A Phase 3 Open-label Interventional Study of Intravenous Recombinant Coagulation Factor VIII Fc-von Willebrand Factor-XTEN Fusion Protein, Efanesoctocog Alfa (BIVV001), in Patients With Severe Hemophilia A

ABR is annualized number of treated bleeding episodes (BE) per participant per year. Treated Bleeding episode: any occurrence of hemorrhage that required administration of BIVV001. It started from 1st sign of bleed and ended no more than 72 hours after last injection to treat bleeding episode, any subsequent bleeding at same location/injections administered less than or equal to (<=) 72 hours apart from previous injection were considered same bleeding episode. ABR=number of treated BE during efficacy period (EP)/number of days during EP*365.25. EP reflects the sum of all intervals of time during which participants were treated with BIVV001 according to the study arms and treatment regimens. This outcome measure (OM) presents estimated results (i.e., results estimated by fitting negative binomial [NB] regression model on data collected during EP).

ABR is annualized number of treated bleeding episodes per participant per year. Treated Bleeding episode: any occurrence of hemorrhage that required administration of BIVV001. It started from 1st sign of bleed and ended no more than 72 hours after last injection to treat bleeding episode, any subsequent bleeding at same location/injections administered <=72 hours apart from previous injection were considered same bleeding episode. ABR=number of treated bleeding episodes during EP/number of days during EP*365.25. EP reflects the sum of all intervals of time during which participants were treated with BIVV001 according to the study arms and treatment regimens. This OM presents observed results (i.e., descriptive statistics values based on the data which was collected during EP).

ABR is annualized number of treated bleeding episodes per participant per year. Treated Bleeding episode: any occurrence of hemorrhage that required administration of BIVV001. It started from 1st sign of bleed and ended no more than 72 hours after last injection to treat bleeding episode, any subsequent bleeding at same location/injections administered <=72 hours apart from previous injection were considered same bleeding episode. ABR=number of treated bleeding episodes during EP/number of days during EP*365.25. EP reflects the sum of all intervals of time during which participants were treated with BIVV001 according to the study arms and treatment regimens. This OM presents estimated results (i.e., results received estimated by fitting NB regression model on data collected during EP).

ABR is annualized number of treated bleeding episodes per participant per year. Treated Bleeding episode: any occurrence of hemorrhage that required administration of BIVV001. It started from 1st sign of bleed and ended no more than 72 hours after last injection to treat bleeding episode, any subsequent bleeding at same location/injections administered <=72 hours apart from previous injection were considered same bleeding episode. ABR=number of treated bleeding episodes during EP/number of days during EP*365.25. EP reflects the sum of all intervals of time during which participants were treated with BIVV001 according to the study arms and treatment regimens. This OM presents observed results (i.e., descriptive statistics values based on the data which was collected during EP).

ABR is annualized number of treated bleeding episodes per participant per year. Treated Bleeding episode: any occurrence of hemorrhage that required administration of BIVV001. It started from 1st sign of bleed and ended no more than 72 hours after last injection to treat bleeding episode, any subsequent bleeding at same location/injections administered <=72 hours apart from previous injection were considered same bleeding episode. ABR=number of treated bleeding episodes during EP/number of days during EP*365.25. EP reflects the sum of all intervals of time during which participants were treated with BIVV001 according to the study arms and treatment regimens. This OM presents estimated results (i.e., results received estimated by fitting NB regression model on data collected during EP).

ABR is annualized number of treated bleeding episodes per participant per year. Treated Bleeding episode: any occurrence of hemorrhage that required administration of BIVV001. It started from 1st sign of bleed and ended no more than 72 hours after last injection to treat bleeding episode, any subsequent bleeding at same location/injections administered <=72 hours apart from previous injection were considered same bleeding episode. ABR=number of treated bleeding episodes during EP/number of days during EP*365.25. EP reflects the sum of all intervals of time during which participants were treated with BIVV001 according to the study arms and treatment regimens. This OM presents observed results (i.e., descriptive statistics values based on the data which was collected during EP).

