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Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of GS-248

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)

Status
Completed
Phases
Phase 1
Study type
Interventional
Source
ClinicalTrials.gov
Registry ID
NCT04036227
Enrollment
72
Registered
2019-07-29
Start date
2019-07-03
Completion date
2019-12-20
Last updated
2023-10-11

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Healthy

Brief summary

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

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.

Interventions

DRUGGS-248

GS-248 oral solution

DRUGPlacebo

Placebo oral solution with the same composition to match active drug

Sponsors

CTC Clinical Trial Consultants AB
CollaboratorINDUSTRY
Gesynta Pharma AB
Lead SponsorINDUSTRY

Study design

Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)

Masking description

The study will be conducted in double-blind fashion and the allocation of treatments will not be disclosed until clean file has been declared and the database has been locked. GS-248 and the placebo are identical in appearance, taste and smell.

Intervention 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.

Eligibility

Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
Yes

Inclusion criteria

1. Willing and able to give written informed consent for participation in the study. 2. Male and female healthy subjects aged 18-70 years inclusive (Part I \[SAD\]) and 40-75 years inclusive (Part II \[MAD\]) 3. 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). 4. Body mass index (BMI) ≥ 19 and ≤ 30 kg/m2. 5. 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

1. Known allergy to any components of the GS-248 formulation. 2. Females who are breast feeding or plan to be pregnant. 3. 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). 4. 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. 5. 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. 6. Inherited or acquired disorders of platelet function, bleeding or coagulation. 7. 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. 8. 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 9. 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. 10. 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. 11. Any positive result for drug abuse and/or alcohol at screening or on admission to the unit prior to administration of the IMP. 12. Participation in another clinical study with an experimental drug within 3 months before the administration of IMP. 13. Consumption of grapefruit or grapefruit juice within 14 days of study drug administration. 14. Any clinically significant illness, medical/surgical procedure or trauma within 4 weeks of the first administration of IMP. 15. Malignancy within the past 5 years with the exception of in situ removal of basal cell carcinoma or resected benign colonic polyps. 16. Any planned major surgery within the duration of the study. 17. 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. 18. 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. 19. Regular excessive caffeine consumption defined by a daily intake of \>5 cups of caffeine containing beverages. 20. Intake of xanthine and/or taurine containing energy drinks within 2 days prior to screening. 21. Plasma donation within one month of screening or blood donation (or corresponding blood loss) during the three months prior to screening. 22. Investigator considers the subject unlikely to comply with study procedures, restrictions and requirements.

Design outcomes

Primary

MeasureTime frameDescription
Clinically Significant Changes in Physical ExaminationPhysical 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).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.
Number of Treatment Related Adverse EventsAEs 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).AEs were assessed as 'unlikely', 'possibly' or 'probably' related to the IMP. 'Possibly' and 'probably' were categorized as treatment related.
Clinically Significant Changes in ECG12-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).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.
Clinically Significant Changes in Vital SignsVital 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).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.
Clinically Significant Changes in Safety Laboratory ParametersBlood 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).Blood samples for analysis of clinical chemistry, haematology and coagulation parameters.

Secondary

MeasureTime frameDescription
AUC 0-infSAD: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48 hours post-doseArea under the curve from time 0 to infinity.
AUCssMAD: Day 10-12: pre-dose, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48 hours post-dose.Area under the plasma concentration curve during a dosing interval at steady state.
Vz/F: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.Apparent volume of distribution following extravascular administration
Accumulation Ratio AUC 0-ssMAD: 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.—
Clearance (CL)/F: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.Apparent total body clearance following extravascular administration.
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) and Day 10-12 (last dose): pre-dose, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48 hours post-dose.Maximum plasma concentration.
Tmax: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.Time to Cmax.
T½: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.Terminal elimination half-life
AUC0-t: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.Area under the concentration time curve from the time of dosing to the time of the last observation.

Other

MeasureTime frameDescription
mPGES-1 ActivityAt 24h after first dose Day 1 and at 24 hours after last dose Day 10.Ex vivo determination of mPGES-1 activity in a Whole Blood Assay (WBA) measured as percent change from baseline of Prostaglandin E2 (PGE2) levels after lipopolysaccharide (LPS) stimulation.

