A Safety, Tolerability, and Pharmacokinetics Study of a Single Intravenous Injection of Recombinant Coagulation Factor VIII Fc - Von Willebrand Factor - XTEN Fusion Protein (rFVIIIFc-VWF-XTEN) (BIVV001) in Previously Treated Adults With Severe Hemophilia A (EXTEN-A)

• Advate (Low Dose) (Biological): Participants received a single IV low dose of Advate 25 IU/kg.
• Advate (High Dose) (Biological): Participants received a single IV high dose of Advate 65 IU/kg.
• BIVV001 (Low Dose) (Biological): Participants received single IV low dose of BIVV001 25 IU/kg.
• BIVV001 (High Dose) (Biological): Participants received single IV high dose of BIVV001 65 IU/kg.

Primary outcomes

• Number of Participants With Treatment Emergent Adverse Events (TEAE) and Treatment Emergent Serious Adverse Event (TESAE) During Advate Treatment Period [Up to Day 3 for Advate 25 IU/kg; up to Day 4 for Advate 65 IU/kg]: AE was defined as any untoward medical occurrence in a participant who received study drug and did not necessarily had a causal relationship with the treatment. TEAE is defined as any AE that begins on or after the single dose of Advate but before the single dose of BIVV001. Serious AE (SAE) was defined as any AE resulting in death, immediate risk of death, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability/incapacity, or a congenital/anomaly/birth defect, or any other medically important event.
• Number of Participants With Treatment Emergent Adverse Events (TEAE) and Treatment Emergent Serious Adverse Event (TESAE) During BIVV001 Treatment Period [Up to 28 days after BIVV001 administration]: AE was defined as any untoward medical occurrence in a participant who received study drug and did not necessarily had a causal relationship with the treatment. TEAE is defined as any AE that begins on or after the study treatment (BIVV001) and within 28 days after BIVV001 administration. SAE was defined as any AE resulting in death, immediate risk of death, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability/incapacity, or a congenital/anomaly/birth defect, or any other medically important event.
• Number of Participants With Clinically Significant Abnormalities in Laboratory Tests During Advate Treatment Period [Up to Day 3 for Advate 25 IU/kg; up to Day 4 for Advate 65 IU/kg]: Number of Participants with Clinically Significant Abnormalities in Laboratory tests (including hematology, clinical chemistry, urinalysis, and coagulation and thrombosis markers) was reported.
• Number of Participants With Clinically Significant Abnormalities in Laboratory Tests During BIVV001 Treatment Period [Up to 28 days after BIVV001 administration]: Number of participants with clinically significant abnormalities (including hematology, clinical chemistry, urinalysis, and coagulation and thrombosis markers) was reported.
• Percentage of Participants With Confirmed Inhibitor Development as Measured by the Nijmegen-Modified Bethesda Assay [Up to 28 days after BIVV001 administration]: Development of an inhibitor was defined as a neutralizing antibody value of greater than or equal to (>=) 0.6 Bethesda units per milliliter (BU/mL) identified and confirmed by a second test on an independent sample, collected within 2 to 4 weeks of the first positive sample, with both tests performed by the central laboratory using Nijmegen-modified Bethesda assay.

