A TEAE is any event not present before exposure to study drug or any event already present that worsens after exposure to study drug.

A serious adverse event is any untoward medical occurrence that resulted in death, was life-threatening, required or prolonged inpatient hospitalization, resulted in persistent disability/incapacity, was a congenital anomaly/birth defect, or other event that may have jeopardized the participant or required intervention to prevent one of the outcomes above.

The investigator assessed the intensity of each AE according to the following:

Grade 1 (Mild): No or minimal interference with usual activities.

Grade 2 (Moderate): More than minimal interference with usual activities, intervention indicated.

Grade 3 (Severe): Inability to perform usual activities, intervention or hospitalization indicated.

Grade 4 (Potentially life-threatening): Inability to perform self-care, intervention indicated to prevent permanent impairment, disability, or death.

The safety analysis population included all participants randomly assigned to study intervention who took at least 1 dose of study intervention.

A TEAE is any event not present before exposure to study drug or any event already present that worsens after exposure to study drug.

A serious adverse event is any untoward medical occurrence that resulted in death, was life-threatening, required or prolonged inpatient hospitalization, resulted in persistent disability/incapacity, was a congenital anomaly/birth defect, or other event that may have jeopardized the participant or required intervention to prevent one of the outcomes above.

The investigator assessed the intensity of each AE according to the following:

Grade 1 (Mild): No or minimal interference with usual activities.

Grade 2 (Moderate): More than minimal interference with usual activities, intervention indicated.

Grade 3 (Severe): Inability to perform usual activities, intervention or hospitalization indicated.

Grade 4 (Potentially life-threatening): Inability to perform self-care, intervention indicated to prevent permanent impairment, disability, or death.

The safety analysis population included all participants randomly assigned to study intervention who took at least 1 dose of study intervention.

A TEAE is any event not present before exposure to study drug or any event already present that worsens after exposure to study drug.

A serious adverse event is any untoward medical occurrence that resulted in death, was life-threatening, required or prolonged inpatient hospitalization, resulted in persistent disability/incapacity, was a congenital anomaly/birth defect, or other event that may have jeopardized the participant or required intervention to prevent one of the outcomes above.

The investigator assessed the intensity of each AE according to the following:

Grade 1 (Mild): No or minimal interference with usual activities.

Grade 2 (Moderate): More than minimal interference with usual activities, intervention indicated.

Grade 3 (Severe): Inability to perform usual activities, intervention or hospitalization indicated.

Grade 4 (Potentially life-threatening): Inability to perform self-care, intervention indicated to prevent permanent impairment, disability, or death.

The safety analysis population included all participants randomly assigned to study intervention who took at least 1 dose of study intervention.

The effect of dolutegravir on the pharmacokinetics (PK) of S-648414 was assessed after administration of multiple oral doses of S-648414 alone (Day 21) and after administration of multiple oral doses of S-648414 co-administered with dolutegravir (Day 28).

The PK parameter population includes all study participants with at least 1 PK parameter estimated appropriately.

The effect of dolutegravir on the pharmacokinetics (PK) of S-648414 was assessed after administration of multiple oral doses of S-648414 alone (Day 21) and after administration of multiple oral doses of S-648414 co-administered with dolutegravir (Day 28).

The PK parameter population

The effect of dolutegravir on the pharmacokinetics (PK) of S-648414 was assessed after administration of multiple oral doses of S-648414 alone (Day 21) and after administration of multiple oral doses of S-648414 co-administered with dolutegravir (Day 28).

The PK parameter population

The effect of dolutegravir on the pharmacokinetics (PK) of S-648414 was assessed after administration of multiple oral doses of S-648414 alone (Day 21) and after administration of multiple oral doses of S-648414 co-administered with dolutegravir (Day 28).

Area under the concentration-time curve over the dosing interval τ (24 hours) was calculated by the linear up/log down trapezoidal method.

The PK parameter population

The effect of dolutegravir on the pharmacokinetics (PK) of S-648414 was assessed after administration of multiple oral doses of S-648414 alone (Day 21) and after administration of multiple oral doses of S-648414 co-administered with dolutegravir (Day 28).