Countries

Sweden

Participant flow

Recruitment details

Subjects were recruited from CTC's database of healthy volunteers and from advertising in media (including social media). Screening visits were performed at CTC research clinic. Part I (SAD): Recruitment period started 19JUN2019 and lasted until 15OCT2019. Part II (MAD): Recruitment period started in August 2019 (when first SAD cohorts had been completed) and lasted until 25NOV2019.

Pre-assignment details

Part I (SAD): 92 subjects screened, 48 randomised to 6 dosing groups each of which included placebo. Did not meet the eligibility criteria=12, withdrew consent prior to randomisation=20, reserves=6, other reasons=6. Part II (MAD): 49 subjects screened, 24 randomised to 3 dosing groups each of which included placebo. Did not meet the eligibility criteria=11, withdrew consent prior to randomisation=9, reserve=1, other reasons=4.

Participants by arm

ArmCount
Part I (SAD): 1 mg
Single dose of 1 mg GS-248 oral solution.
6
Part I (SAD): 5 mg
Single dose of 5 mg GS-248 oral solution.
6
Part I (SAD): 8 mg
Single dose of 8 mg GS-248 oral solution.
6
Part I (SAD): 40 mg
Single dose of 40 mg GS-248 oral solution.
6
Part I (SAD): 100 mg
Single dose of 100 mg GS-248 oral solution.
6
Part I (SAD): 300 mg
Single dose of 300 mg GS-248 oral solution.
6
Part I (SAD): Placebo
Single dose of matching placebo oral solution.
12
Part II (MAD): 20 mg
Multiple ascending doses for 10 days with 20 mg.
6
Part II (MAD): 60 mg
Multiple ascending doses for 10 days with 60 mg.
6
Part II (MAD): 180 mg
Multiple ascending doses for 10 days with 180 mg.
6
Part II (MAD): Placebo
Multiple ascending doses for 10 days with matching placebo oral solution.
6
Total72

