A Study of Milvexian Using an IV Microtracer With Additional Formulation and Food Effect Comparison in Healthy Participants

Absolute bioavailability is defined as the amount of drug from a formulation that reaches the systemic circulation relative to an intravenous (IV) dose. Treatment A (milvexian oral solution with IV microdose) was assessed versus each treatment phase of milvexian administered as: a oral solution (fasted), high dose SDD (Spray-Dried Dispersion) capsule (fed and fasted) and low dose SDD capsule (fed and fasted).

The number of participants experiencing AEs following single oral and IV administration. AEs are defined as any unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or disease temporally associated with the use of study treatment, whether or not considered related to the study treatment.

The number of participants experiencing SAEs following single oral and IV administration. SAEs are defined as any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalization or causes prolongation of existing hospitalization.

Occurrence of abnormalities in vital sign measurements exceeding pre-defined thresholds following single oral and IV administration. The pre-defined thresholds include:

Heart Rate(bpm) Value > 100 and change from baseline > 30, or Value < 55 and change from baseline < -15 Systolic Blood Pressure(mmHg) Value > 140 and change from baseline > 20, or Value < 90 and change from baseline < -20 Diastolic Blood Pressure(mmHg) Value > 90 and change from baseline > 10, or Value < 55 and change from baseline < -10 Respiratory Rate(breaths/min) Value > 16 or change from baseline > 10 Temperature (°C) Value > 38.3°C or change from baseline > 1.6°C

The number of participants with abnormal findings on ECGs following single oral and IV administration. Participants with ECG intervals outside of a pre-specified range and investigator identified ECG abnormalities will be listed. The following criteria will be used to determine ECG results that are outside of a pre-specified range:

PR (msec)-Value > 200; QRS (msec)-Value > 120; QT (msec)-Value > 500 or change from baseline > 30; QTcF (msec)-Value > 450 or change from baseline > 30

The number of participants with abnormal findings on physical examinations following single oral and IV administration.

Number of participants with abnormalities in clinical lab test measurements exceeding pre-defined thresholds following single oral and IV administration. The pre-defined thresholds include:

Alanine transaminase > 3 × upper limit of normal (ULN) Aspartate transaminase > 3 × ULN Alkaline phosphatase > 1.5 × ULN Total bilirubin > 2 × ULN

Cmax is defined as the maximum observed plasma concentration following single administration in the fed and fasted states to healthy participants.

Tmax is defined as the time of maximum observed plasma concentration in the fed and fasted states to healthy participants.

AUC(0-T) is defined as the area under the plasma concentration-time curve from time zero to time of last quantifiable concentration following single administration in the fed and fasted states to healthy participants.

AUC(INF) is defined as area under the concentration-time curve from time zero extrapolated to infinity following single administration in the fed and fasted states to healthy participants

CLT/F is defined as the apparent clearance of drug after extravascular administration.

CLR is defined as the volume of plasma completely cleared of a substance by the kidneys per unit of time, in this case by hour.

Vz/F is defined as the apparent volume of distribution at terminal phase after extravascular administration.

Ae is defined as the total amount of unchanged drug excreted into the urine following single administration in the fed and fasted states to healthy participants

%UR is defined as a percent or absolute amount of dose that is recovered in the urine as the unchanged drug.

T-HALF is defined as the time required for half the quantity of a drug to be metabolized or eliminated by normal biological processes.

Mean residence time (MRT) represents the average time the drug stays in the body and is evaluated for the IV dose of Treatment A only.

Characterize the IV dose of Treatment A by Vss, which is defined as the apparent volume of distribution at steady state

Point estimates and 90% CI for the ratio of geometric means for Cmax will be constructed for the comparison of each milvexian capsule treatment (Treatments B, C, D, and E) separately versus the oral solution (Treatment A). No data is reported for Treatment A because it is the comparison treatment.

Relative bioavailability is defined as the amount of drug from a formulation that reaches the systemic circulation relative to a different formulation (non-IV) such as an oral solution. Cmax is defined as the maximum observed plasma concentration.

Point estimates and 90% CI for the ratio of geometric means for AUC(0-T) and AUC(INF) will be constructed for the comparison of each milvexian capsule treatment (Treatments B, C, D, and E) separately versus the oral solution (Treatment A). No data is reported for Treatment A because it is the comparison treatment.

Relative bioavailability is defined as the amount of drug from a formulation that reaches the systemic circulation relative to a different formulation (non-IV) such as an oral solution. AUC(0-T) is defined as the area under the plasma concentration-time curve from time zero to time of last quantifiable concentration. AUC(INF) is defined as area under the concentration-time curve from time zero extrapolated to infinity.

Food effect analysis of the high and low dose SDD capsules based on ratios of Cmax. The food effect analysis will be run separately for each dose level. For the low dose level, low dose milvexian SDD fed (Treatment C) is the test treatment and low dose milvexian SDD fasted (Treatment D) is the reference treatment. For the high dose dose level, high dose milvexian SDD fed (Treatment E) is the test treatment and high dose milvexian SDD fasted (Treatment B) is the reference treatment.

Cmax is defined as the maximum observed plasma concentration.

Food effect with low and high dose SDD capsules based on ratios of AUC(0-T) and AUC(INF). The food effect analysis will be run separately for each dose level. For the low dose level, low dose milvexian SDD fed (Treatment C) is the test treatment and low dose milvexian SDD fasted (Treatment D) is the reference treatment. For the high dose level, high dose milvexian SDD fed (Treatment E) is the test treatment and high dose milvexian SDD fasted (Treatment B) is the reference treatment.

AUC(0-T) is defined as the area under the plasma concentration-time curve from time zero to time of last quantifiable concentration.

AUC(INF) is defined as area under the concentration-time curve from time zero extrapolated to infinity.