Apparent total clearance was calculated as CL/F = Dose/AUC0-τ

The PK parameter population

The effect of S-648414 on the PK of dolutegravir was assessed after administration of multiple oral doses of dolutegravir alone and after administration of multiple oral doses of S-648414 co-administered with dolutegravir.

The PK parameter population

The effect of S-648414 on the PK of dolutegravir was assessed after administration of multiple oral doses of dolutegravir alone and after administration of multiple oral doses of S-648414 co-administered with dolutegravir.

The PK parameter population

The effect of S-648414 on the PK of dolutegravir was assessed after administration of multiple oral doses of dolutegravir alone and after administration of multiple oral doses of S-648414 co-administered with dolutegravir.

The PK parameter population

The effect of S-648414 on the PK of dolutegravir was assessed after administration of multiple oral doses of dolutegravir alone and after administration of multiple oral doses of S-648414 co-administered with dolutegravir.

Area under the concentration-time curve over the dosing interval τ (24 hours) was calculated by the linear up/log down trapezoidal method.

The PK parameter population

The effect of S-648414 on the PK of dolutegravir was assessed after administration of multiple oral doses of dolutegravir alone and after administration of multiple oral doses of S-648414 co-administered with dolutegravir.

Apparent total clearance calculated as CL/F =Dose/AUC0-τ

The PK parameter population

The PK parameter population

The PK parameter population

Area under the concentration-time curve from time zero to the time of the last quantifiable concentration after dosing, calculated by the linear trapezoidal method when concentrations are increasing and by the logarithmic trapezoidal method when concentrations are decreasing (linear up/log down trapezoidal method).

The PK parameter population

Area under the concentration-time curve extrapolated from time zero to infinity defined as AUC0-last + (Clast/λz), where Clast is the last measurable plasma concentration and λz is the plasma terminal elimination rate constant.

The PK parameter population

Terminal elimination half-life calculated as t1/2,z = (ln2)/λz, where λz is the terminal elimination rate constant.

The PK parameter population

The PK parameter population

Mean residence time, calculated as MRT = AUMC0-inf / AUC0-inf, where AUMC0-inf is the area under the first moment curve extrapolated to infinity.

The PK parameter population

Apparent total clearance estimated according to: CL/F = Dose / AUC0-inf.

The PK parameter population

Apparent volume of distribution in the terminal elimination phase was estimated according to: Vz /F = Dose / AUC0-inf / λz.

The PK parameter population

The fraction of S-648414 dose excreted in urine from 0 to 96 hours postdose was calculated as:

Cumulative amount of S-648414 excreted in urine from time zero to 96 hours postdose (Aeu0-96) / Dose × 100

The PK parameter population

Renal clearance was estimated according to: CLR = cumulative amount of S-648414 excreted in urine from time zero to 96 hours postdose (Aeu0-96) / area under the concentration-time curve from time zero to the time of the last quantifiable concentration after dosing (AUC0-last).

PK parameter population

The PK parameter population with available data at each time point

The PK parameter population with available data at each time point

Area under the concentration-time curve over the dosing interval (24 hours) on Day 1 and Day 14, calculated by the linear up/log down trapezoidal method.

The PK parameter population with available data at each time point

Terminal elimination half-life, where t1/2,z = (ln2)/λz on Day 14.

The PK parameter population with available data

Terminal elimination rate constant, where λz is the magnitude of the slope of the linear regression of the log concentration versus time profile during the terminal phase on Day 14.

The PK parameter population with available data

Apparent total clearance estimated according to: CL/F = Dose/AUC0-τ on Day 14

The PK parameter population with available data

Apparent volume of distribution in the terminal elimination phase on Day 14, estimated according to: Vz /F = Dose/AUC0-τ/λz

The PK parameter population with available data

Fraction of dose excreted in urine over the dosing interval τ (24 hours) on Day 14 calculated as Aeu0-τ/Dose × 100, where Aeu0-τ is the amount of drug excreted in urine over the dosing interval τ (24 hours).