Baseline characteristics

CharacteristicPart II (MAD): 20 mgPart II (MAD): 60 mgPart II (MAD): 180 mgPart II (MAD): PlaceboTotalPart I (SAD): 300 mgPart I (SAD): 5 mgPart I (SAD): PlaceboPart I (SAD): 8 mgPart I (SAD): 1 mgPart I (SAD): 100 mgPart I (SAD): 40 mg
Age, Continuous
Part II (MAD)
56.7 years
STANDARD_DEVIATION 12.2
58.2 years
STANDARD_DEVIATION 11
58.2 years
STANDARD_DEVIATION 12.2
59.0 years
STANDARD_DEVIATION 13.9
58.0 years
STANDARD_DEVIATION 11.6
———————
Age, Continuous
Part I (SAD)
————37.8 years
STANDARD_DEVIATION 15.8
33.7 years
STANDARD_DEVIATION 13
33.7 years
STANDARD_DEVIATION 9.8
32.4 years
STANDARD_DEVIATION 14.1
36.8 years
STANDARD_DEVIATION 21.4
40.7 years
STANDARD_DEVIATION 21.5
50.7 years
STANDARD_DEVIATION 10.8
41.8 years
STANDARD_DEVIATION 15.9
BMI
Part II (MAD)
26.0 kg/m^2
STANDARD_DEVIATION 1.3
23.5 kg/m^2
STANDARD_DEVIATION 2.7
24.3 kg/m^2
STANDARD_DEVIATION 1.6
25.8 kg/m^2
STANDARD_DEVIATION 3.5
24.9 kg/m^2
STANDARD_DEVIATION 2.5
———————
BMI
Part I (SAD)
————24.4 kg/m^2
STANDARD_DEVIATION 3.2
22.0 kg/m^2
STANDARD_DEVIATION 2
25.2 kg/m^2
STANDARD_DEVIATION 3.9
24.0 kg/m^2
STANDARD_DEVIATION 3
25.2 kg/m^2
STANDARD_DEVIATION 3.4
22.3 kg/m^2
STANDARD_DEVIATION 2.6
26.0 kg/m^2
STANDARD_DEVIATION 2.2
25.7 kg/m^2
STANDARD_DEVIATION 3.4
Ethnicity (NIH/OMB)
Part II (MAD)
Hispanic or Latino
0 Participants0 Participants0 Participants0 Participants0 Participants———————
Ethnicity (NIH/OMB)
Part II (MAD)
Not Hispanic or Latino
6 Participants6 Participants6 Participants6 Participants24 Participants———————
Ethnicity (NIH/OMB)
Part II (MAD)
Unknown or Not Reported
0 Participants0 Participants0 Participants0 Participants0 Participants———————
Ethnicity (NIH/OMB)
Part I (SAD)
Hispanic or Latino
0 Participants0 Participants0 Participants0 Participants1 Participants0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants1 Participants
Ethnicity (NIH/OMB)
Part I (SAD)
Not Hispanic or Latino
0 Participants0 Participants0 Participants0 Participants47 Participants6 Participants6 Participants12 Participants6 Participants6 Participants6 Participants5 Participants
Ethnicity (NIH/OMB)
Part I (SAD)
Unknown or Not Reported
0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants
Height
Part II (MAD)
171.0 cm
STANDARD_DEVIATION 11.9
171.7 cm
STANDARD_DEVIATION 8
172.2 cm
STANDARD_DEVIATION 6.8
176.0 cm
STANDARD_DEVIATION 12.7
172.7 cm
STANDARD_DEVIATION 9.7
———————
Height
Part I (SAD)
————174.1 cm
STANDARD_DEVIATION 10.6
173.3 cm
STANDARD_DEVIATION 10.3
169.0 cm
STANDARD_DEVIATION 11
175.7 cm
STANDARD_DEVIATION 10.4
178.0 cm
STANDARD_DEVIATION 4.4
171.3 cm
STANDARD_DEVIATION 13.6
176.2 cm
STANDARD_DEVIATION 9.6
176.7 cm
STANDARD_DEVIATION 13.9
Race (NIH/OMB)
Part II (MAD)
American Indian or Alaska Native
0 Participants0 Participants0 Participants0 Participants0 Participants———————
Race (NIH/OMB)
Part II (MAD)
Asian
0 Participants0 Participants0 Participants0 Participants0 Participants———————
Race (NIH/OMB)
Part II (MAD)
Black or African American
0 Participants0 Participants0 Participants0 Participants0 Participants———————
Race (NIH/OMB)
Part II (MAD)
More than one race
0 Participants0 Participants0 Participants0 Participants0 Participants———————
Race (NIH/OMB)
Part II (MAD)
Native Hawaiian or Other Pacific Islander
0 Participants0 Participants0 Participants0 Participants0 Participants———————
Race (NIH/OMB)
Part II (MAD)
Unknown or Not Reported
0 Participants0 Participants0 Participants0 Participants0 Participants———————
Race (NIH/OMB)
Part II (MAD)
White
6 Participants6 Participants6 Participants6 Participants24 Participants———————
Race (NIH/OMB)
part I (MAD)
American Indian or Alaska Native
0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants
Race (NIH/OMB)
part I (MAD)
Asian
0 Participants0 Participants0 Participants0 Participants4 Participants0 Participants1 Participants1 Participants0 Participants2 Participants0 Participants0 Participants
Race (NIH/OMB)
part I (MAD)
Black or African American
0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants
Race (NIH/OMB)
part I (MAD)
More than one race
0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants
Race (NIH/OMB)
part I (MAD)
Native Hawaiian or Other Pacific Islander
0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants
Race (NIH/OMB)
part I (MAD)
Unknown or Not Reported
0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants0 Participants
Race (NIH/OMB)
part I (MAD)
White
0 Participants0 Participants0 Participants0 Participants44 Participants6 Participants5 Participants11 Participants6 Participants4 Participants6 Participants6 Participants
Region of Enrollment
Sweden
6 participants6 participants6 participants6 participants72 participants6 participants6 participants12 participants6 participants6 participants6 participants6 participants
Sex: Female, Male
Part II (MAD)
Female
4 Participants4 Participants4 Participants3 Participants15 Participants———————
Sex: Female, Male
Part II (MAD)
Male
2 Participants2 Participants2 Participants3 Participants9 Participants———————
Sex: Female, Male
Part I (SAD)
Female
————20 Participants4 Participants3 Participants3 Participants1 Participants2 Participants4 Participants3 Participants
Sex: Female, Male
Part I (SAD)
Male
————28 Participants2 Participants3 Participants9 Participants5 Participants4 Participants2 Participants3 Participants
Weight
Part II (MAD)
76.2 kg
STANDARD_DEVIATION 9
69.8 kg
STANDARD_DEVIATION 11.9
72.3 kg
STANDARD_DEVIATION 5.5
81.0 kg
STANDARD_DEVIATION 17.2
74.8 kg
STANDARD_DEVIATION 11.7
———————
Weight
Part I (SAD)
————74.4 kg
STANDARD_DEVIATION 14.5
66.3 kg
STANDARD_DEVIATION 8.2
72.5 kg
STANDARD_DEVIATION 16.9
74.7 kg
STANDARD_DEVIATION 13.8
79.8 kg
STANDARD_DEVIATION 13.3
65.7 kg
STANDARD_DEVIATION 13.4
81.0 kg
STANDARD_DEVIATION 11
81.0 kg
STANDARD_DEVIATION 18