Haem-A-QoL is a participant-reported questionnaire designed for adult participants (greater than or equal to [>=] 17 years of age) with hemophilia; and consisted of 46 items comprising 10 domains (physical health [5 items], feelings [4 items], view of self [5 items], sports and leisure [5 items], work and school [4 items], dealing with hemophilia [3 items], treatment [8 items], future [5 items], family planning [4 items], partnership and sexuality [3 items]). Items were rated along five response options: never, rarely, sometimes, often, or all the time. Raw score for physical health domain were transformed to a scale ranged from 0 to 100, where lower scores denoted better physical health. Change from baseline in physical Health domain score was reported in this OM.

PROMIS is a system of reliable and precise measures of participant-reported heath status. PROMIS measures cover physical, mental and social health and can be used for many chronic conditions. PROMIS - Pain Intensity - Short Form 3a consisted of 3 questions, participants reported for the intensity of pain experienced in the past 7 days. Each question had 5 responses scored between 1 (had no pain) to 5 (very severe pain). Total PROMIS pain intensity 3a score range was from 3 (no pain) to 15 (very severe pain), where higher score indicated more intense pain. Total raw score was converted into a T-score which rescaled raw score into standardized score with mean of 50 and standard deviation (SD) of 10. Higher PROMIS T-score represented worst outcome. For PROMIS pain intensity 3a, T-score of 60 was one SD worse than average.

HJHS is a validated 11-item scoring tool developed for the assessment of joint health in participants with hemophilia. It comprised an evaluation of the elbows, knee and ankle joints: swelling (0 to 3), duration of swelling (0 and 1), muscle atrophy (0 to 2), crepitus on motion (0 to 2), flexion loss (0 to 3), extension loss (0 to 3), joint pain (0 to 2) and strength (0 to 4), in each item 0 = none and higher score = severe damage and global gait (walking, stairs, running, hopping on 1 leg) scored on scale ranged from 0 to 4, where 0 = all skills in normal limit and 4 = no skills within normal limits). Total HJHS score = sum of joint totals (0 to 120) + general gait (1 to 4) and ranged from 0 (no joint damage) to 124 (severe joint damage), where higher score indicated severe joint damage.

ABR: annualized number of treated bleeding episodes per participant per year. EP reflects sum of all intervals of time during which participants were treated with BIVV001 according to study arms and treatment regimens. Treated bleeding episode: episode that started from 1st sign of bleed and ended no more than 72 hours after last injection to treat bleeding episode, any subsequent bleeding at same location/injections administered <=72 hours apart from previous injection were considered same bleeding episode. Any bleed at different location was considered as separate bleeding episode, regardless of time from last injection. Spontaneous bleeding: bleeding episode without contributing factor (definite trauma/antecedent "strenuous" activity). Traumatic bleeding: bleeding episode with known/believed reason for bleed.

ABR: annualized number of treated bleeding episodes per participant per year. Efficacy period reflects sum of all intervals of time during which participants were treated with BIVV001 according to study arms and treatment regimens. Treated bleeding episode: episode that started from 1st sign of bleed and ended no more than 72 hours after last injection to treat bleeding episode, any subsequent bleeding at same location/injections administered <=72 hours apart from previous injection were considered same bleeding episode. Any bleed at different location was considered as separate bleeding episode, regardless of time from last injection. Spontaneous bleeding: bleeding episode without contributing factor (definite trauma/antecedent "strenuous" activity). Traumatic bleeding: bleeding episode with known/believed reason for bleed.

