Trial Outcomes & Findings for Study to Evaluate Safety and Tolerability of a Single Dose of PF-06741086 in Chinese Adult Participants With Severe Hemophilia (NCT NCT04878731)

A total of 6 participants were enrolled and received a single dose of marstacimab 300 mg.

Study to Evaluate Safety and Tolerability of a Single Dose of PF-06741086 in Chinese Adult Participants With Severe Hemophilia

An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship with study treatment. TEAEs=AEs that started during the effective duration of treatment regardless of whether a similar event existed at baseline. Grades of AEs were defined by National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) version 5.0. Grade 1=asymptomatic/mild symptoms, clinical or diagnostic observations only, intervention not indicated;Grade 2=minimal, local or noninvasive intervention indicated, limiting age-appropriate instrumental activity of daily living (ADL);Grade 3=severe or medically significant but not immediately life-threatening, hospitalization of prolongation of hospitalization indicated; disabling limiting self-care ADL;Grade 4=events with life-threatening consequences, urgent intervention indicated;Grade 5= death related to AE.Treatment-related TEAEs were determined by investigator.

An SAE was any untoward medical occurrence at any dose that resulted in death; was life threatening; required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent disability/incapacity; was a congenital anomaly/birth defect. Treatment-related SAEs were determined by the investigator.

An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship with study treatment. TEAEs=AEs that started during the effective duration of treatment regardless of whether a similar event existed in the baseline period. Grades of AEs were defined by NCI CTCAE version 5.0. Grade 1=asymptomatic/mild symptoms, clinical or diagnostic observations only, intervention not indicated; Grade 2=minimal, local or noninvasive intervention indicated, limiting age-appropriate instrumental activity of daily living (ADL); Grade 3=severe or medically significant but not immediately life-threatening, hospitalization of prolongation of hospitalization indicated; disabling limiting self-care ADL; Grade 4=events with life-threatening consequences, urgent intervention indicated; Grade 5= death related to AE. Treatment-related TEAEs were determined by the investigator.

An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship with study treatment. TEAEs=AEs that started during the effective duration of treatment regardless of whether a similar event of equal or greater severity existed in the baseline period. Grades of AEs were defined by NCI CTCAE version 5.0. Grade 1=asymptomatic/mild symptoms, clinical or diagnostic observations only, intervention not indicated; Grade 2=minimal, local or noninvasive intervention indicated, limiting age-appropriate instrumental activity of daily living (ADL); Grade 3=severe or medically significant but not immediately life-threatening, hospitalization of prolongation of hospitalization indicated; disabling limiting self-care ADL; Grade 4=events with life-threatening consequences, urgent intervention indicated; Grade 5= death related to AE. Treatment-related TEAEs were determined by the investigator.

Laboratory assessments included chemistry, hematology, Prothrombin Time/International Normalized Ratio (PT/INR), Activated Partial Thromboplastin Time (APTT), urinalysis, fibrinogen, Antithrombin III (ATIII) activity, and Cardiac Troponin I (cTnI). Laboratory test abnormalities reported by at least 1 participant are reported in this outcome measure. ULN = upper limit of normal.

PT is one of the laboratory tests to evaluate the ability of blood clotting. The INR is derived from PT which is calculated as a ratio of a participant's PT to a control PT standardized for the potency of the thromboplastin reagent developed by the World Health Organization (WHO) using the following formula: INR = Participant PT / Control PT. Blood samples were obtained to evaluate PT/INR.

PT is one of the laboratory tests to evaluate the ability of blood clotting. The INR is derived from PT which is calculated as a ratio of a participant's PT to a control PT standardized for the potency of the thromboplastin reagent developed by the WHO using the following formula: INR = Participant PT / Control PT. Blood samples were obtained to evaluate PT/INR.

The APTT is a screening test that helps evaluate a person's ability to appropriately form blood clots. It measures the number of seconds it takes for a clot to form in a sample of blood after substances (reagents) are added. Blood samples were obtained to evaluate APTT.

The APTT is a screening test that helps evaluate a person's ability to appropriately form blood clots. It measures the number of seconds it takes for a clot to form in a sample of blood after substances (reagents) are added. Blood samples were obtained to evaluate APTT.

Fibrinogen is a protein, specifically a clotting factor (factor I), that is essential for proper blood clot formation. Blood samples were obtained to evaluate the amount of fibrinogen.

Fibrinogen is a protein, specifically a clotting factor (factor I), that is essential for proper blood clot formation. Blood samples were obtained to evaluate the amount of fibrinogen.

ATIII is a nonvitamin K-dependent protease that inhibits coagulation by lysing thrombin and factor Xa. The antithrombin activity test measures how well the protein inhibits thrombin, with a reference range of 75% - 125%. Blood samples were obtained to evaluate ATIII activity.

ATIII is a nonvitamin K-dependent protease that inhibits coagulation by lysing thrombin and factor Xa. The antithrombin activity test measures how well the protein inhibits thrombin, with a reference range of 75% - 125%. Blood samples were obtained to evaluate ATIII activity.

cTnI is one of the cardiac regulatory proteins that control the calcium mediated interaction between actin and myosin, and is considered a specific marker for cardiac damage. Blood samples were obtained to evaluate the amount of cTnI.

cTnI is one of the cardiac regulatory proteins that control the calcium mediated interaction between actin and myosin, and is considered a specific marker for cardiac damage. Blood samples were obtained to evaluate the amount of cTnI.