Secondary outcomes

• Pharmacokinetics (PK): Maximum Observed Plasma Concentration (Cmax) for Advate and BIVV001 (Low Dose Comparison) [For Advate: Pre-dose and Post dose at 0.5, 1, 6, 24, 48, and 72 hours; For BIVV001: Pre-dose and Post dose at 0.17, 0.5, 1, 3, 6, 9, 24, 48, 72, 96, 120, 168, and 240 hours]: Cmax of Advate and BIVV001 at low dose was assessed and compared based on One-stage activated partial thromboplastin time (aPTT)-based clotting assay.
• PK: Maximum Observed Plasma Concentration (Cmax) for Advate and BIVV001 (High Dose Comparison) [For Advate: Pre-dose and Post dose at 0.5, 1, 6, 24, 48, and 72 hours; For BIVV001: Pre-dose and Post dose at 0.17, 0.5, 1, 3, 6, 9, 24, 48, 72, 96, 120, 168, 240, 288, and 336 hours]: Cmax of Advate and BIVV001 at high dose was assessed and compared based on One-stage aPTT-based clotting assay.
• PK: Half-Life (t1/2) for Advate and BIVV001 (Low Dose Comparison) [For Advate: Pre-dose and Post dose at 0.5, 1, 6, 24, 48, and 72 hours; For BIVV001: Pre-dose and Post dose at 0.17, 0.5, 1, 3, 6, 9, 24, 48, 72, 96, 120, 168, and 240 hours]: Half-life is defined as time required for the concentration of the drug to reach half of its original value. t1/2 of Advate and BIVV001 at low dose was assessed and compared based on One-stage aPTT-based clotting assay.
• PK: Half-Life for Advate and BIVV001 (High Dose Comparison) [For Advate: Pre-dose and Post dose at 0.5, 1, 6, 24, 48, and 72 hours; For BIVV001: Pre-dose and Post dose at 0.17, 0.5, 1, 3, 6, 9, 24, 48, 72, 96, 120, 168, 240, 288, and 336 hours]: Half-life is defined as time required for the concentration of the drug to reach half of its original value. t1/2 of Advate and BIVV001 at high dose was assessed and compared based on One-stage aPTT-based clotting assay.
• PK: Total Body Clearance (CL) for Advate and BIVV001 (Low Dose Comparison) [For Advate: Pre-dose and Post dose at 0.5, 1, 6, 24, 48, and 72 hours; For BIVV001: Pre-dose and Post dose at 0.17, 0.5, 1, 3, 6, 9, 24, 48, 72, 96, 120, 168, and 240 hours]: Clearance is defined as a quantitative measure of the rate at which a drug substance is removed from the body. CL of Advate and BIVV001 at low dose was assessed and compared based on One-stage aPTT-based clotting assay.
• PK: Total Body Clearance (CL) for Advate and BIVV001 (High Dose Comparison) [For Advate: Pre-dose and Post dose at 0.5, 1, 6, 24, 48, and 72 hours; For BIVV001: Pre-dose and Post dose at 0.17, 0.5, 1, 3, 6, 9, 24, 48, 72, 96, 120, 168, 240, 288, and 336 hours]: Clearance is defined as a quantitative measure of the rate at which a drug substance is removed from the body. CL of Advate and BIVV001 at high dose was assessed and compared based on One-stage aPTT-based clotting assay.
• PK: Volume of Distribution at Steady State (Vss) for Advate and BIVV001 (Low Dose Comparison) [For Advate: Pre-dose and Post dose at 0.5, 1, 6, 24, 48, and 72 hours; For BIVV001: Pre-dose and Post dose at 0.17, 0.5, 1, 3, 6, 9, 24, 48, 72, 96, 120, 168, and 240 hours]: 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. Vss of Advate and BIVV001 at low dose was assessed and compared based on One-stage aPTT-based clotting assay.
• PK: Volume of Distribution at Steady State (Vss) for Advate and BIVV001 (High Dose Comparison) [For Advate: Pre-dose and Post dose at 0.5, 1, 6, 24, 48, and 72 hours; For BIVV001: Pre-dose and Post dose at 0.17, 0.5, 1, 3, 6, 9, 24, 48, 72, 96, 120, 168, 240, 288, and 336 hours]: 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. Vss of Advate and BIVV001 at high dose was assessed and compared based on One-stage aPTT-based clotting assay.