ABR: annualized number of all bleeding (treated and untreated) episodes/participant/year. ABR = number of all bleeding episodes during EP/number of days in EP*365.25. EP reflects sum of all time intervals during which participants were treated with BIVV001 according to study arms and treatment regimens. Bleeding episode: episode started from 1st sign of bleed and ended no more than 72 hours after last injection to treat bleeding episode, any subsequent bleeding at same location/injections administered <=72 hours apart from previous injection were considered same bleeding episode. Any bleed at different location: considered as separate bleeding episode, regardless of time from last injection. Spontaneous: bleeding without contributing factor (definite trauma/antecedent "strenuous" activity). Traumatic: bleeding with known/believed reason.

ABR is annualized number of treated bleeding episodes per participant per year. Treated Bleeding episode: any occurrence of hemorrhage that required administration of BIVV001. It started from 1st sign of bleed and ended no more than 72 hours after last injection to treat bleeding episode, any subsequent bleeding at same location/injections administered <=72 hours apart from previous injection were considered same bleeding episode. ABR = (Number of treated bleeding episodes during EP/number of days during EP*365.25. EP reflects the sum of all intervals of time during which participants were treated with BIVV001 according to the study arms and treatment regimens.

FVIII activity level was measured using activated partial thromboplastin time (aPTT)-based one stage clotting assay. Percentage of participants who achieved steady-state trough FVIII activity levels above (>) 1%, 5%, 10%, 15%, and 20% were reported for Arm A: Prophylaxis in this OM. Participants were counted in more than one row, as applicable.

The number of injections required to resolve each bleeding episode was averaged across all bleeding episodes per participant. A bleeding episode was defined as an episode that started from 1st sign of bleed and ended no more than 72 hours after last injection to treat bleeding episode, any subsequent bleeding at same location or injections administered <=72 hours apart from previous injection were considered same bleeding episode.

The total dose (IU/kg) used to resolve each bleeding episode was averaged across all bleeding episodes per participant. A bleeding episode was defined as an episode that started from 1st sign of bleed and ended no more than 72 hours after last injection to treat bleeding episode, any subsequent bleeding at same location or injections administered <=72 hours apart from previous injection were considered same bleeding episode.

A bleeding episode was defined as an episode that started from 1st sign of bleed and ended no more than 72 hours after last injection to treat bleeding episode, any subsequent bleeding at same location or injections administered <=72 hours apart from previous injection were considered same bleeding episode. Percentage of bleeding episodes (of all bleeding episodes occurred) which were treated with single injection was reported in this OM.

The participant's response related to each injection of BIVV001 treatment for treating a bleed was evaluated using ISTH 4-point response scale categorized as: Excellent (complete pain relief/complete resolution of signs of bleeding), Good (significant pain relief/improvement in signs of bleeding), Moderate (modest pain relief/improvement in signs of bleeding) and none (no or minimal improvement/condition worsened). Assessment was performed approximately 72 hours after the initial treatment for the bleeding episode. Bleeding episode was defined as an episode that started from first sign of a bleed and ended no more than 72 hours after last treatment for bleed, within which any symptoms of bleeding at same location or injections <=72 hours apart were considered same bleeding episode. Participants were counted in more than one row, as applicable.

Physicians assessed participant's response to BIVV001 treatment using 4-point response scale: Excellent=bleeding episodes (BE) responded to fewer than/usual number of injections/less than/usual dose of FVIII/rate of breakthrough bleeding during prophylaxis was <= that usually observed; Effective = most BE responded to same number of injections and dose, but some required more injections/higher doses/there was minor increase in rate of breakthrough bleeding; partially effective = BE most often required more injections and/or higher doses than expected/adequate breakthrough bleeding prevention during prophylaxis required more frequent injections and/or higher doses; Ineffective = routine failure to control hemostasis or hemostatic control required additional agents. Percentages were based on total number of responses.

Total annualized BIVV001 consumption (in IU/kg) was calculated for each participant as: Total IU/kg of BIVV001 during EP divided by total number of days during EP*365.25. EP reflects the sum of all intervals of time during which participants were treated with BIVV001 according to the study arms and treatment regimens.