Vital signs measurements included blood pressure (BP), pulse rate, respiratory rate and oral temperature. Categorical classes for vital signs of potential clinical concern included: (1) systolic BP - minimum (min) value \<90 mmHg, maximum (max) decrease/increase from baseline \>=30 mmHg; (2) diastolic BP - min value \<50 mmHg, max decrease/increase from baseline \>=20 mmHg; (3) supine pulse rate - min \<40 beat per minute (bpm) or max \>120 bpm; (4) standing pulse rate - min \<40 bpm or max \>140 bpm; (5) oral temperature \> 38.5 celsius degree (°C). BPs were measured in a supine position so standing BPs were not evaluated and not reported.

BPs were assessed in a supine position with a completely automated device. Categorical classes for supine systolic BP of potential clinical concern included min value \<90 mmHg, max decrease/increase from baseline \>=30 mmHg.

BPs were assessed in a supine position with a completely automated device. Categorical classes for supine diastolic BP of potential clinical concern included min value \<50 mmHg, max decrease/increase from baseline \>=20 mmHg.

Pulse rates were assessed in a supine position with a completely automated device. Categorical classes for supine pulse rate of potential clinical concern included min value \<40 bpm or max value \>120 bpm.

No eating, drinking, or smoking was allowed for 15 minutes prior to the measurement of oral temperature. The criterion for oral temperature of potential clinical concern was oral temperature \> 38.5°C.

Respiratory rate measurement was preceded by at least 5 minutes of rest for the participant in a quiet setting without distractions. Respiratory rate was measured in terms of "breaths per minute", and was measured by observing and counting the respirations of the participant for 30 seconds and multiplied by 2.

Single 12-lead ECGs were performed for all participants in a supine position using an ECG machine that automatically calculated heart rate and measured PR, QRS and QT intervals. If a single time point ECG was abnormal, a triplicate ECG was required and obtained approximately 2-4 minutes apart; the average of triplicate ECG measurements collected at pre-dose Day 1 served as each participant's baseline value. Categorical classes for ECG data of potential clinical concern included: (1) QTcF - 450 millisecond (msec)≤ max value \<480 msec, 480 msec ≤ max value \<500 msec, max value ≥500 msec; 30 msec ≤ QTcF max increase from baseline \<60 msec; max increase from baseline ≥60 msec; (2) PR interval - max value ≥300 msec, baseline value\>200 and max increase from baseline ≥25%, baseline value ≤200 and max increase from baseline ≥50%; (3) QRS interval - max value ≥140 msec, increase from baseline ≥50%.

Heart rate was measured in terms of "beats per minute". Single 12-lead ECGs were performed for all participants in a supine position using an ECG machine that automatically calculated the heart rate and measured PR, QRS, and QT intervals. If a single time point ECG was abnormal, a triplicate ECG was required, which were obtained approximately 2-4 minutes apart; the average of the triplicate ECG measurements collected at pre-dose Day 1 served as each participant's baseline value.

Single 12-lead ECGs were performed for all participants in a supine position using an ECG machine that automatically calculated the heart rate and measured PR, QRS, and QT intervals. Categorical classes for PR interval data of potential clinical concern included: max value ≥300 ms, baseline value\>200 and max increase from baseline≥25%, baseline value ≤200 and max increase from baseline ≥50%.

Single 12-lead ECGs were performed for all participants in a supine position using an ECG machine that automatically calculated the heart rate and measured PR, QRS, and QT intervals. Categorical classes for QRS interval data of potential clinical concern included: max value ≥140 ms, increase from baseline ≥50%.

Single 12-lead ECGs were performed for all participants in a supine position using an ECG machine that automatically calculated the heart rate and measured PR, QRS, and QT intervals.

Single 12-lead ECGs were performed for all participants in a supine position using an ECG machine that automatically calculated the heart rate and measured PR, QRS, and QT intervals. The corrected QT interval (QTc) estimates the QT interval at a standard heart rate of 60 bpm.

Single 12-lead ECGs were performed for all participants in a supine position using an ECG machine that automatically calculated the heart rate and measured PR, QRS, and QT intervals. QTcF = QT interval corrected using the Fridericia method. Categorical classes for QTcF data of potential clinical concern included: 450 ms≤ max value \<480 ms, 480≤ max value \<500 ms, max value ≥500 ms; 30 ms ≤ QTcF max increase from baseline \<60 ms; max increase from baseline ≥60 ms.

A complete PE included assessments of the head, ears, eyes, nose, mouth, skin, heart and lung examinations, lymph nodes, gastrointestinal, musculoskeletal, and neurological systems. A brief PE included assessments of the general appearance, the respiratory and cardiovascular systems, as well as participant reported symptoms. The full PE planned for Screening may have been performed on Day -1 before dosing at the discretion of the Investigator. If a full PE was done at Screening visit, a brief PE was to be conducted on Day-1. After Day -1, brief examinations based on signs and symptoms may have been performed if clinically indicated at the discretion of the Investigator to assess changes from baseline/previous visits of any ongoing symptoms.

