Pharmacokinetic Assessment of Standard Half-Life (SHL) FVIII, Extended Half-Life (EHL) FVIII, and Efanesoctocog Alfa (BIVV001) in Severe Hemophilia A

Study Overview
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Brief Summary
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Primary objective • To assess the half-life of BIVV001, Standard Half-Life (SHL) rFVIII and Extended Half-Life (EHL) rFVIII after a single intravenous (IV) injection Secondary objectives To characterize additional pharmacokinetic (PK) parameters of BIVV001, SHL rFVIII and EHL rFVIII after a single IV injection To evaluate the safety and tolerability of a single IV injection of BIVV001

Detailed Description
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This is a Phase 1, single center, open-label, sequential treatment, 3-period fixed sequence study to assess PK profiles of BIVV001, SHL and EHL rFVIII after a single IV injection in male, previously treated patients, 18-65 years of age, with severe hemophilia A (defined as <1 IU/dL [<1%] endogenous FVIII). The expected duration of the study is up to approximately 67 days including Screening and washout up to 28 days, Advate® dosing, PK sampling, including washout: approximately 4 days, Adynovi® dosing and PK sampling, including washout: approximately 7 days, BIVV001 dosing and PK sampling: approximately 14 days, Remainder of Safety Observation Period: approximately 14 days.

Official Title
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A Phase 1, Single-Site, Open-Label Study to Assess Pharmacokinetics of Efanesoctocog Alfa (BIVV001), Standard Half-Life and Extended Half-Life FVIII After Each Single Intravenous Injection in a Fixed Sequence, in Previously Treated Adults With Severe Hemophilia A

Conditions
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Hemophilia A

Intervention / Treatment
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* Drug: Efanesoctocog alfa
* Drug: Octocog alfa
* Drug: Rurioctocog alfa pegol


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Severe hemophilia A, defined as <1 IU/dL (<1%) endogenous FVIII activity. Previous treatment for hemophilia A, defined as at least 150 days documented prior exposure to any recombinant and/or plasma-derived FVIII and/or cryoprecipitate products at Day 1. Platelet count ≥100,000 cells/µL at Screening. 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 enrollment. (CD4 lymphocyte count >200 cells/mm³ - Viral load of <400 copies/mL). Exclusion Criteria: Any concurrent clinically significant liver disease that, in the opinion of the Investigator, would make the participant unsuitable for enrollment. This may include, but is not limited to cirrhosis, portal hypertension, and acute hepatitis. Serious active bacterial, fungal 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. History of a positive inhibitor test defined as ≥0.6 BU/mL, or any value greater than or equal to the lower sensitivity cut-off for laboratories with cut-offs for inhibitor detection between 0.7 and 1.0 BU/mL, or clinical signs or symptoms of decreased response to FVIII administrations. Family history of inhibitors will not exclude the participant. Positive inhibitor result, defined as ≥0.6 BU/mL at Screening. Major surgery within 8 weeks of Screening. Sensitivity to any of the study interventions, or components thereof, or drug or other allergy. The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: efanesoctocog alfa (BIVV001)<br>Each participant will be sequentially dosed with three single intravenous (IV) doses of first rFVIII (Advate®), second Polyethylene Glycol (PEG)-rFVIII (Adynovi® or Adynovate®), and lastly, BIVV001 | Drug: Efanesoctocog alfa<br>* Solution for injection Intravenous<br>* Other names: BIVV001;Drug: Octocog alfa<br>* Solution for injection Intravenous<br>* Other names: Advate®;Drug: Rurioctocog alfa pegol<br>* Solution for injection Intravenous<br>* Other names: Adynovi®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Half-life of BIVV001 |  | BIVV001 period: Predose, and post-dose from 0.17 hr to 336 hr, and at day 28 | 
| Half-life of SHL rFVIII |  | Advate® period: Predose, and post-dose from 0.17 hr to 72 hr | 
| Half-Life of EHL rFVIII |  | Adynovi® period: Predose, and post-dose from 0.17 hr to 120 hr | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessment of pharmacokinetic (PK) parameter : maximum activity (Cmax) |  | Predose of each period, 0.17 hr to 72 hr for Advate® ; 0.17 hr to 120 hr for Adynovi® ; 0.17 hr to 336 hr and at day 28 for BIVV001 | 
| Assessment of PK parameter : clearance (CL) |  | Predose of each period, 0.17 hr to 72 hr for Advate® ; 0.17 hr to 120 hr for Adynovi® ; 0.17 hr to 336 hr and at day 28 for BIVV001 | 
| Assessment of PK parameter : volume of distribution at steady state (Vss) |  | Predose of each period, 0.17 hr to 72 hr for Advate® ; 0.17 hr to 120 hr for Adynovi® ; 0.17 hr to 336 hr and at day 28 for BIVV001 | 
| Assessment of PK parameter : area under the activity time curve extrapolated to infinity (AUC∞) |  | Predose of each period, 0.17 hr to 72 hr for Advate® ; 0.17 hr to 120 hr for Adynovi® ; 0.17 hr to 336 hr and at day 28 for BIVV001 | 
| Assessment of PK parameter : mean residence time (MRT) |  | Predose of each period, 0.17 hr to 72 hr for Advate® ; 0.17 hr to 120 hr for Adynovi® ; 0.17 hr to 336 hr and at day 28 for BIVV001 | 
| Assessment of PK parameter : incremental recovery (IR) |  | Predose of each period, 0.17 hr to 72 hr for Advate® ; 0.17 hr to 120 hr for Adynovi® ; 0.17 hr to 336 hr and at day 28 for BIVV001 | 
| Number of participants with Adverse events (AE), serious AEs and treatment-emergent AEs (TEAEs) |  | From Day 1 up to 28 days after administration of BIVV001 (total 39 days including Advate® and Adynovi® period) | 
| Development of inhibitors (neutralizing antibodies directed against FVIII) | Number of participants with development of inhibitors | Advate® period: Pre-dose; Adynovi® period: Pre-dose; BIVV001 period: Pre-dose and at day 14 and 28 after administration. |