• PK: Area Under the Concentration Time Curve (AUC) From Time 0 to Infinity (AUCinfinity) for Advate and BIVV001 (Low Dose Comparison) [For Advate: Pre-dose and Post dose at 0.5, 1, 6, 24, 48, and 72 hours; For BIVV001: Pre-dose and Post dose at 0.17, 0.5, 1, 3, 6, 9, 24, 48, 72, 96, 120, 168, and 240 hours]: AUCinfinity of Advate and BIVV001 at low dose was assessed and compared based on One-stage aPTT-based clotting assay.
• PK: Area Under the Concentration Time Curve From Time 0 to Infinity (AUCinfinity) for Advate and BIVV001 (High Dose Comparison) [For Advate: Pre-dose and Post dose at 0.5, 1, 6, 24, 48, and 72 hours; For BIVV001: Pre-dose and Post dose at 0.17, 0.5, 1, 3, 6, 9, 24, 48, 72, 96, 120, 168, 240, 288, and 336 hours]: AUCinfinity of Advate and BIVV001 at high dose was assessed and compared based on One-stage aPTT-based clotting assay.
• PK: Mean Residence Time (MRT) for Advate and BIVV001 (Low Dose Comparison) [For Advate: Pre-dose and Post dose at 0.5, 1, 6, 24, 48, and 72 hours; For BIVV001: Pre-dose and Post dose at 0.17, 0.5, 1, 3, 6, 9, 24, 48, 72, 96, 120, 168, and 240 hours]: The average time at which the number of absorbed molecules reside in the body, after single-dose administration. MRT of Advate and BIVV001 at low dose was assessed and compared based on One-stage aPTT-based clotting assay.
• PK: Mean Residence Time (MRT) for Advate and BIVV001 (High Dose Comparison) [For Advate: Pre-dose and Post dose at 0.5, 1, 6, 24, 48, and 72 hours; For BIVV001: Pre-dose and Post dose at 0.17, 0.5, 1, 3, 6, 9, 24, 48, 72, 96, 120, 168, 240, 288, and 336 hours]: The average time at which the number of absorbed molecules reside in the body, after single-dose administration. MRT of Advate and BIVV001 at high dose was assessed and compared based on One-stage aPTT-based clotting assay.
• PK: Incremental Recovery (IR) for Advate and BIVV001 (Low Dose Comparison) [For Advate: Pre-dose and Post dose at 0.5, 1, 6, 24, 48, and 72 hours; For BIVV001: Pre-dose and Post dose at 0.17, 0.5, 1, 3, 6, 9, 24, 48, 72, 96, 120, 168, and 240 hours]: Incremental Recovery is defined as the increase in the circulating FVIII activity level for one unit (IU) of the FVIII product per kilogram body weight. IR of Advate and BIVV001 at low dose was assessed and compared based on One-stage aPTT-based clotting assay.
• PK: Incremental Recovery (IR) for Advate and BIVV001 (High Dose Comparison) [For Advate: Pre-dose and Post dose at 0.5, 1, 6, 24, 48, and 72 hours; For BIVV001: Pre-dose and Post dose at 0.17, 0.5, 1, 3, 6, 9, 24, 48, 72, 96, 120, 168, 240, 288, and 336 hours]: Incremental Recovery is defined as the increase in the circulating FVIII activity level for one unit (IU) of the FVIII product per kilogram body weight. IR of Advate and BIVV001 at high dose was assessed and compared based on One-stage aPTT-based clotting assay.
• PK: Time to 1% Above Baseline for FVIII Activity for Advate and BIVV001 (Low Dose Comparison) [For Advate: Pre-dose and Post dose at 0.5, 1, 6, 24, 48, and 72 hours; For BIVV001: Pre-dose and Post dose at 0.17, 0.5, 1, 3, 6, 9, 24, 48, 72, 96, 120, 168, and 240 hours]: Time to 1% activity is the time required from the start of dosing for the FVIII activity to reach 1 IU/dL (1%) above their baseline levels. Time to 1% above baseline for FVIII Activity of Advate and BIVV001 at low dose was assessed and compared based on One-stage aPTT-based clotting assay.
• PK: Time to 1% Above Baseline for FVIII Activity for Advate and BIVV001 (High Dose Comparison) [For Advate: Pre-dose and Post dose at 0.5, 1, 6, 24, 48, and 72 hours; For BIVV001: Pre-dose and Post dose at 0.17, 0.5, 1, 3, 6, 9, 24, 48, 72, 96, 120, 168, 240, 288, and 336 hours]: Time to 1% activity is the time required from the start of dosing for the FVIII activity to reach 1 IU/dL (1%) above their baseline levels. Time to 1% above baseline for FVIII Activity of Advate and BIVV001 at high dose was assessed and compared based on One-stage aPTT-based clotting assay.