Grades of injection site reactions were defined according to NCI CTCAE version 5.0. Grade 1=Tenderness with or without associated symptoms (eg, warmth, erythema, itching); Grade 2= Pain, lipodystrophy, edema, phlebitis; Grade 3= Ulceration or necrosis, severe tissue damage, operative intervention indicated; Grade 4=Life-threatening consequences, urgent intervention indicated; Grade 5=death. Participants with any grade of injection site reaction are reported in this outcome measure.

Mean plasma concentration of marstacimab after participants received a single SC injection of marstacimab 300 mg.

Maximum plasma concentration of marstacimab after participants received a single SC injection of marstacimab 300 mg.

Time for Cmax of marstacimab after participants received a single SC injection of marstacimab 300 mg.

Area under the plasma concentration-time profile from time zero to the time of the last quantifiable concentration of marstacimab after participants received a single SC injection of marstacimab 300 mg.

Area under the concentration time curve from time zero to infinity of marstacimab after participants received a single SC injection of marstacimab 300 mg.

Terminal half life (t1/2) of marstacimab after participants received a single SC injection of marstacimab 300 mg. t1/2 is defined as the time for plasma concentration to decrease by one half.

Apparent volume of distribution of marstacimab after participants received a single SC injection of marstacimab 300 mg. Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Vz/F was influenced by the fraction absorbed. Vz/F was calculated as dose/AUCinf. AUCinf = area under the concentration time curve from time zero to infinity.

Apparent clearance (CL/F) of marstacimab after participants received a single SC injection of marstacimab 300 mg. Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. CL/F was calculated as Dose/ (AUCinf\*kel). AUCinf = area under the concentration time curve from time zero to infinity. kel = terminal phase rate constant calculated by a linear regression of the log linear concentration time curve.

TFPI is a protease inhibitor, which acts as an antagonist of the extrinsic coagulation pathway via inhibition of tissue factor-activated coagulation factor VII (FVIIa) and activated factor X (FXa). Plasma total TFPI levels were measured to reflect target binding with marstacimab. TFPI in results represented total TFPI.

A change from baseline-time profile was established based on changes from baseline in TFPI at specific time points. Area under the TFPI change from baseline-time profile from time zero (Day 1) to Day 7, from time zero to Day 14 and from time zero to Day 28 are presented in this outcome measure. TFPI represented total TFPI.

PF1+2 is an in vivo endpoint reflective of coagulation pathway activation. Maximum increase from baseline for PF 1+2 was provided.

A change from baseline-time profile was established based on changes from baseline in PF 1+2 at specific time points. Area under the PF 1+2 change from baseline-time profile from time zero (Day 1) to Day 7, from time zero to Day 14 and from time zero to Day 28 are presented in this outcome measure.

D-dimer is an in vivo endpoint reflective of coagulation pathway activation. Maximum increase from baseline for D-Dimer is provided.

A change from baseline-time profile was established based on changes from baseline in D-dimer at specific time points. Area under the D-dimer change from baseline-time profile from time zero (Day 1) to Day 7, from time zero to Day 14 and from time zero to Day 28 are presented in this outcome measure.

The dilute prothrombin time (dPT) is an ex vivo endpoint reflective of coagulation pathway activation. Maximum decrease from baseline for dPT is provided.

A change from baseline-time profile was established based on changes from baseline in dPT at specific time points. Area under the dPT change from baseline-time profile from time zero (Day 1) to Day 7, from time zero to Day 14 and from time zero to Day 28 are presented in this outcome measure.

TGA lag time is an ex vivo endpoint reflective of coagulation pathway activation. Maximum decrease from baseline for TGA Lag Time is provided.

A change from baseline-time profile was established based on changes from baseline in TGA lag time at specific time points. Area under the TGA lag time change from baseline-time profile from time zero (Day 1) to Day 7, from time zero to Day 14 and from time zero to Day 28 are presented in this outcome measure.

TGA peak is an ex vivo endpoint reflective of coagulation pathway activation. Maximum increase from baseline for TGA Peak is provided.

A change from baseline-time profile was established based on changes from baseline in TGA peak at specific time points. Area under the TGA peak change from baseline-time profile from time zero (Day 1) to Day 7, from time zero to Day 14 and from time zero to Day 28 are presented in this outcome measure.

TGA EGTP is an ex vivo endpoint reflective of coagulation pathway activation. Maximum increase from baseline for TGA Endogenous Thrombin Potential is provided.

A change from baseline-time profile was established based on changes from baseline in TGA EGTP at specific time points. Area under the TGA EGTP change from baseline-time profile from time zero (Day 1) to Day 7, from time zero to Day 14 and from time zero to Day 28 are presented in this outcome measure.

Summary of ADA incidence by visit is presented. ADA positive was defined as titer \>=1.54.

Summary of NAb incidence by visit is presented. NAb positive was defined as titer \>=1.08. ADA-positive participants (defined as titer \>=1.54) were analyzed for NAb.