Study of Coagulation Faction VIIa Variant Marzeptacog Alfa (Activated) in Adult Subjects With Hemophilia

Study Overview
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Brief Summary
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This multi-center, open label Phase 1 study will evaluate the pharmacokinetics, pharmacodynamics, and safety of a single IV dose of MarzAA followed by ascending single SC doses of MarzAA in adult subjects with moderate or severe Hemophilia A or B, with or without an inhibitor.

Detailed Description
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This multi-center, open label Phase 1 study will evaluate the pharmacokinetics, pharmacodynamics, and safety of a single IV dose of MarzAA followed by ascending single SC doses of MarzAA in adult subjects with moderate or severe Hemophilia A or B, with or without an inhibitor. The study will enroll at least 8 adult male subjects with moderate or severe Hemophilia A or B with or without an inhibitor, in each dosing stage. Each subject will receive escalating doses of MarzAA for each stage of the study (except for Stage 5, where subjects receive the same dose as in Stage 4 split between two anatomical sites).

Official Title
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Phase 1 Study to Evaluate the Pharmacokinetics, Pharmacodynamics, and Safety of Ascending Doses of Subcutaneous Marzeptacog Alfa (Activated) in Adult Subjects With Hemophilia

Conditions
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Hemophilia B, Hemophilia A, Hemophilia A With Inhibitor, Hemophilia B With Inhibitor, Hemophilia A Without Inhibitor, Hemophilia B Without Inhibitor

Intervention / Treatment
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* Biological: MarzAA (marzeptacog alfa [activated])


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Moderate or severe congenital Hemophilia A or B, with or without an inhibitor Male, age 18 or older Affirmation of informed consent with signature confirmation before any trial related activities Exclusion Criteria: Inability to discontinue and washout prophylaxis treatment 72 hours prior to dosing. Previous participation in a trial involving SC Administration of rFVIIa or any trial using a modified amino-acid sequence FVIIa Known positive antibody to FVII or FVIIa detected by central laboratory at screening Have a coagulation disorder other than hemophilia A or B, with or without an inhibitor Significant contraindication to participate

