Phase 1, single‐dose escalating study of marzeptacog alfa (activated), a recombinant factor VIIa variant, in patients with severe hemophilia

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...

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Published in:	Journal of thrombosis and haemostasis Vol. 16; no. 10; pp. 1984 - 1993
Main Authors:	Gruppo, R. A., Malan, D., Kapocsi, J., Nemes, L., Hay, C. R. M., Boggio, L., Chowdary, P., Tagariello, G., Drygalski, A., Hua, F., Scaramozza, M., Arkin, S., Hermans, C. R. J. R., Claes, C., Hanes, I., Huyghe, I., Kantaridis, C., Costa, L. M., Ndongo, M.‐N., Petit, W., Santagostino, E. M., Cannavo, A., Fasulo, M. R., Mancuso, M. E., Tosetto, A., Castaman, G., Candiotto, L., Radossi, P., Scarpa, E., Smith, M. P., Dick, A. E., Robson, R. A., Waaka, D. S., Wynne, C. J., Punt, Z. E., Kavakli, K. R., Balkan, C., Duyu, M., Goksel, S., Karapinar, B., Ozyurek, A. R., Saydam, G., Karapinar, D. Y., Laffan, M., Millar, C. M., Suppiah, P. I., Rizleigh, C. K., Chowdary, G. P., Davies, J. S., Fosbury, E. L., Gill, S., Pike, G. N., Varghese Thachil, J., Recht, M., Deutsche, J., Taylor, J., Kalinyak, K. A., Mullins, E. S., Palumbo, J. S., Quinn, C. T., Tarango, C., Tarabar, S., Chandler, P. A., Deats, L., Deshpande, S. R., Epstein, N. U., Hansson, A. G., Pawlak, S. S., Rudin, D., Valentino, L. A. J., Kakodkar, N. C., Simpson, M. L., Fogarty, P. F., Bach, Tami L., Chiang, Elaine Y., Adamson, J. W., Glass, C. S., Sidhu, N., Tucker‐Greene, T. D.
Format:	Journal Article
Language:	English
Published:	England Elsevier Limited 01-10-2018
Subjects:	Administration, Intravenous Adolescent Adult Amino acids blood coagulation clinical trial Clinical trials Coagulants - administration & dosage Coagulants - adverse effects Coagulants - pharmacokinetics Coagulation factor VIIa Coagulation factors Europe factor VIIa Factor VIIa - administration & dosage Factor VIIa - adverse effects Factor VIIa - pharmacokinetics Factor VIII deficiency Hemophilia hemophilia A Hemophilia A - blood Hemophilia A - diagnosis Hemophilia A - drug therapy hemophilia B Hemophilia B - blood Hemophilia B - diagnosis Hemophilia B - drug therapy Humans Immunogenicity Intravenous administration Male Middle Aged Patients Pharmacodynamics Pharmacokinetics Prothrombin Recombinant Proteins - administration & dosage Recombinant Proteins - adverse effects Recombinant Proteins - pharmacokinetics Safety Severity of Illness Index South Africa Thrombin Thromboplastin Time Factors Toxicity Treatment Outcome United States Young Adult United States South Africa Europe clinical trial hemophilia A blood coagulation factor VIIa hemophilia B
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Summary:	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.
ISSN:	1538-7933 1538-7836 1538-7836
DOI:	10.1111/jth.14247