@article{5bb213ca24aa4fd398444d45ab009b20,
title = "Phase 1, single-dose escalating study of marzeptacog alfa (activated), a recombinant factor VIIa variant, in patients with severe hemophilia",
abstract = "Essentials Marzeptacog alfa (activated) [MarzAA] is a novel variant of activated human factor VII. A phase 1 dose escalation trial of MarzAA was conducted in subjects with severe hemophilia. MarzAA was safe and tolerated at intravenous doses up to 30 μg kg−1 Data observed support further trials for hemophilia patients with inhibitors to factors VIII/IX. Summary: 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−1). 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−1 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−1. The safety profile and pharmacological effects observed support further clinical trials for the treatment of hemophilic patients with inhibitors.",
keywords = "blood coagulation, clinical trial, factor VIIa, hemophilia A, hemophilia B",
author = "{the Marzeptacog alfa (activated) Study Group Investigators} and Gruppo, {R. A.} and D. Malan and J. Kapocsi and L. Nemes and Hay, {C. R.M.} and L. Boggio and P. Chowdary and G. Tagariello and {von Drygalski}, A. and F. Hua and M. Scaramozza and S. Arkin and Hermans, {C. R.J.R.} and C. Claes and I. Hanes and I. Huyghe and C. Kantaridis and {da Costa}, {L. M.} and Ndongo, {M. N.} and W. Petit and Santagostino, {E. M.} and A. Cannavo and Fasulo, {M. R.} and Mancuso, {M. E.} and A. Tosetto and G. Castaman and L. Candiotto and P. Radossi and E. Scarpa and Smith, {M. P.} and Dick, {A. E.} and Robson, {R. A.} and Waaka, {D. S.} and Wynne, {C. J.} and Punt, {Z. E.} and Kavakli, {K. R.} and C. Balkan and M. Duyu and S. Goksel and B. Karapinar and Ozyurek, {A. R.} and G. Saydam and Karapinar, {D. Y.} and M. Laffan and Millar, {C. M.} and Suppiah, {P. I.} and Rizleigh, {C. K.} and M. Recht and J. Deutsche and J. Taylor",
note = "Funding Information: The authors thank the patients who participated in this study. This study was supported by Pfizer Inc. Medical writing and editorial support was provided by B. Boyes, sponsored by Catalyst Bioscience, as well as B. Patel and T. O{\textquoteright}Neill of Peloton Advantage, sponsored by Pfizer Inc. Funding Information: S. Arkin is an employee of Pfizer and owns stock in the company. M. Scaramozza was employed full-time at the time of writing of this manuscript by Pfizer. A. von Drygalski has served on advisory boards and received personal fees from Bayer, Bioverativ, CSL Behring, Pfizer, Novo Nordisk, Octapharma, and Shire, all outside the submitted work. P. Chowdary reports receiving grants and personal fees from Pfizer, grants, personal fees and non-financial support from Bayer, CSL Behring, NovoNordisk, and Swedish Orphan Biovitrum AB (Sobi), personal fees and non-financial support from Baxalta (Shire), and personal fees from Freeline and Roche, all outside the submitted work. L. Boggio reports receiving grants from Baxalta/Shire, and has participated in advisory meetings at Shire, Bayer, Bioverativ, NovoNordisk, Pfizer, Genentech, and Octa Pharma, all outside the submitted work. L. Nemes reports receiving personal fees from Octapharma, Novo Nordisk, Baxalta, Bayer, Biotest, CSL Behring and Pfizer as a speaker, and personal fees from Novo Nordisk, Baxalta, Bayer, CSL Behring and Pfizer as a consultant, all outside the submitted work. The other authors state that they have no conflict of interest. Publisher Copyright: {\textcopyright} 2018 International Society on Thrombosis and Haemostasis",
year = "2018",
month = oct,
doi = "10.1111/jth.14247",
language = "English (US)",
volume = "16",
pages = "1984--1993",
journal = "Journal of Thrombosis and Haemostasis",
issn = "1538-7933",
publisher = "Wiley-Blackwell",
number = "10",
}