Adverse events

Event typeEG000
affected / at risk
EG001
affected / at risk
EG002
affected / at risk
EG003
affected / at risk
EG004
affected / at risk
EG005
affected / at risk
EG006
affected / at risk
EG007
affected / at risk
EG008
affected / at risk
EG009
affected / at risk
EG010
affected / at risk
deaths
Total, all-cause mortality
0 / 60 / 60 / 60 / 60 / 60 / 60 / 120 / 60 / 60 / 60 / 6
other
Total, other adverse events
2 / 64 / 60 / 61 / 63 / 64 / 65 / 125 / 65 / 65 / 64 / 6
serious
Total, serious adverse events
0 / 60 / 60 / 60 / 60 / 60 / 60 / 120 / 60 / 60 / 60 / 6

Outcome results

Primary

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.

Time frame: 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).

Population: All subjects who have been randomised and received at least one dose of IMP.

ArmMeasureValue (NUMBER)
GS-248 1 mg (SAD)Clinically Significant Changes in ECG0 Number of abnormal CS events
GS-248 5 mg (SAD)Clinically Significant Changes in ECG0 Number of abnormal CS events
GS-248 8 mg (SAD)Clinically Significant Changes in ECG0 Number of abnormal CS events
GS-248 40 mg (SAD)Clinically Significant Changes in ECG0 Number of abnormal CS events
GS-248 100 mg (SAD)Clinically Significant Changes in ECG0 Number of abnormal CS events
GS-248 300 mg (SAD)Clinically Significant Changes in ECG0 Number of abnormal CS events
Placebo (SAD)Clinically Significant Changes in ECG0 Number of abnormal CS events
GS-248 20 mg (MAD)Clinically Significant Changes in ECG1 Number of abnormal CS events
GS-248 60 mg (MAD)Clinically Significant Changes in ECG0 Number of abnormal CS events
GS-248 180 mg (MAD)Clinically Significant Changes in ECG0 Number of abnormal CS events
Placebo (MAD)Clinically Significant Changes in ECG0 Number of abnormal CS events
Primary

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.

Time frame: 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).

Population: All subjects who have been randomised and received at least one dose of IMP.

ArmMeasureValue (COUNT_OF_PARTICIPANTS)
GS-248 1 mg (SAD)Clinically Significant Changes in Physical Examination0 Participants
GS-248 5 mg (SAD)Clinically Significant Changes in Physical Examination0 Participants
GS-248 8 mg (SAD)Clinically Significant Changes in Physical Examination0 Participants
GS-248 40 mg (SAD)Clinically Significant Changes in Physical Examination0 Participants
GS-248 100 mg (SAD)Clinically Significant Changes in Physical Examination0 Participants
GS-248 300 mg (SAD)Clinically Significant Changes in Physical Examination0 Participants
Placebo (SAD)Clinically Significant Changes in Physical Examination0 Participants
GS-248 20 mg (MAD)Clinically Significant Changes in Physical Examination0 Participants
GS-248 60 mg (MAD)Clinically Significant Changes in Physical Examination0 Participants
GS-248 180 mg (MAD)Clinically Significant Changes in Physical Examination0 Participants
Placebo (MAD)Clinically Significant Changes in Physical Examination1 Participants
Placebo (MAD)Clinically Significant Changes in Physical Examination1 Participants
Total (MAD)Clinically Significant Changes in Physical Examination2 Participants
Primary

Clinically Significant Changes in Safety Laboratory Parameters

Blood samples for analysis of clinical chemistry, haematology and coagulation parameters.