HJHS is a validated 11-item scoring tool developed for the assessment of joint health in participants with hemophilia. Following domains were assessed for elbows, knee and ankle joints: swelling (score 0 = no swelling to 3=severe), duration of swelling (score 0 = no swelling and 1 = >=6 months), muscle atrophy (score 0 = none to 2 = severe), crepitus on motion (score 0 = none to 2=severe), flexion loss (score 0 = <5' to 3 = >20'), extension loss (score 0 = <5' to 3 = >20'), joint pain (score 0 = no pain through active range of motion to 2 = pain through active range) and strength (score 0 = holds test position with maximum resistance to 4 = trace/no muscle contraction), in each item 0 = none and higher score = severe damage.

AJBR: annualized number of joint bleeding/participant/year. ABR = number of treated joint bleeding episodes during EP divided by total number of days during EP*365.25. Joint bleeding episode: an unusual sensation in joint ('aura') in combination with 1) increasing swelling/warmth over skin, joint; 2) increasing pain or 3) progressive loss of range of motion or difficulty in using limb as compared with Baseline. Bleeding episode (BE): episode that started from first sign of bleed and ended no more than 72 hours after last treatment for bleed, within which any symptoms of bleeding at same location/injections <=72 hours apart were considered same bleeding episode. EP reflects the sum of all intervals of time during which participants were treated with BIVV001 according to study arms and treatment regimens.

AJBR: annualized number of joint bleeding/participant/year. ABR = number of treated joint bleeding episodes during EP divided by total number of days during EP*365.25. Joint bleeding episode: unusual sensation in joint ('aura') with 1) in combination with increasing swelling/warmth over skin, joint; 2) increasing pain or 3) progressive loss of range of motion or difficulty in using limb as compared with Baseline. BE: episode that started from first sign of bleed and ended no more than 72 hours after last treatment for bleed, within which any symptoms of bleeding at same location/injections <= 72 hours apart were considered same bleeding episode. EP reflects sum of all intervals of time during which participants were treated with BIVV001 according to study arms and treatment regimens.

A target joint at baseline was defined as a major joint with >=3 spontaneous bleeding episodes in a consecutive 6 month period prior to entry to the study, captured at Baseline. A target joint resolved was defined as <=2 spontaneous bleeds into that joint during 12 months of continuous exposure. Total number of target joints resolved at Week 52 were reported.

Haem-A-QoL: participant-reported questionnaire designed for adult participants (>=17 years of age) with hemophilia; and consisted of 46 items comprising 10 domains (physical health [5 items], feelings [4 items], view of self [5 items], sports and leisure [5 items], work and school [4 items], dealing with hemophilia [3 items], treatment [8 items], future [5 items], family planning [4 items], partnership and sexuality [3 items]). Items were rated along 5 response options: 1=never, 2=rarely, 3=sometimes,4=often, and 5=all the time and higher scores represent greater impairment. Raw score for each domain were transformed to a scale ranged between 0 and 100, where lower scores denoted better physical health. Haem-A-QoL Total Score was average of all domain scores and ranged from 0 to 100, where lower scores = better quality of life.

PROMIS-SF v2.0 PF 6b consisted of 2-items from item-improved Health Assessment Questionnaire (HAQ) and 4-items from item-improved Physical Function-10 (PF-10) instruments. Both of these instruments assessed participant's present abilities and had 5-response options: HAQ: 1=without any difficulty, 2=with little difficulty, 3=with some difficulty, 4=with much difficulty,5=unable to do and PF-10: 1=not at all, 2=very little, 3=somewhat, 4=quite a lot, 5=cannot do. Total score of PROMIS-SF PF 6b: average scores of component items, which ranged from 0 (no disability) to 100 (worst disability). T-score rescales raw scale score (sum of scores from all questions answered) into a standardized score with a mean of 50 and standard deviation of 10, based on scoring tables provided in PROMIS Scoring Manuals. Higher PROMIS T-score=more of concept being measured.