The PK parameter population with available data

Renal clearance on Day 14, calculated as CLR = Aeu0-τ/AUC0-τ, where Aeu0-τ is the amount of drug excreted in urine over the dosing interval τ (24 hours)

The PK parameter population with available data

The effect of S-648414 on the PK of midazolam (a cytochrome P450 3A [CYP3A] substrate) was assessed in Part 2 following 5 mg midazolam administration alone (Day -2) and co-administration with S-648414 30 or 50 mg (Day 14).

The PK parameter population with available data

The effect of S-648414 on the PK of midazolam (a cytochrome P450 3A [CYP3A] substrate) was assessed in Part 2 following 5 mg midazolam administration alone (Day -2) and co-administration with S-648414 30 or 50 mg (Day 14).

The PK parameter population with available data

The effect of S-648414 on the PK of midazolam (a cytochrome P450 3A [CYP3A] substrate) was assessed in Part 2 following 5 mg midazolam administration alone (Day -2) and co-administration with S-648414 30 or 50 mg (Day 14).

Area under the concentration-time curve from time zero to the time of the last quantifiable concentration after dosing, calculated by linear up/log down trapezoidal method.

The PK parameter population with available data

The effect of S-648414 on the PK of midazolam (a cytochrome P450 3A [CYP3A] substrate) was assessed in Part 2 following 5 mg midazolam administration alone (Day -2) and co-administration with S-648414 30 or 50 mg (Day 14).

Area under the concentration-time curve extrapolated from time zero to infinity defined as AUC0-last + (Clast/λz), where Clast is the last measurable plasma concentration and λz is the plasma terminal elimination rate constant.

The PK parameter population with available data

The effect of S-648414 on the PK of midazolam (a cytochrome P450 3A [CYP3A] substrate) was assessed in Part 2 following 5 mg midazolam administration alone (Day -2) and co-administration with S-648414 30 or 50 mg (Day 14).

The PK parameter population with available data

The effect of S-648414 on the PK of midazolam (a cytochrome P450 3A [CYP3A] substrate) was assessed in Part 2 following 5 mg midazolam administration alone (Day -2) and co-administration with S-648414 30 or 50 mg (Day 14).

The PK parameter population with available data

The effect of S-648414 on the PK of midazolam (a cytochrome P450 3A [CYP3A] substrate) was assessed in Part 2 following 5 mg midazolam administration alone (Day -2) and co-administration with S-648414 30 or 50 mg (Day 14).

Mean residence time was calculated as MRT = AUMC0-inf/AUC0-inf where AUMC0-inf is the area under the first moment curve extrapolated to infinity.

The PK parameter population with available data

Continuous 12-lead digital electrocardiogram (ECG) recording was performed on Day 1. The QT interval is a measure between Q and T wave in heart's electrical cycle. ECGs were analyzed at a blinded, central ECG laboratory. At each specified time point, ten 14-second 12-lead ECG tracings were extracted from the continuous recordings. The median QT in each replicate was calculated; the mean of available medians was used as the participant's reportable value at that time point.

QT interval was corrected for heart rate using Fridericia's correction (QTcF). Baseline was defined as the average of the measured ECG intervals from the 3 pre-dose time points (45, 30, and 15 minutes before dosing) on Day 1.

Change from Baseline (ΔQTcF) was calculated based on a linear mixed-effects model with time (categorical), treatment, and time-by-treatment interaction as fixed effects and Baseline QTcF as covariate.

The QT/QTc population included all study participants randomly assigned to study intervention and who took at least 1 dose of study intervention.who had measurements at Baseline as well as on-treatment, with at least 1 post-dose time point with a valid ΔQTcF value. Participants with available data at each time point are included. Cardiodynamic ECG assessments were performed for Part 1 only.

Continuous 12-lead digital electrocardiogram (ECG) recording was performed on Day 1. ECGs were analyzed at a blinded, central ECG laboratory. At each specified time point, ten 14-second 12-lead ECG tracings were extracted from the continuous recordings. The median HR in each replicate was calculated; the mean of available medians was used as the participant's reportable value at that time point.