Time frame: 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).

Population: All subjects who have been randomised and received at least one dose of IMP.

ArmMeasureValue (COUNT_OF_PARTICIPANTS)
GS-248 1 mg (SAD)Clinically Significant Changes in Safety Laboratory Parameters0 Participants
GS-248 5 mg (SAD)Clinically Significant Changes in Safety Laboratory Parameters0 Participants
GS-248 8 mg (SAD)Clinically Significant Changes in Safety Laboratory Parameters0 Participants
GS-248 40 mg (SAD)Clinically Significant Changes in Safety Laboratory Parameters0 Participants
GS-248 100 mg (SAD)Clinically Significant Changes in Safety Laboratory Parameters0 Participants
GS-248 300 mg (SAD)Clinically Significant Changes in Safety Laboratory Parameters0 Participants
Placebo (SAD)Clinically Significant Changes in Safety Laboratory Parameters0 Participants
GS-248 20 mg (MAD)Clinically Significant Changes in Safety Laboratory Parameters0 Participants
GS-248 60 mg (MAD)Clinically Significant Changes in Safety Laboratory Parameters0 Participants
GS-248 180 mg (MAD)Clinically Significant Changes in Safety Laboratory Parameters2 Participants
Placebo (MAD)Clinically Significant Changes in Safety Laboratory Parameters0 Participants
Placebo (MAD)Clinically Significant Changes in Safety Laboratory Parameters1 Participants
Total (MAD)Clinically Significant Changes in Safety Laboratory Parameters3 Participants
Primary

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.

Time frame: 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).

Population: All subjects who have been randomised and received at least one dose of IMP.

ArmMeasureValue (NUMBER)
GS-248 1 mg (SAD)Clinically Significant Changes in Vital Signs0 Number of abnormal CS events
GS-248 5 mg (SAD)Clinically Significant Changes in Vital Signs0 Number of abnormal CS events
GS-248 8 mg (SAD)Clinically Significant Changes in Vital Signs0 Number of abnormal CS events
GS-248 40 mg (SAD)Clinically Significant Changes in Vital Signs0 Number of abnormal CS events
GS-248 100 mg (SAD)Clinically Significant Changes in Vital Signs0 Number of abnormal CS events
GS-248 300 mg (SAD)Clinically Significant Changes in Vital Signs0 Number of abnormal CS events
Placebo (SAD)Clinically Significant Changes in Vital Signs0 Number of abnormal CS events
GS-248 20 mg (MAD)Clinically Significant Changes in Vital Signs0 Number of abnormal CS events
GS-248 60 mg (MAD)Clinically Significant Changes in Vital Signs0 Number of abnormal CS events
GS-248 180 mg (MAD)Clinically Significant Changes in Vital Signs0 Number of abnormal CS events
Placebo (MAD)Clinically Significant Changes in Vital Signs0 Number of abnormal CS events
Placebo (MAD)Clinically Significant Changes in Vital Signs0 Number of abnormal CS events
Total (MAD)Clinically Significant Changes in Vital Signs0 Number of abnormal CS events
Primary

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.

Time frame: 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).

Population: All subjects who have been randomised and received at least one dose of IMP.

ArmMeasureValue (NUMBER)
GS-248 1 mg (SAD)Number of Treatment Related Adverse Events3 Number of events
GS-248 5 mg (SAD)Number of Treatment Related Adverse Events4 Number of events
GS-248 8 mg (SAD)Number of Treatment Related Adverse Events0 Number of events
GS-248 40 mg (SAD)Number of Treatment Related Adverse Events3 Number of events
GS-248 100 mg (SAD)Number of Treatment Related Adverse Events2 Number of events
GS-248 300 mg (SAD)Number of Treatment Related Adverse Events1 Number of events
Placebo (SAD)Number of Treatment Related Adverse Events4 Number of events
GS-248 20 mg (MAD)Number of Treatment Related Adverse Events1 Number of events
GS-248 60 mg (MAD)Number of Treatment Related Adverse Events12 Number of events
GS-248 180 mg (MAD)Number of Treatment Related Adverse Events9 Number of events
Placebo (MAD)Number of Treatment Related Adverse Events0 Number of events
Secondary

Accumulation Ratio AUC 0-ss

Time frame: 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.