The Investigators/Surgeons who complete the surgical procedures assess the participant's response to surgery with BIVV001 treatment using a 4-point scale, where responses were categorized as worst response: 1 = Excellent, 2 = Good, 3 = Fair, and 4 = Poor/none. Higher score indicated worst response. This assessment was performed 24 hours after the surgery. A surgery can be counted in more than one response category.

Perioperative period was time lapse surrounding the surgical act which was divided into 3 stages: preoperative (4 weeks prior to surgery), operative (during the surgery) and post-operative (24-hour post-surgery). The number of injections to maintain hemostasis (a process to prevent and stop bleeding from a blood vessel) per surgery included all injections from loading dose (i.e., the preoperative injection, administered either on the day of surgery or one day prior to the surgery), to the end of surgery. Major surgery: defined as any invasive operative procedure that required any of the following: opening into major body cavity (e.g., abdomen, thorax, skull); operation on a joint; removal of an organ; dental extraction of any molar teeth or >=3 non-molar teeth; operative alteration of normal anatomy; crossing of a mesenchymal barrier (e.g., pleura, peritoneum, dura).

Perioperative period was time lapse surrounding surgical act which was divided into 3 stages: preoperative (4 weeks prior to surgery), operative (during the surgery) and post-operative (24-hour post-surgery). Total dose (IU/kg) was the sum across all injections per major surgery (including loading dose) needed to maintain hemostasis (a process to prevent and stop bleeding from a blood vessel) during surgery. Major surgery: defined as any invasive operative procedure that required any of the following: opening into major body cavity (e.g., abdomen, thorax, skull); operation on a joint; removal of an organ; dental extraction of any molar teeth or >=3 non-molar teeth; operative alteration of normal anatomy; crossing of a mesenchymal barrier (e.g., pleura, peritoneum, dura). Day 0 was defined as the surgery day. The loading dose for a given surgery was the preoperative injection, administered either on the day of surgery or one day prior to the surgery (i.e., Day -1).

Perioperative period: time lapse surrounding surgical act which was divided into 3 stages: preoperative (4 weeks prior to surgery), operative (during the surgery) and post-operative (24-hour post-surgery). Total BIVV001 consumption were summarized from the loading dose (the day before surgery, i.e, on Day -1) up to 2 weeks following the surgery (i.e., Day 14) and were reported in this OM.

The perioperative period was the time lapse surrounding the surgical act which was divided into 3 stages: preoperative (4 weeks prior to surgery), operative (during the surgery) and post-operative (24-hour post-surgery). The number of blood component transfusions used during perioperative period were summarized categorically (0, 1, 2, 3 and >3) for all major surgeries for the surgery subgroup. Major surgery: defined as any invasive operative procedure that required any of the following: opening into major body cavity (e.g., abdomen, thorax, skull); operation on a joint; removal of an organ; dental extraction of any molar teeth or >=3 non-molar teeth; operative alteration of normal anatomy; crossing of a mesenchymal barrier (e.g., pleura, peritoneum, dura).

The perioperative period was the time lapse surrounding the surgical act which was divided into 3 stages: preoperative (4 weeks prior to surgery), operative (during the surgery) and post-operative (24-hour post-surgery). The type of blood component (Red blood cell, platelet, fresh frozen plasma, whole blood and other) transfusions used were summarized for all major surgeries. Post-operative referred to the day following the end of surgery to the date of hospital discharge. Major surgery: defined as any invasive operative procedure that required any of the following: opening into major body cavity (e.g., abdomen, thorax, skull); operation on a joint; removal of an organ; dental extraction of any molar teeth or >=3 non-molar teeth; operative alteration of normal anatomy; crossing of a mesenchymal barrier (e.g., pleura, peritoneum, dura).

