Study of Coagulation Factor VIIa Variant Marzeptacog Alfa (Activated) in Adult Subjects With Hemophilia A and B

Conditions

Hemophilia A With Inhibitor, Hemophilia B With Inhibitor

Brief summary

Phase 2, multi-center, open-label study designed to evaluate the PK, bioavailability, PD, efficacy and safety of a daily subcutaneous \[SC\] treatment regimen with MarzAA for bleeding prophylaxis in 12 adult subjects with hemophilia A or B with an inhibitor and history of frequent spontaneous bleeding episodes.

Detailed description

Multi-center, open-label Phase 2 study to evaluate the PK, bioavailability, PD, efficacy and safety of a daily SC treatment regimen with MarzAA for bleeding prophylaxis in adult subjects with hemophilia A or B with an inhibitor. The study will enroll and dose, both intravenously and subcutaneously, a total of 12 adult male subjects with severe congenital hemophilia A or B with an inhibitor, and history of frequent bleeding episodes during the 6 months prior to enrollment, as per the individual's bleeding and treatment records. Once a subject is enrolled into the trial, the study will be conducted in three parts (occurring consecutively): Part 1a (24 hours): Single IV administration of MarzAA; Part 1b (48 hours): Single SC administration of MarzAA; Part 2: Daily SC administration. Dose escalation in Part 2 will occur if breakthrough bleeding occurs. Subjects are treated for 50 days at the final dose level required.

Mahlangu J, Levy H, Kosinova MV, Khachatryan H, Korczowski B, Makhaldiani L, Iosava G, Lee M, Del Greco F.

2021-08-1713 citations

10.1002/rth2.12576

Opportunities for Improvement: The Lot of the Inhibitor Patient Is Not a Happy One

Frank V. McL. Booth, Johnny Mahlangu, Howard Levy

Blood2018-11-29

10.1182/blood-2018-99-111720

Interventions

BIOLOGICALCoagulation Factor VIIa variant

Single intravenous injection of MarzAA, followed by single subcutaneous injection of MarzAA, followed by daily subcutaneous injection of MarzAA for 50 days at final dose level required.

Study design

Allocation

NON_RANDOMIZED

Intervention model

SEQUENTIAL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

MALE

Age

18 Years to No maximum

Healthy volunteers

No

Inclusion criteria

* Severe congenital hemophilia A or B with an inhibitor. * History of frequent spontaneous bleeding episodes. * Male, age 18 or older. * Affirmation of informed consent with signature confirmation before any trial-related activities.

Exclusion criteria

* Receiving prophylaxis treatment. * Previous participation in a clinical trial evaluating a modified rFVIIa agent. * Known positive antibody to FVII or FVIIa detected by central laboratory at screening. * Have a coagulation disorder other than hemophilia A or B. * Significant contraindication to participation.

Design outcomes

Primary

Measure	Time frame	Description
Bleeding Episode Prevention Success	Day 1 of final MarzAA dose level - Day 50	Annualized bleed rate (ABR; spontaneous and total) during Part 2 when on final MarzAA dose level versus recorded historical ABR. The analysis of the primary endpoint (annualized bleeding rate ABR for spontaneous and traumatic bleeds) of the final dose of MarzAA each subject was treated was based on the 1-sample test compared to a predefined rate assumed for the on-demand therapy. The latter was assumed to be 12 (or 1 bleed per month), which was the minimum ABR for each subject according to inclusion criterion 2 (defined as the H0), with no maximum value. A higher score indicated a worse outcome. ABR is on a scale of 0 to 365, with a lower score reflective of a lower number of bleeding events in a year.