Sex: Male, ages: 18 Years to 65 Years

Inclusion Criteria:

* Ability of the participant, or his legally authorized representative (e.g., parent or legal guardian) if applicable in accordance with local regulations, to understand the purpose and risks of the study and provide signed and dated informed consent/assent and authorization to use confidential health information in accordance with national and local participant privacy regulations.
* Severe hemophilia A, defined as less than (<) 1 international units per deciliter (IU/dL) (<1 percent \[%\]) endogenous FVIII at screening as determined by the one-stage clotting assay from the central laboratory. If the initial screening result was greater than or equal to (>=) 1%, then a repeat endogenous FVIII activity level was performed using the one stage clotting assay from the central laboratory. If the repeated result was < 1 IU/dL (<1%), then the participant met this inclusion requirement.
* Previous treatment for hemophilia A, defined as at least 150 documented prior exposure days to any recombinant and/or plasma-derived FVIII and/or cryoprecipitate products at Day 1. Fresh frozen plasma treatment must not be considered in the count for documented exposure days.
* Platelet count >=100,000 cells/ microliter (mcL) at screening (test performed by the central laboratory and reviewed prior to the Day 1 Advate dose).
* A participant known to be human immunodeficiency virus (HIV) antibody positive, either previously documented or identified from screening assessments, must have the following results prior to Day 1 Advate dose: cluster of differentiation 4 (CD4) lymphocyte count greater than (>) 200 cells/millimeter (mm)\^3; viral load of <400 copies/mL.

Exclusion Criteria:

Medical History:

* Any concurrent clinically significant major disease that, in the opinion of the Investigator, made the participant unsuitable for enrollment.
* Serious active bacterial or viral infection (other than chronic hepatitis or HIV) present within 30 days of screening.
* Other known coagulation disorder(s) in addition to hemophilia A.
* History of hypersensitivity or anaphylaxis associated with any FVIII product.
* Known or suspected allergy to mice, hamsters, or any ingredient in Advate.
* History of a positive inhibitor test or clinical signs of decreased response to FVIII administrations. Family history of inhibitors not excluded the participant.

Medications and Procedures:

\- Current enrollment or participation within 30 days prior to screening in any other investigational study.

Other:

* Inability to comply with study requirements as assessed by the Investigator.
* Other unspecified reasons that, in the opinion of the Investigator or Sponsor, made the participant unsuitable for enrollment.

