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

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

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.

Study Overview

• Status: Completed
• Conditions: Hemophilia A; Hemophilia B; Hemophilia A With Inhibitor; Hemophilia B With Inhibitor; Hemophilia A Without Inhibitor; Hemophilia B Without Inhibitor
• Intervention / Treatment: Biological: MarzAA (marzeptacog alfa [activated])

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).

• Study Type: Interventional
• Enrollment (Actual): 11
• Phase: Phase 1

Contacts and Locations

Study Locations

• Bulgaria
  • Plovdiv, Bulgaria
    • Medical Center "Hippocrates - N"
  • Sofia, Bulgaria
    • Specialized Hospital for Active Treatment of Hematological Diseases
• Russian Federation
  • Kirov, Russian Federation
    • Kirov Research Institute of Hematology and Blood Transfusion
  • Moscow, Russian Federation
    • National Medical Hematology Research Center
  • Saint Petersburg, Russian Federation
    • Municipal Policlinic # 37, City Center for Hemophilia Treatment

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: DIAGNOSTIC
• Allocation: NA
• Interventional Model: SEQUENTIAL
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Study Population; 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]); Single intravenous dose and ascending doses of subcutaneous injection of MarzAA (Coagulation Faction VIIa Variant)

What is the study measuring?

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.

Collaborators and Investigators

• Sponsor: Catalyst Biosciences
• Investigators: Study Director: Howard Levy, MD, PhD, MMM, Sponsor GmbH

Study record dates

Study Major Dates

• Study Start (ACTUAL): September 24, 2019
• Primary Completion (ACTUAL): April 30, 2020
• Study Completion (ACTUAL): June 17, 2020

Study Registration Dates

• First Submitted: August 22, 2019
• First Submitted That Met QC Criteria: August 26, 2019
• First Posted (ACTUAL): August 28, 2019

Study Record Updates

• Last Update Posted (ACTUAL): September 13, 2021
• Last Update Submitted That Met QC Criteria: September 9, 2021
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Hematologic Diseases; Blood Coagulation Disorders, Inherited; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Blood Coagulation Disorders; Hemophilia A; Hemophilia B
• Other Study ID Numbers: MAA-102

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: This is an open label study so each investigator will have full access to all study subject data that is entered into the database.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No