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.
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).
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
DIAGNOSTIC
Masking
NONE
Enrollment
11
Single intravenous dose and ascending doses of subcutaneous injection of MarzAA (Coagulation Faction VIIa Variant)
Medical Center "Hippocrates - N"
Plovdiv, Bulgaria
Specialized Hospital for Active Treatment of Hematological Diseases
Sofia, Bulgaria
Kirov Research Institute of Hematology and Blood Transfusion
Kirov, Russia
National Medical Hematology Research Center
Moscow, Russia
Municipal Policlinic # 37, City Center for Hemophilia Treatment
Saint Petersburg, Russia
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
Time frame: 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
Time frame: 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 - Cmax
Change in Cmax at each stage for each dose group
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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)
Time frame: 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)
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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.
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