ArmMeasureValue (MEAN)Dispersion
GS-248 1 mg (SAD)Accumulation Ratio AUC 0-ss1.148 ratioStandard Deviation 0.3148
GS-248 5 mg (SAD)Accumulation Ratio AUC 0-ss1.171 ratioStandard Deviation 0.5541
GS-248 8 mg (SAD)Accumulation Ratio AUC 0-ss2.390 ratioStandard Deviation 1.135
Secondary

AUC 0-inf

Area under the curve from time 0 to infinity.

Time frame: SAD: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48 hours post-dose

ArmMeasureValue (MEAN)Dispersion
GS-248 1 mg (SAD)AUC 0-inf8.542 h*nmol/LStandard Deviation 0.8438
GS-248 5 mg (SAD)AUC 0-inf40.22 h*nmol/LStandard Deviation 24.62
GS-248 8 mg (SAD)AUC 0-inf41.77 h*nmol/LStandard Deviation 13.8
GS-248 40 mg (SAD)AUC 0-inf489.3 h*nmol/LStandard Deviation 282.3
GS-248 100 mg (SAD)AUC 0-inf894.7 h*nmol/LStandard Deviation 380.8
GS-248 300 mg (SAD)AUC 0-inf2713 h*nmol/LStandard Deviation 2906
Secondary

AUC0-t:

Area under the concentration time curve from the time of dosing to the time of the last observation.

Time frame: 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.

Population: All subjects who received at least one dose of the study drug and provided at least one evaluable plasma concentration profile without any AEs or protocol deviations judged to affect the PK analysis.

ArmMeasureValue (MEAN)Dispersion
GS-248 1 mg (SAD)AUC0-t:2.437 h*nmol/LStandard Deviation 1.846
GS-248 5 mg (SAD)AUC0-t:30.57 h*nmol/LStandard Deviation 22.88
GS-248 8 mg (SAD)AUC0-t:39.08 h*nmol/LStandard Deviation 13.4
GS-248 40 mg (SAD)AUC0-t:478.6 h*nmol/LStandard Deviation 285.3
GS-248 100 mg (SAD)AUC0-t:879.8 h*nmol/LStandard Deviation 380
GS-248 300 mg (SAD)AUC0-t:2667 h*nmol/LStandard Deviation 2850
Placebo (SAD)AUC0-t:180.1 h*nmol/LStandard Deviation 75.75
GS-248 20 mg (MAD)AUC0-t:655.8 h*nmol/LStandard Deviation 473.7
GS-248 60 mg (MAD)AUC0-t:1735 h*nmol/LStandard Deviation 1164
GS-248 180 mg (MAD)AUC0-t:211.0 h*nmol/LStandard Deviation 115.5
Placebo (MAD)AUC0-t:650.5 h*nmol/LStandard Deviation 267.2
Placebo (MAD)AUC0-t:4798 h*nmol/LStandard Deviation 3702
Secondary

AUCss

Area under the plasma concentration curve during a dosing interval at steady state.

Time frame: MAD: Day 10-12: pre-dose, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 16, 24, 48 hours post-dose.

ArmMeasureValue (MEAN)Dispersion
GS-248 1 mg (SAD)AUCss205.9 h*nmol/LStandard Deviation 103.4
GS-248 5 mg (SAD)AUCss604.6 h*nmol/LStandard Deviation 233.1
GS-248 8 mg (SAD)AUCss4046 h*nmol/LStandard Deviation 2823
Secondary

Clearance (CL)/F:

Apparent total body clearance following extravascular administration.

Time frame: 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.

Population: All subjects who received at least one dose of the study drug and provided at least one evaluable plasma concentration profile without any AEs or protocol deviations judged to affect the PK analysis.