Ages Eligible for Study
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Minimum Age: 18 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: Diagnostic
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Study Population<br>MarzAA (Coagulation Factor VIIa variant) 18 µg/kg intravenously (Stage 1) followed by MarzAA 30 µg/kg subcutaneously (SC) (Stage 2), MarzAA 45 µg/kg SC (Stage 3), MarzAA 60 µg/kg SC (Stage 4), MarzAA 2x30 µg/kg SC (Stage 5), MarzAA 90 µg/kg SC (Stage 6), MarzAA 120 µg/kg SC (Stage 7), MarzAA 2×60 µg/kg SC (Stage 8), MarzAA 3x60 µg/kg SC (Stage 9) | Biological: MarzAA (marzeptacog alfa [activated])<br>* Single intravenous dose and ascending doses of subcutaneous injection of MarzAA (Coagulation Faction VIIa Variant)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Comparative MarzAA Activity by Dose Level/Stage - AUC0-∞ and AUC0-last | Comparative pharmacokinetics (PK) by dose level/stage based on examination of AUC frequencies of these for each of the dose groups | Dosing period for each stage was approximately 3 days, with a maximum of approximately 8 weeks of dosing, depending on participation in all 9 stages and time elapsed between each study stage. | 
| Comparative MarzAA Activity by Dose Level/Stage - AUCT1-T2 Normalized by Dose = AUC0-last/Dose | Comparative pharmacokinetics by dose level/stage based on examination of AUC frequency of these for each of the dose groups | Dosing period for each stage was approximately 3 days, with a maximum of approximately 8 weeks of dosing, depending on participation in all 9 stages and time elapsed between each study stage. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Comparative MarzAA Activity of Intravenous and Subcutaneous - Cmax | Change in Cmax at each stage for each dose group | Dosing period for each stage was approximately 3 days, with a maximum of approximately 8 weeks of dosing, depending on participation in all 9 stages and time elapsed between each study stage. | 
| Comparative MarzAA Activity of Intravenous and Subcutaneous - Tmax | Change in Tmax at each stage for each dose group | Dosing period for each stage was approximately 3 days, with a maximum of approximately 8 weeks of dosing, depending on participation in all 9 stages and time elapsed between each study stage. | 
| Comparative MarzAA Activity of Intravenous and Subcutaneous - T1/2eqα | Change in T1/2eqα at each stage for each dose group | Dosing period for each stage was approximately 3 days, with a maximum of approximately 8 weeks of dosing, depending on participation in all 9 stages and time elapsed between each study stage. | 
| Comparative MarzAA Activity of Intravenous and Subcutaneous - T1/2λ-z | Change in T1/2λ-z at each stage for each dose group | Dosing period for each stage was approximately 3 days, with a maximum of approximately 8 weeks of dosing, depending on participation in all 9 stages and time elapsed between each study stage. | 
| Comparative MarzAA Activity of Intravenous and Subcutaneous - CL | Change in CL at each stage for each dose group | Dosing period for each stage was approximately 3 days, with a maximum of approximately 8 weeks of dosing, depending on participation in all 9 stages and time elapsed between each study stage. | 
| Comparative MarzAA Activity of Intravenous and Subcutaneous - Vd1 | Change in Vd1 at each stage for each dose group | Dosing period for each stage was approximately 3 days, with a maximum of approximately 8 weeks of dosing, depending on participation in all 9 stages and time elapsed between each study stage. | 
| Comparative MarzAA Activity of Intravenous and Subcutaneous - BAabs | Change in BAabs at each stage for each dose group | Dosing period for each stage was approximately 3 days, with a maximum of approximately 8 weeks of dosing, depending on participation in all 9 stages and time elapsed between each study stage. | 
| Comparative MarzAA Activity of Intravenous and Subcutaneous - Mean Residence Time | Change in Mean Residence Time at each stage for each dose group | Dosing period for each stage was approximately 3 days, with a maximum of approximately 8 weeks of dosing, depending on participation in all 9 stages and time elapsed between each study stage. | 
| Effect of Split Injections on MarzAA Activity by Dose Level/Stage - AUC From T1 to T2 Norm by Dose | PK analysis by route of administration, dose level/stage of the study based on examination of AUC for each of the dose groups. Split dose (2*30 µg/kg) vs. (60 µg/kg) | Dosing period for each stage was approximately 3 days, with a maximum of approximately 8 weeks of dosing, depending on participation in all 9 stages and time elapsed between each study stage. | 
| Effect of Split Injections on MarzAA Activity by Dose Level/Stage - AUC Infinity Obs and AUC to Last Nonzero Conc | PK analysis by route of administration, dose level/stage of the study based on examination of AUC for each of the dose groups. Split dose (2*30 µg/kg) vs. (60 µg/kg) | Dosing period for each stage was approximately 3 days, with a maximum of approximately 8 weeks of dosing, depending on participation in all 9 stages and time elapsed between each study stage. | 
| Change in Coagulation Parameters - Prothrombin Time (PT) | Maximum change in PT from pre-dose | From predose to Day 2 at stage 1 (IV). From predose to Day 3 at stages 2-7 (SC). | 
| Change in Coagulation Parameters - Activated Partial Thromboplastin Time (aPTT) | Maximum change in aPTT from pre-dose | From predose to Day 2 at stage 1 (IV). From predose to Day 3 at stages 2-9 (SC). | 
| Change in Coagulation Parameters - Thrombin Generation Time (TGT) - TGT-Peak | Maximum change in TGT parameter from pre-dose | From predose to Day 2 at stage 1 (IV). From predose to Day 3 at stages 2-9 (SC). | 
| Change in Coagulation Parameters - Thrombin Generation Time (TGT) - TGT-Lag and TGT-Time to Peak | Maximum change in TGT parameters from pre-dose | From predose to Day 2 at stage 1 (IV). From predose to Day 3 at stages 2-9 (SC). | 
| Change in Coagulation Parameters - Thrombin Generation Time (TGT) - TGT-Endogenous Thrombin Potential | Maximum change in TGT parameter from pre-dose | From predose to Day 2 at stage 1 (IV). From predose to Day 3 at stages 2-9 (SC). | 
| Change in Thrombogenicity Parameter - Fibrinogen | Maximum change in thrombogenicity parameter from pre-dose | From predose to Day 2 at stage 1 (IV). From predose to Day 3 at stages 2-9 (SC). | 
| Change in Thrombogenicity Parameter - Prothrombin Fragments 1 + 2 | Maximum change in thrombogenicity parameter from pre-dose | From predose to Day 2 at stage 1 (IV). From predose to Day 3 at stages 2-9 (SC). | 
| Change in Thrombogenicity Parameter - Thrombin/Antithrombin | Maximum change in thrombogenicity parameter from pre-dose | From predose to Day 2 at stage 1 (IV). From predose to Day 3 at stages 2-9 (SC). | 
| Change in Thrombogenicity Parameter - D-Dimer | Maximum change in thrombogenicity parameter from pre-dose | From predose to Day 2 at stage 1 (IV). From predose to Day 3 at stages 2-9 (SC). | 
| Occurrence of an Antibody Response to MarzAA | Occurrence of an antibody response to MarzAA and whether it is inhibitory and cross-reactive to wild-type recombinant coagulation FVII (wt-rFVII) or wt-FVIIa | From time of first dose of MarzAA until date of first occurrence of clinical event, assessed up to End of Study. Dosing period for each stage was approximately 3 days, with a maximum of approximately 8 weeks of dosing. | 
| Occurrence of Clinical Thrombotic Event | Occurrence of clinical thrombotic event not attributable to another cause | From the date of first dose of MarzAA until date of first occurrence of clinical event, assessed up to End of Study. Dosing period for each stage was approximately 3 days, with a maximum of approximately 8 weeks of dosing. |