) and 20 days in Part 2 (MAD). | 
| Clinically Significant Changes in ECG | Single 12-lead ECG was recorded in supine position after 10 minutes of rest using an ECG machine. Heart rate and PQ/PR, QRS, QT and QTcF intervals were recorded. Ambulatory ECG telemetry was used for cardiac surveillance up to 24 h after IMP administration in the SAD part of the study. | 12-lead ECG was measured at pre-defined timepoints from the screening visit until the end-of-study visit, an average of 10 days in Part I (SAD) and 20 days in Part II (MAD). | 
| Clinically Significant Changes in Vital Signs | Systolic and diastolic blood pressure and pulse were measured in supine position after 10 minutes of rest. Body temperature was measured orally using a digital thermometer. | Vital signs was checked at pre-defined timepoints from the screening visit until the end-of-study visit, an average of 10 days in Part 1 (SAD) and 20 days in Part 2 (MAD). | 
| Clinically Significant Changes in Safety Laboratory Parameters | Blood samples for analysis of clinical chemistry, haematology and coagulation parameters. | Blood samples were collected at pre-defined timepoints from the screening visit until the end-of-study visit, an average of 10 days in Part I (SAD) and 20 days in Part II (MAD). | 
| Clinically Significant Changes in Physical Examination | A complete physical examination included assessments of the head, eyes, ears, nose, throat, skin, thyroid, neurological, lungs, cardiovascular, abdomen (liver and spleen), lymph nodes and extremities. | Physical examination was performed at pre-defined timepoints from the screening visit until the end-of- study visit, an average of 10 days in Part I (SAD) and 20 days in Part II (MAD). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax: | Maximum plasma concentration. | SAD: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48 hours post-dose; MAD Day 1-3 (first dose) and Day 10-12 (last dose): pre-dose, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48 hours post-dose. | 
| Tmax: | Time to Cmax. | SAD: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48 hours post-dose; MAD: Day 1-3 (first dose) Day 10-12 (last dose): pre-dose, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48 hours post-dose. | 
| T½: | Terminal elimination half-life | SAD: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48 hours post-dose); MAD: Day 1-3 and Day 10-12: pre-dose, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48 hours post-dose. | 
| AUC0-t: | Area under the concentration time curve from the time of dosing to the time of the last observation. | SAD: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48 hours post-dose); MAD: Day 1-3 and Day 10-12: pre-dose, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48 hours post-dose. | 
| AUC 0-inf | Area under the curve from time 0 to infinity. | SAD: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48 hours post-dose | 
| AUCss | Area under the plasma concentration curve during a dosing interval at steady state. | MAD: Day 10-12: pre-dose, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48 hours post-dose. | 
| Clearance (CL)/F: | Apparent total body clearance following extravascular administration. | SAD: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48 hours post-dose); MAD Day 1-3 and Day 10-12: pre-dose, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48 hours post-dose. | 
| Vz/F: | Apparent volume of distribution following extravascular administration | SAD: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48 hours post-dose); MAD: Day 1-3 and Day 10-12: pre-dose, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48 hours post-dose. | 
| Accumulation Ratio AUC 0-ss |  | MAD: Day 1-3 and Day 10-12: pre-dose, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48 hours post-dose. |