ArmMeasureValue (MEAN)Dispersion
GS-248 1 mg (SAD)Clearance (CL)/F:173.7 L/hStandard Deviation 17.51
GS-248 5 mg (SAD)Clearance (CL)/F:228.2 L/hStandard Deviation 102.7
GS-248 8 mg (SAD)Clearance (CL)/F:304.8 L/hStandard Deviation 83.8
GS-248 40 mg (SAD)Clearance (CL)/F:161.4 L/hStandard Deviation 92.39
GS-248 100 mg (SAD)Clearance (CL)/F:184.8 L/hStandard Deviation 58.74
GS-248 300 mg (SAD)Clearance (CL)/F:318.2 L/hStandard Deviation 223.4
Placebo (SAD)Clearance (CL)/F:187.0 L/hStandard Deviation 79.05
GS-248 20 mg (MAD)Clearance (CL)/F:190.2 L/hStandard Deviation 109.1
GS-248 60 mg (MAD)Clearance (CL)/F:181.2 L/hStandard Deviation 101.4
GS-248 180 mg (MAD)Clearance (CL)/F:175.4 L/hStandard Deviation 81.81
Placebo (MAD)Clearance (CL)/F:166.2 L/hStandard Deviation 63.62
Placebo (MAD)Clearance (CL)/F:97.59 L/hStandard Deviation 74.02
Secondary

Cmax:

Maximum plasma concentration.

Time frame: 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.

Population: All subjects who received at least one dose of the study drug and provided at least one evaluable plasma concentration profile without any AEs or protocol deviations judged to affect the PK analysis.

ArmMeasureValue (MEAN)Dispersion
GS-248 1 mg (SAD)Cmax:1.247 nmol/LStandard Deviation 0.9537
GS-248 5 mg (SAD)Cmax:8.975 nmol/LStandard Deviation 4.971
GS-248 8 mg (SAD)Cmax:11.82 nmol/LStandard Deviation 4.365
GS-248 40 mg (SAD)Cmax:145.3 nmol/LStandard Deviation 69.75
GS-248 100 mg (SAD)Cmax:263.3 nmol/LStandard Deviation 65.07
GS-248 300 mg (SAD)Cmax:818.3 nmol/LStandard Deviation 783.3
Placebo (SAD)Cmax:41.47 nmol/LStandard Deviation 18.45
GS-248 20 mg (MAD)Cmax:231.8 nmol/LStandard Deviation 187.3
GS-248 60 mg (MAD)Cmax:478.5 nmol/LStandard Deviation 310
GS-248 180 mg (MAD)Cmax:43.93 nmol/LStandard Deviation 30.1
Placebo (MAD)Cmax:176.5 nmol/LStandard Deviation 83.04
Placebo (MAD)Cmax:903.0 nmol/LStandard Deviation 590.6
Secondary

T½:

Terminal elimination half-life

Time frame: 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.

Population: All subjects who received at least one dose of the study drug and provided at least one evaluable plasma concentration profile without any AEs or protocol deviations judged to affect the PK analysis.

ArmMeasureValue (MEAN)Dispersion
GS-248 1 mg (SAD)T½:4.539 hoursStandard Deviation 2.435
GS-248 5 mg (SAD)T½:1.089 hoursStandard Deviation 0.1879
GS-248 8 mg (SAD)T½:1.660 hoursStandard Deviation 0.3684
GS-248 40 mg (SAD)T½:9.220 hoursStandard Deviation 6.697
GS-248 100 mg (SAD)T½:9.513 hoursStandard Deviation 3.683
GS-248 300 mg (SAD)T½:11.14 hoursStandard Deviation 1.63
Placebo (SAD)T½:3.469 hoursStandard Deviation 2.073
GS-248 20 mg (MAD)T½:6.705 hoursStandard Deviation 3.12
GS-248 60 mg (MAD)T½:11.86 hoursStandard Deviation 10.76
GS-248 180 mg (MAD)T½:6.504 hoursStandard Deviation 3.98
Placebo (MAD)T½:18.00 hoursStandard Deviation 8.75
Placebo (MAD)T½:15.01 hoursStandard Deviation 5.225
Secondary

Tmax:

Time to Cmax.