The estimated total blood loss (in milliliters) during major surgeries were summarized. Major surgery: defined as any invasive operative procedure that required any of the following: opening into major body cavity (e.g., abdomen, thorax, skull); operation on a joint; removal of an organ; dental extraction of any molar teeth or >=3 non-molar teeth; operative alteration of normal anatomy; crossing of a mesenchymal barrier (e.g., pleura, peritoneum, dura).

An adverse event (AE) was defined as any untoward medical occurrence in a participant who received study drug which did not necessarily have a causal relationship with the treatment. A serious AE (SAE) was defined as any untoward medical occurrence that at any dose: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability or incapacity, was a congenital anomaly or birth defect, or was a medically important event. Treatment-emergent AEs were AEs that developed, worsened or became serious from Baseline (Day 1) up to 3 weeks post last dose.

Development of inhibitors was defined as an inhibitor result of >=0.6 bethesda unit per milliliter (BU/mL) that was confirmed by a second test result of >=0.6 BU/mL from a separate sample, drawn 2 to 4 weeks following the date when the original sample was drawn. Both tests must have been performed by the central laboratory using the Nijmegen-modified Bethesda assay.

Embolic and thrombotic events were defined as arterial or venous thrombosis, confirmed by imaging.

Cmax was defined as the maximum observed plasma FVIII Activity.

Plasma t1/2z was the time measured for the plasma concentration of drug to decrease by one half. Only for participants who were enrolled in sequential PK subgroup of study, PK samples were collected for all timepoints at Baseline and at Week 26; however, participants did not receive BIVV001 dose in week 2 and week 27.

CL is defined as the rate at which the drug is removed from the body. Only for participants who were enrolled in sequential PK subgroup of study, PK samples were collected for all timepoints at Baseline; however, participants did not receive BIVV001 dose in week 2 and week 27.

CLss is defined as the rate at which the drug is removed from the body at steady state. Only for participants who were enrolled in sequential PK subgroup of study, PK samples were collected for all timepoints at Week 26; however, participants did not receive BIVV001 dose in week 2 and week 27.

AI is the ratio of accumulation of a drug under steady state conditions (i.e., after repeated administration) as compared to a single dose. AI was calculated as ratio of area under the curve (AUC) at Week 26 (Day 183) divided by AUC at Day 1, where AUC is the area under the plasma concentration versus time curve from time 0 to infinity. Only for participants who were enrolled in sequential PK subgroup of study, PK samples were collected for all timepoints at Week 26; however, participants did not receive BIVV001 dose in week 2 and week 27.

AUC0-tau was defined as area under the plasma concentration-time profile from time zero (pre-dose) to dosing interval. Only for participants who were enrolled in sequential PK subgroup of study, PK samples were collected for all timepoints at Baseline and at Week 26; however, participants did not receive BIVV001 dose in week 2 and week 27.

Volume of distribution (Vd) 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. Vss is the apparent volume of distribution at steady-state. Only for participants who were enrolled in sequential PK subgroup of study, PK samples were collected for all timepoints at Baseline and at Week 26; however, participants did not receive BIVV001 dose in week 2 and week 27.

MRT is the average total time a drug molecule spends in the body. Only for participants who were enrolled in sequential PK subgroup of study, PK samples were collected for all timepoints at Baseline and at Week 26; however, participants did not receive BIVV001 dose in week 2 and week 27.

IR was calculated as (Peak activity [in IU/dL] - Trough activity [in IU/dL])/Actual Dose (in IU/kg), and peak activity at each visit was the highest activity level after the dosing, and trough activity at each visit was the activity level prior to the dosing.

Ctrough is the pre-dose concentration of a drug.

Time above predefined (10 and 40%) FVIII activity levels mean time which BIVV001 maintains above 10 IU/dL and 40 IU/dL with single dose of 50 IU/kg. Only for participants who were enrolled in sequential PK subgroup of study, PK samples were collected for all timepoints at Baseline; however, participants did not receive BIVV001 dose in week 2 and week 27.