Phase 1, single‐dose escalating study of marzeptacog alfa (activated), a recombinant factor VIIa variant, in patients with severe hemophilia. (27th August 2018)

• Record Type: Journal Article
• Authors: Gruppo, R. A.; Malan, D.; Kapocsi, J.; Nemes, L.; Hay, C. R. M.; Boggio, L.; Chowdary, P.; Tagariello, G.; von Drygalski, A.; Hua, F.; Scaramozza, M.; Arkin, S.
• Other Names: Hermans C. R. J. R. investigator.; Claes C. investigator.; Hanes I. investigator.; Huyghe I. investigator.; Kantaridis C. investigator.; da Costa L. M. investigator.; Ndongo M.‐N. investigator.; Petit W. investigator.; Santagostino E. M. investigator.; Cannavo A. investigator.; Fasulo M. R. investigator.; Mancuso M. E. investigator.; Tosetto A. investigator.; Castaman G. investigator.; Candiotto L. investigator.; Radossi P. investigator.; Scarpa E. investigator.; Smith M. P. investigator.; Dick A. E. investigator.; Robson R. A. investigator.; Waaka D. S. investigator.; Wynne C. J. investigator.; Punt Z. E. investigator.; Kavakli K. R. investigator.; Balkan C. investigator.; Duyu M. investigator.; Goksel S. investigator.; Karapinar B. investigator.; Ozyurek A. R. investigator.; Saydam G. investigator.; Karapinar D. Y. investigator.; Laffan M. investigator.; Millar C. M. investigator.; Suppiah P. I. investigator.; Rizleigh C. K. investigator.; Chowdary G. P. investigator.; Davies J. S. investigator.; Fosbury E. L. investigator.; Gill S. investigator.; Pike G. N. investigator.; Varghese Thachil J. investigator.; Recht M. investigator.; Deutsche J. investigator.; Taylor J. investigator.; Kalinyak K. A. investigator.; Mullins E. S. investigator.; Palumbo J. S. investigator.; Quinn C. T. investigator.; Tarango C. investigator.; Tarabar S. investigator.; Chandler P. A. investigator.; Deats L. investigator.; Deshpande S. R. investigator.; Epstein N. U. investigator.; Hansson A. G. investigator.; Pawlak S. S. investigator.; Rudin D. investigator.; Valentino L. A. J. investigator.; Kakodkar N. C. investigator.; Simpson M. L. investigator.; Fogarty P. F. investigator.; Bach Tami L. investigator.; Chiang Elaine Y. investigator.; Adamson J. W. investigator.; Glass C. S. investigator.; Sidhu N. investigator.; Tucker‐Greene T. D. investigator.;
• Is Part Of: Journal of thrombosis and haemostasis. Volume 16:Number 10(2018)
• Page Start: 1984
• Page End: 1993
• Publication Date: 2018-08-27
• Subjects: blood coagulation -- clinical trial -- factor VIIa -- hemophilia A -- hemophilia B; Thrombosis -- Periodicals; Hemostasis -- Periodicals; Blood coagulation disorders -- Periodicals; 616.1
• DOI: 10.1111/jth.14247
• Languages: English
• ISSNs: 1538-7933

Abstract

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.