Time frame: 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.

Population: All subjects who received at least one dose of the study drug and provided at least one evaluable plasma concentration profile without any AEs or protocol deviations judged to affect the PK analysis.

ArmMeasureValue (MEDIAN)
GS-248 1 mg (SAD)Tmax:1.500 hours
GS-248 5 mg (SAD)Tmax:2.500 hours
GS-248 8 mg (SAD)Tmax:1.000 hours
GS-248 40 mg (SAD)Tmax:1.000 hours
GS-248 100 mg (SAD)Tmax:1.000 hours
GS-248 300 mg (SAD)Tmax:1.500 hours
Placebo (SAD)Tmax:1.000 hours
GS-248 20 mg (MAD)Tmax:1.000 hours
GS-248 60 mg (MAD)Tmax:1.108 hours
GS-248 180 mg (MAD)Tmax:2.000 hours
Placebo (MAD)Tmax:1.000 hours
Placebo (MAD)Tmax:2.000 hours
Secondary

Vz/F:

Apparent volume of distribution following extravascular administration

Time frame: 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.

Population: All subjects who received at least one dose of the study drug and provided at least one evaluable plasma concentration profile without any AEs or protocol deviations judged to affect the PK analysis.

ArmMeasureValue (MEAN)Dispersion
GS-248 1 mg (SAD)Vz/F:1097 LStandard Deviation 516.4
GS-248 5 mg (SAD)Vz/F:341.9 LStandard Deviation 120.5
GS-248 8 mg (SAD)Vz/F:719.7 LStandard Deviation 192.1
GS-248 40 mg (SAD)Vz/F:2117 LStandard Deviation 2445
GS-248 100 mg (SAD)Vz/F:2378 LStandard Deviation 918.8
GS-248 300 mg (SAD)Vz/F:4856 LStandard Deviation 3394
Placebo (SAD)Vz/F:1354 LStandard Deviation 392.3
GS-248 20 mg (MAD)Vz/F:3945 LStandard Deviation 1685
GS-248 60 mg (MAD)Vz/F:2157 LStandard Deviation 2139
Other Pre-specified

mPGES-1 Activity

Ex vivo determination of mPGES-1 activity in a Whole Blood Assay (WBA) measured as percent change from baseline of Prostaglandin E2 (PGE2) levels after lipopolysaccharide (LPS) stimulation.

Time frame: At 24h after first dose Day 1 and at 24 hours after last dose Day 10.

Population: All subjects who were randomised, received at least one dose of IMP and who had at least one post-baseline assessment of efficacy data.

ArmMeasureValue (MEAN)Dispersion
GS-248 1 mg (SAD)mPGES-1 Activity7.2 Relative change from baseline (%)Standard Deviation 98.8
GS-248 5 mg (SAD)mPGES-1 Activity-97.1 Relative change from baseline (%)Standard Deviation 12.1
GS-248 8 mg (SAD)mPGES-1 Activity-108.3 Relative change from baseline (%)Standard Deviation 11.5
GS-248 40 mg (SAD)mPGES-1 Activity-105.2 Relative change from baseline (%)Standard Deviation 11.6
GS-248 100 mg (SAD)mPGES-1 Activity-65.9 Relative change from baseline (%)Standard Deviation 20.2
GS-248 300 mg (SAD)mPGES-1 Activity-94.9 Relative change from baseline (%)Standard Deviation 9.3
Placebo (SAD)mPGES-1 Activity-104.3 Relative change from baseline (%)Standard Deviation 6.8
GS-248 20 mg (MAD)mPGES-1 Activity9.8 Relative change from baseline (%)Standard Deviation 59.6
GS-248 60 mg (MAD)mPGES-1 Activity-86.9 Relative change from baseline (%)Standard Deviation 26.8
GS-248 180 mg (MAD)mPGES-1 Activity-104.3 Relative change from baseline (%)Standard Deviation 13.9
Placebo (MAD)mPGES-1 Activity-109.8 Relative change from baseline (%)Standard Deviation 7.8
Placebo (MAD)mPGES-1 Activity18.6 Relative change from baseline (%)Standard Deviation 57.7

Source: ClinicalTrials.gov · Data processed: Feb 4, 2026