Participant flow

Outcome results

• Number of Participants With Treatment Emergent Adverse Events (TEAE) and Treatment Emergent Serious Adverse Event (TESAE) During Advate Treatment Period (Primary), Count of participants, Participants: Advate 25 IU/kg 2; Advate 65 IU/kg 1
• Number of Participants With Treatment Emergent Adverse Events (TEAE) and Treatment Emergent Serious Adverse Event (TESAE) During BIVV001 Treatment Period (Primary), Count of participants, Participants: BIVV001 25 IU/kg 3; BIVV001 65 IU/kg 6
• Number of Participants With Clinically Significant Abnormalities in Laboratory Tests During Advate Treatment Period (Primary), Count of participants, Participants: Advate 25 IU/kg 0; Advate 65 IU/kg 0
• Number of Participants With Clinically Significant Abnormalities in Laboratory Tests During BIVV001 Treatment Period (Primary), Count of participants, Participants: BIVV001 25 IU/kg 0; BIVV001 65 IU/kg 0
• Percentage of Participants With Confirmed Inhibitor Development as Measured by the Nijmegen-Modified Bethesda Assay (Primary), Number, percentage of participants: Low Dose Cohort (LDC): Advate 25 IU/kg Then BIVV001 25 IU/kg 0; High Dose Cohort (HDC): Advate 65 IU/kg Then BIVV001 65 IU/kg 0
• Pharmacokinetics (PK): Maximum Observed Plasma Concentration (Cmax) for Advate and BIVV001 (Low Dose Comparison) (Secondary), Geometric mean, International unit/deciliter (IU/dL): Advate 25 IU/kg 51.8 (43.3 to 61.9); BIVV001 25 IU/kg 70.1 (49.7 to 98.9) (p 0.032)
• PK: Maximum Observed Plasma Concentration (Cmax) for Advate and BIVV001 (High Dose Comparison) (Secondary), Geometric mean, IU/dL: Advate 65 IU/kg 138 (117 to 162); BIVV001 65 IU/kg 161 (142 to 183) (p <0.001)
• PK: Half-Life (t1/2) for Advate and BIVV001 (Low Dose Comparison) (Secondary), Geometric mean, hours: Advate 25 IU/kg 9.12 (6.24 to 13.33); BIVV001 25 IU/kg 37.61 (33.28 to 42.50) (p <0.001)
• PK: Half-Life for Advate and BIVV001 (High Dose Comparison) (Secondary), Geometric mean, hours: Advate 65 IU/kg 13.15 (10.89 to 15.87); BIVV001 65 IU/kg 42.54 (39.72 to 45.56) (p <0.001)
• PK: Total Body Clearance (CL) for Advate and BIVV001 (Low Dose Comparison) (Secondary), Geometric mean, milliliter/hour/kilogram (mL/hr/kg): Advate 25 IU/kg 3.91 (3.05 to 5.02); BIVV001 25 IU/kg 0.558 (0.411 to 0.757) (p <0.001)
• PK: Total Body Clearance (CL) for Advate and BIVV001 (High Dose Comparison) (Secondary), Geometric mean, mL/hr/kg: Advate 65 IU/kg 3.31 (2.81 to 3.88); BIVV001 65 IU/kg 0.505 (0.436 to 0.586) (p <0.001)
• PK: Volume of Distribution at Steady State (Vss) for Advate and BIVV001 (Low Dose Comparison) (Secondary), Geometric mean, milliliter/kilogram (mL/kg): Advate 25 IU/kg 55.9 (51.2 to 61.0); BIVV001 25 IU/kg 34.8 (27.3 to 44.3) (p 0.003)
• PK: Volume of Distribution at Steady State (Vss) for Advate and BIVV001 (High Dose Comparison) (Secondary), Geometric mean, mL/kg: Advate 65 IU/kg 58.3 (49.8 to 68.2); BIVV001 65 IU/kg 35.0 (29.7 to 41.1) (p <0.001)
• PK: Area Under the Concentration Time Curve (AUC) From Time 0 to Infinity (AUCinfinity) for Advate and BIVV001 (Low Dose Comparison) (Secondary), Geometric mean, hour*international unit/deciliter: Advate 25 IU/kg 638 (495 to 822); BIVV001 25 IU/kg 4470 (3280 to 6080) (p <0.001)
• PK: Area Under the Concentration Time Curve From Time 0 to Infinity (AUCinfinity) for Advate and BIVV001 (High Dose Comparison) (Secondary), Geometric mean, hour*international unit/deciliter: Advate 65 IU/kg 1960 (1670 to 2310); BIVV001 65 IU/kg 12800 (11100 to 14900) (p <0.001)
• PK: Mean Residence Time (MRT) for Advate and BIVV001 (Low Dose Comparison) (Secondary), Geometric mean, hours: Advate 25 IU/kg 12.54 (9.82 to 16.01); BIVV001 25 IU/kg 56.93 (49.19 to 65.89) (p <0.001)
• PK: Mean Residence Time (MRT) for Advate and BIVV001 (High Dose Comparison) (Secondary), Geometric mean, hours: Advate 65 IU/kg 15.66 (14.06 to 17.45); BIVV001 65 IU/kg 67.66 (62.59 to 73.14) (p <0.001)
• PK: Incremental Recovery (IR) for Advate and BIVV001 (Low Dose Comparison) (Secondary), Geometric mean, IU/dL per IU/kg: Advate 25 IU/kg 2.0 (1.60 to 2.50); BIVV001 25 IU/kg 2.72 (1.95 to 3.80) (p 0.063)
• PK: Incremental Recovery (IR) for Advate and BIVV001 (High Dose Comparison) (Secondary), Geometric mean, IU/dL per IU/kg: Advate 65 IU/kg 2.11 (1.79 to 2.49); BIVV001 65 IU/kg 2.48 (2.18 to 2.82) (p <0.001)
• PK: Time to 1% Above Baseline for FVIII Activity for Advate and BIVV001 (Low Dose Comparison) (Secondary), Geometric mean, hours: Advate 25 IU/kg 56.97 (49.25 to 65.89); BIVV001 25 IU/kg 260.53 (222.34 to 305.30) (p <0.001)
• 1 more outcome measures not shown.

Adverse events

Time frame: All Adverse Events (AEs) were collected from signature of the informed consent form up to end of the study (28 days after BIVV001 administration) regardless of seriousness or relationship to investigational product.

Serious adverse events by term

Other adverse events by term

• Results publication: Konkle BA, Shapiro AD, Quon DV, Staber JM, Kulkarni R, Ragni MV, Chhabra ES, Poloskey S, Rice K, Katragadda S, Fruebis J, Benson CC. BIVV001 Fusion Protein as Factor VIII Replacement Therapy for Hemophilia A. N Engl J Med. 2020 Sep 10;383(11):1018-1027. doi: 10.1056/NEJMoa2002699. PMID 32905674

• Study Protocol (PDF, 2018-01-04)
• Statistical Analysis Plan (PDF, 2018-04-13)