Baseline was defined as the average of the measured ECG values from the 3 pre-dose time points (45, 30, and 15 minutes before dosing) on Day 1.

Change from Baseline in HR (ΔHR) was calculated based on a linear mixed-effects model with time (categorical), treatment, and time-by-treatment interaction as fixed effects and Baseline HR as covariate.

The QT/QTc population with available data at each time point

Continuous 12-lead digital electrocardiogram (ECG) recording was performed on Day 1. The PR interval is the time from the onset of the P-wave to the start of the next QRS complex. ECGs were analyzed at a blinded, central ECG laboratory. At each specified time point, ten 14-second 12-lead ECG tracings were extracted from the continuous recordings. The median PR in each replicate was calculated; the mean of available medians was used as the participant's reportable value at that time point.

Baseline was defined as the average of the measured ECG intervals from the 3 pre-dose time points (45, 30, and 15 minutes before dosing) on Day 1.

Change from Baseline in PR interval (ΔPR) was calculated based on a linear mixed-effects model with time (categorical), treatment, and time-by-treatment interaction as fixed effects and Baseline PR as covariate.

The QT/QTc population with available data at each time point

Continuous 12-lead digital electrocardiogram (ECG) recording was performed on Day 1. The QRS complex is a combination of the Q wave, R wave and S wave on an ECG tracing, and represents ventricular depolarization. ECGs were analyzed at a blinded, central ECG laboratory. At each specified time point, ten 14-second 12-lead ECG tracings were extracted from the continuous recordings. The median QRS in each replicate was calculated; the mean of available medians was used as the participant's reportable value at that time point.

Baseline was defined as the average of the measured ECG intervals from the 3 pre-dose time points (45, 30, and 15 minutes before dosing) on Day 1.

Change from Baseline in QRS interval (ΔQRS) was calculated based on a linear mixed-effects model with time (categorical), treatment, and time-by-treatment interaction as fixed effects and Baseline QRS as covariate.

The QT/QTc population with available data at each time point

Continuous 12-lead digital electrocardiogram (ECG) recording was performed on Day 1. ECGs were analyzed at a blinded, central ECG laboratory. At each specified time point, ten 14-second 12-lead ECG tracings were extracted from the continuous recordings. The median QT in each replicate was calculated; the mean of available medians was used as the participant's reportable value at that time point.

QT interval was corrected for heart rate using Fridericia's correction (QTcF). Baseline was defined as the average of the measured ECG intervals from the 3 pre-dose time points (45, 30, and 15 minutes before dosing) on Day 1.

Change from Baseline (ΔQTcF) was calculated based on a linear mixed-effects model with time (categorical), treatment, and time-by-treatment interaction as fixed effects and Baseline QTcF as covariate.

Placebo-corrected ΔQTcF (ΔΔQTcF) was calculated as the adjusted mean ΔQTcF in the S-648414 group minus adjusted mean ΔQTcF in the placebo group at each time point.

The QT/QTc population with available data at each time point. The number of participants analyzed includes participants in each S-648414 group with available data; reported values are corrected for placebo data collected for the 12 participants in the Part 1 Placebo group.

Continuous 12-lead digital electrocardiogram (ECG) recording was performed on Day 1. ECGs were analyzed at a blinded, central ECG laboratory. At each specified time point, ten 14-second 12-lead ECG tracings were extracted from the continuous recordings. The median HR in each replicate was calculated; the mean of available medians was used as the participant's reportable value at that time point.

Baseline was defined as the average of the measured values from the 3 pre-dose time points (45, 30, and 15 minutes before dosing) on Day 1.

Change from Baseline (ΔHR) was calculated based on a linear mixed-effects model with time (categorical), treatment, and time-by-treatment interaction as fixed effects and Baseline HR as covariate.

Placebo-corrected ΔHR (ΔΔHR) was calculated as the adjusted mean ΔHR in the S-648414 group minus adjusted mean ΔHR in the placebo group at each time point.

