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Phase 1, single‐dose escalating study of marzeptacog alfa (activated), a recombinant factor VIIa variant, in patients with severe hemophilia
Author(s): ,
R. A. Gruppo
Affiliations:
Comprehensive Hemophilia and Thrombosis Center, Cincinnati Children's Hospital Medical Center, Cincinnati, USA
Correspondence: Ralph A. Gruppo, Comprehensive Hemophilia and Thrombosis Center, ML 7015, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229‐3026, USA|Tel.: +1 513 636 4269|E‐mail: ralph.gruppo@fuse.net
,
D. Malan
Affiliations:
Phoenix Pharma Pty Ltd, Mount Croix, Port Elizabeth, South Africa
,
J. Kapocsi
Affiliations:
Semmelweis University 1st Department of Medicine, Budapest, Hungary
,
L. Nemes
Affiliations:
National Hemophilia Center and Hemostasis Department, Medical Center of the Hungarian Defense Forces, Budapest, Hungary
,
C. R. M. Hay
Affiliations:
University Department of Haematology, Manchester Royal Infirmary, Manchester, UK
,
L. Boggio
Affiliations:
Hemophilia and Thrombophilia Center, Rush University Medical Center, Chicago, USA
,
P. Chowdary
Affiliations:
KD Haemophilia and Thrombosis Centre, Royal Free Hospital, London, UK
,
G. Tagariello
Affiliations:
Department of Medicine, Hemophilia Center, Castelfranco Veneto Hospital, Castelfranco, Italy
,
A. Drygalski
Affiliations:
University of California San Diego, San Diego, USA
,
F. Hua
Affiliations:
Applied BioMath, Concord, USA
,
M. Scaramozza
Affiliations:
Early Clinical Development, Pfizer Worldwide R&D, Pfizer Inc., Cambridge, USA
,
S. Arkin
Affiliations:
Rare Disease Research Unit, Pfizer Inc., Cambridge, USA
,

Affiliations:
C. R. J. R. Hermans
,
C. R. J. R. Hermans
Affiliations:
C. Claes
,
C. Claes
Affiliations:
I. Hanes
,
I. Hanes
Affiliations:
I. Huyghe
,
I. Huyghe
Affiliations:
C. Kantaridis
,
C. Kantaridis
Affiliations:
L. M. Costa
,
L. M. Costa
Affiliations:
M.‐N. Ndongo
,
M.‐N. Ndongo
Affiliations:
W. Petit
,
W. Petit
Affiliations:
E. M. Santagostino
,
E. M. Santagostino
Affiliations:
A. Cannavo
,
A. Cannavo
Affiliations:
M. R. Fasulo
,
M. R. Fasulo
Affiliations:
M. E. Mancuso
,
M. E. Mancuso
Affiliations:
A. Tosetto
,
A. Tosetto
Affiliations:
G. Castaman
,
G. Castaman
Affiliations:
L. Candiotto
,
L. Candiotto
Affiliations:
P. Radossi
,
P. Radossi
Affiliations:
E. Scarpa
,
E. Scarpa
Affiliations:
M. P. Smith
,
M. P. Smith
Affiliations:
A. E. Dick
,
A. E. Dick
Affiliations:
R. A. Robson
,
R. A. Robson
Affiliations:
D. S. Waaka
,
D. S. Waaka
Affiliations:
C. J. Wynne
,
C. J. Wynne
Affiliations:
Z. E. Punt
,
Z. E. Punt
Affiliations:
K. R. Kavakli
,
K. R. Kavakli
Affiliations:
C. Balkan
,
C. Balkan
Affiliations:
M. Duyu
,
M. Duyu
Affiliations:
S. Goksel
,
S. Goksel
Affiliations:
B. Karapinar
,
B. Karapinar
Affiliations:
A. R. Ozyurek
,
A. R. Ozyurek
Affiliations:
G. Saydam
,
G. Saydam
Affiliations:
D. Y. Karapinar
,
D. Y. Karapinar
Affiliations:
M. Laffan
,
M. Laffan
Affiliations:
C. M. Millar
,
C. M. Millar
Affiliations:
P. I. Suppiah
,
P. I. Suppiah
Affiliations:
C. K. Rizleigh
,
C. K. Rizleigh
Affiliations:
G. P. Chowdary
,
G. P. Chowdary
Affiliations:
J. S. Davies
,
J. S. Davies
Affiliations:
E. L. Fosbury
,
E. L. Fosbury
Affiliations:
S. Gill
,
S. Gill
Affiliations:
G. N. Pike
,
G. N. Pike
Affiliations:
J. Varghese Thachil
,
J. Varghese Thachil
Affiliations:
M. Recht
,
M. Recht
Affiliations:
J. Deutsche
,
J. Deutsche
Affiliations:
J. Taylor
,
J. Taylor
Affiliations:
K. A. Kalinyak
,
K. A. Kalinyak
Affiliations:
E. S. Mullins
,
E. S. Mullins
Affiliations:
J. S. Palumbo
,
J. S. Palumbo
Affiliations:
C. T. Quinn
,
C. T. Quinn
Affiliations:
C. Tarango
,
C. Tarango
Affiliations:
S. Tarabar
,
S. Tarabar
Affiliations:
P. A. Chandler
,
P. A. Chandler
Affiliations:
L. Deats
,
L. Deats
Affiliations:
S. R. Deshpande
,
S. R. Deshpande
Affiliations:
N. U. Epstein
,
N. U. Epstein
Affiliations:
A. G. Hansson
,
A. G. Hansson
Affiliations:
S. S. Pawlak
,
S. S. Pawlak
Affiliations:
D. Rudin
,
D. Rudin
Affiliations:
L. A. J. Valentino
,
L. A. J. Valentino
Affiliations:
N. C. Kakodkar
,
N. C. Kakodkar
Affiliations:
M. L. Simpson
,
M. L. Simpson
Affiliations:
P. F. Fogarty
,
P. F. Fogarty
Affiliations:
Tami L. Bach
,
Tami L. Bach
Affiliations:
Elaine Y. Chiang
,
Elaine Y. Chiang
Affiliations:
J. W. Adamson
,
J. W. Adamson
Affiliations:
C. S. Glass
,
C. S. Glass
Affiliations:
N. Sidhu
,
N. Sidhu
Affiliations:
T. D. Tucker‐Greene
T. D. Tucker‐Greene
Affiliations:
ISTH Academy. A. Gruppo R. Oct 4, 2018; 234172
Ralph A. Gruppo
Ralph  A. Gruppo

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Journal Abstract
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Background
Marzeptacog alfa (activated) (MarzAA), a new recombinant activated human factor VII (rFVIIa) variant with four amino acid substitutions, was developed to provide increased procoagulant activity and a longer duration of action in people with hemophilia.
Objectives
To investigate the safety, tolerability, immunogenicity, pharmacokinetics (PK) and pharmacodynamics (PD) of single ascending intravenous bolus doses of MarzAA in non‐bleeding patients with congenital hemophilia A or B with or without inhibitors.
Methods
This international, phase 1, open‐label study (NCT01439971) enrolled males aged 18–64 years with severe hemophilia A or B, with or without FVIII or FIX inhibitors. Subjects were assigned to single‐dose MarzAA cohorts (0.5, 4.5, 9, 18 or 30 μg kg). Blood sampling was performed predose and postdose, and subjects were monitored for 60 days postdose. Safety endpoints included adverse events, vital sign changes, electrocardiograms, laboratory abnormalities, and immunogenicity; secondary endpoints included evaluation of PK and PD.
Results
Overall, in 25 patients, MarzAA was well tolerated at all dose levels tested, and was not associated with dose‐limiting toxicity. No treatment‐emergent severe or serious adverse events occurred. MarzAA showed linear dose–response PK across the 4.5–30 μg kg dose range, with a terminal half‐life of ⁓ 3.5 h. Dose‐dependent shortening of the activated partial thromboplastin time and prothrombin time, and evidence of an increase in peak thrombin as determined with a thrombin generation assay, were observed at all doses.
Conclusions
MarzAA was tolerated at doses up to 30 μg kg. The safety profile and pharmacological effects observed support further clinical trials for the treatment of hemophilic patients with inhibitors.
Keyword(s)
blood coagulation, clinical trial, factor VIIa, hemophilia A, hemophilia B
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