Secondary

Measure	Time frame	Description
Occurrence of Clinical Thrombotic Event	From date of first dose until date of first occurrence of clinical event, assessed up to treatment Day 50	Occurrence of clinical thrombotic event not attributable to another cause
Coagulation Assessment - Prothrombin Time	From date of pre-dose to 24 hours (Part 1a), pre-dose to 48 hours (Part 1b), and pre-dose to Day 50 (Part 2)	Change in coagulation parameter (prothrombin time \[PT\]) from pre-dose. Min-max values are reflective of the highest and lowest values for all measured timepoints.
Coagulation Assessment - Activated Partial Thromboplastin Time	From date of pre-dose to 24 hours (Part 1a), 48 hours (Part 1b), to Day 50/end of study (Part 2)	Change in coagulation parameter (activated partial thromboplastin time \[aPTT\]) from pre-dose. Min-max values are reflective of the highest and lowest values for all measured timepoints.
Occurrence of Breakthrough Bleeding	From Day 5 of dose level until occurrence of event	Occurrence of breakthrough bleeds requiring escalation to higher dose level
Number of Events of Antibody Formation	From time of first dose of MarzAA until date of first occurrence of clinical event, assessed up to treatment Day 50	Occurrence of antibody formation resulting in a decreased endogenous level of coagulation Factor VII (FVII) or Factor VII activated (FVIIa)
Number of Events of an Antibody Response	From time of first dose of MarzAA until date of first occurrence of clinical event, assessed up to treatment Day 50.	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.
Thrombogenicity Assessment	From time of pre-dose of MarzAA at Day 1 until date of first occurrence of thrombotic event, assessed up to treatment Day 50.	Number of participants with clinically significant levels of thrombogenicity markers (D-dimer, Prothrombin fragment 1+2 (F1+2), and thrombin-antithrombin complex \[TAT\]), based on standard laboratory tests and clinical examination with a specific search for any signs of thrombosis
Coagulation Assessment - Fibrinogen	From date of pre-dose to 24 hours (Part 1a), 48 hours (Part 1b), or Day 50 (Part 2).	Change in coagulation parameter (fibrinogen) from pre-dose. Min-max values are reflective of the highest and lowest values for all measured timepoints.

Countries

Armenia, Georgia, Poland, Russia, South Africa

Participant flow

Recruitment details

A total of 11 subjects participated in the study.

Participants by arm

Arm	Count
Safety Population Safety Population	11
Total	11

Baseline characteristics

Characteristic	Safety Population
Age, Continuous	31.0 years STANDARD_DEVIATION 9.21
BMI	23.091 kg/m^2 STANDARD_DEVIATION 5.1478
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	11 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants
Height	171.57 cm STANDARD_DEVIATION 11.061
Race (NIH/OMB) American Indian or Alaska Native	0 Participants
Race (NIH/OMB) Asian	0 Participants
Race (NIH/OMB) Black or African American	0 Participants
Race (NIH/OMB) More than one race	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants
Race (NIH/OMB) White	11 Participants
Sex: Female, Male Female	0 Participants
Sex: Female, Male Male	11 Participants
Weight	69.05 kg STANDARD_DEVIATION 21.255

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk
deaths Total, all-cause mortality	0 / 10	0 / 9	1 / 10	0 / 2
other Total, other adverse events	1 / 10	1 / 9	8 / 10	1 / 2
serious Total, serious adverse events	0 / 10	0 / 9	1 / 10	0 / 2

Outcome results

Primary

Bleeding Episode Prevention Success

Annualized bleed rate (ABR; spontaneous and total) during Part 2 when on final MarzAA dose level versus recorded historical ABR. The analysis of the primary endpoint (annualized bleeding rate ABR for spontaneous and traumatic bleeds) of the final dose of MarzAA each subject was treated was based on the 1-sample test compared to a predefined rate assumed for the on-demand therapy. The latter was assumed to be 12 (or 1 bleed per month), which was the minimum ABR for each subject according to inclusion criterion 2 (defined as the H0), with no maximum value. A higher score indicated a worse outcome. ABR is on a scale of 0 to 365, with a lower score reflective of a lower number of bleeding events in a year.

Time frame: Day 1 of final MarzAA dose level - Day 50

Population: Overall number of participants analyzed was based on the Intent-to-Treat Population.

Arm	Measure	Value (MEAN)	Dispersion
Part 2	Bleeding Episode Prevention Success	1.4640 score on a scale	Standard Deviation 3.08638

Secondary

Coagulation Assessment - Activated Partial Thromboplastin Time

Change in coagulation parameter (activated partial thromboplastin time \[aPTT\]) from pre-dose. Min-max values are reflective of the highest and lowest values for all measured timepoints.

Time frame: From date of pre-dose to 24 hours (Part 1a), 48 hours (Part 1b), to Day 50/end of study (Part 2)