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

Phase 1

Completed

Conditions: Hemophilia A
Hemophilia B
Hemophilia A With Inhibitor
Hemophilia B With Inhibitor
Hemophilia A Without Inhibitor
Hemophilia B Without Inhibitor

Interventions: Biological: MarzAA (marzeptacog alfa [activated])

Registration Number: NCT04072237

Lead Sponsor: Catalyst Biosciences

Brief Summary: 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: 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).

Recruitment & Eligibility

Status: COMPLETED

Sex: Male

Target Recruitment: 11

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Study Population	MarzAA (marzeptacog alfa [activated])	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)

Primary Outcome Measures

Name	Time	Method
Comparative MarzAA Activity by Dose Level/Stage - AUC0-∞ and AUC0-last	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 pharmacokinetics (PK) by dose level/stage based on examination of AUC frequencies of these for each of the dose groups
Comparative MarzAA Activity by Dose Level/Stage - AUCT1-T2 Normalized by Dose = AUC0-last/Dose	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 pharmacokinetics by dose level/stage based on examination of AUC frequency of these for each of the dose groups

Secondary Outcome Measures

Name	Time	Method
Effect of Split Injections on MarzAA Activity by Dose Level/Stage - AUC From T1 to T2 Norm by Dose	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.	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)
Effect of Split Injections on MarzAA Activity by Dose Level/Stage - AUC Infinity Obs and AUC to Last Nonzero Conc	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.	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)
Comparative MarzAA Activity of Intravenous and Subcutaneous - T1/2eqα	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 T1/2eqα at each stage for each dose group
Comparative MarzAA Activity of Intravenous and Subcutaneous - Cmax	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 Cmax at each stage for each dose group
Comparative MarzAA Activity of Intravenous and Subcutaneous - Tmax	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 Tmax at each stage for each dose group
Comparative MarzAA Activity of Intravenous and Subcutaneous - BAabs	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 BAabs at each stage for each dose group
Comparative MarzAA Activity of Intravenous and Subcutaneous - Mean Residence Time	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 Mean Residence Time at each stage for each dose group
Change in Coagulation Parameters - Activated Partial Thromboplastin Time (aPTT)	From predose to Day 2 at stage 1 (IV). From predose to Day 3 at stages 2-9 (SC).	Maximum change in aPTT from pre-dose
Change in Coagulation Parameters - Thrombin Generation Time (TGT) - TGT-Lag and TGT-Time to Peak	From predose to Day 2 at stage 1 (IV). From predose to Day 3 at stages 2-9 (SC).	Maximum change in TGT parameters from pre-dose
Comparative MarzAA Activity of Intravenous and Subcutaneous - T1/2λ-z	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 T1/2λ-z at each stage for each dose group
Comparative MarzAA Activity of Intravenous and Subcutaneous - Vd1	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 Vd1 at each stage for each dose group
Comparative MarzAA Activity of Intravenous and Subcutaneous - CL	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 CL at each stage for each dose group
Change in Thrombogenicity Parameter - Fibrinogen	From predose to Day 2 at stage 1 (IV). From predose to Day 3 at stages 2-9 (SC).	Maximum change in thrombogenicity parameter from pre-dose
Change in Thrombogenicity Parameter - Prothrombin Fragments 1 + 2	From predose to Day 2 at stage 1 (IV). From predose to Day 3 at stages 2-9 (SC).	Maximum change in thrombogenicity parameter from pre-dose
Change in Thrombogenicity Parameter - Thrombin/Antithrombin	From predose to Day 2 at stage 1 (IV). From predose to Day 3 at stages 2-9 (SC).	Maximum change in thrombogenicity parameter from pre-dose
Occurrence of an Antibody Response to MarzAA	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 an antibody response to MarzAA and whether it is inhibitory and cross-reactive to wild-type recombinant coagulation FVII (wt-rFVII) or wt-FVIIa
Change in Coagulation Parameters - Prothrombin Time (PT)	From predose to Day 2 at stage 1 (IV). From predose to Day 3 at stages 2-7 (SC).	Maximum change in PT from pre-dose
Change in Coagulation Parameters - Thrombin Generation Time (TGT) - TGT-Peak	From predose to Day 2 at stage 1 (IV). From predose to Day 3 at stages 2-9 (SC).	Maximum change in TGT parameter from pre-dose
Change in Coagulation Parameters - Thrombin Generation Time (TGT) - TGT-Endogenous Thrombin Potential	From predose to Day 2 at stage 1 (IV). From predose to Day 3 at stages 2-9 (SC).	Maximum change in TGT parameter from pre-dose
Change in Thrombogenicity Parameter - D-Dimer	From predose to Day 2 at stage 1 (IV). From predose to Day 3 at stages 2-9 (SC).	Maximum change in thrombogenicity parameter from pre-dose
Occurrence of Clinical Thrombotic Event	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.	Occurrence of clinical thrombotic event not attributable to another cause

Trial Locations

Locations (5): Specialized Hospital for Active Treatment of Hematological Diseases
🇧🇬
Sofia, Bulgaria
Medical Center "Hippocrates - N"
🇧🇬
Plovdiv, Bulgaria
National Medical Hematology Research Center
🇷🇺
Moscow, Russian Federation
Kirov Research Institute of Hematology and Blood Transfusion
🇷🇺
Kirov, Russian Federation
Municipal Policlinic # 37, City Center for Hemophilia Treatment
🇷🇺
Saint Petersburg, Russian Federation