The QT/QTc population with available data at each time point. The number of participants analyzed includes participants in each S-648414 group with available data; reported values are corrected for placebo data collected for the 12 participants in the Part 1 Placebo group.

Continuous 12-lead digital electrocardiogram (ECG) recording was performed on Day 1. ECGs were analyzed at a blinded, central ECG laboratory. At each specified time point, ten 14-second 12-lead ECG tracings were extracted from the continuous recordings. The median PR interval in each replicate was calculated; the mean of available medians was used as the participant's reportable value at that time point.

Baseline was defined as the average of the measured ECG intervals from the 3 pre-dose time points (45, 30, and 15 minutes before dosing) on Day 1.

Change from Baseline (ΔPR) was calculated based on a linear mixed-effects model with time (categorical), treatment, and time-by-treatment interaction as fixed effects and Baseline PR as covariate.

Placebo-corrected ΔPR (ΔΔPR) was calculated as the adjusted mean ΔPR in the S-648414 group minus adjusted mean ΔPR in the placebo group at each time point.

The QT/QTc population with available data at each time point. The number of participants analyzed includes participants in each S-648414 group with available data; reported values are corrected for placebo data collected for the 12 participants in the Part 1 Placebo group.

Continuous 12-lead digital electrocardiogram (ECG) recording was performed on Day 1. ECGs were analyzed at a blinded, central ECG laboratory. At each specified time point, ten 14-second 12-lead ECG tracings were extracted from the continuous recordings. The median QRS duration in each replicate was calculated; the mean of available medians was used as the participant's reportable value at that time point.

Baseline was defined as the average of the measured ECG intervals from the 3 pre-dose time points (45, 30, and 15 minutes before dosing) on Day 1.

Change from Baseline in QRS duration (ΔQRS) was calculated based on a linear mixed-effects model with time (categorical), treatment, and time-by-treatment interaction as fixed effects and Baseline QRS as covariate.

Placebo-corrected ΔQRS (ΔΔQRS) was calculated as the adjusted mean ΔQRS in the S-648414 group minus adjusted mean ΔQRS in the placebo group at each time point.

The QT/QTc population with available data at each time point. The number of participants analyzed includes participants in each S-648414 group with available data; reported values are corrected for placebo data collected for the 12 participants in the Part 1 Placebo group.

A participant was determined as an outlier if the following criteria (assessed separately) were met for the ECG intervals at any time point:

QTcF:

• Treatment-emergent value of > 450 and ≤ 480 ms when not present at Baseline (new onset)
• Treatment-emergent value of > 480 and ≤ 500 ms when not present at Baseline (new onset)
• Treatment-emergent value of > 500 ms when not present at Baseline (new onset)
• Increase of QTcF (ΔQTcF) from Baseline of > 30 and ≤ 60 ms
• Increase of QTcF from Baseline > 60 ms

HR:

• Decrease of HR from Baseline > 25% resulting in HR < 50 bpm
• Increase of HR from Baseline > 25% resulting in HR > 100 bpm

PR:

• Increase of PR from Baseline > 25% resulting in PR > 200 ms

QRS:

• Increase of QRS from Baseline > 25% resulting in QRS > 120 ms

QT/QTc population

T-wave abnormalities were categorized as follows:

• Normal T wave: Any positive T wave not meeting any criterion below
• Flat T wave: T amplitude < 1 mm (either positive or negative) including flat isoelectric line
• Notched T wave (+): Presence of notch(es) of at least 0.05 mV amplitude on ascending or descending arm of the positive T wave
• Biphasic: T wave that contains a second component with an opposite phase that is at least 0.1 mV deep (both positive/negative and negative/positive and polyphasic T waves included)
• Normal T wave (-): T amplitude that is negative, without biphasic T wave or notches
• Notched T wave (-): Presence of notch(es) of at least 0.05 mV amplitude on descending or ascending arm of the negative T wave
• U waves: Presence of abnormal U waves

QT/QTc population)