R A Gruppo1, D Malan2, J Kapocsi3, L Nemes4, C R M Hay5, L Boggio6, P Chowdary7, G Tagariello8, A von Drygalski9, F Hua10, M Scaramozza11, S Arkin12. 1. Comprehensive Hemophilia and Thrombosis Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA. 2. Phoenix Pharma Pty Ltd, Mount Croix, Port Elizabeth, South Africa. 3. Semmelweis University 1st Department of Medicine, Budapest, Hungary. 4. National Hemophilia Center and Hemostasis Department, Medical Center of the Hungarian Defense Forces, Budapest, Hungary. 5. University Department of Haematology, Manchester Royal Infirmary, Manchester, UK. 6. Hemophilia and Thrombophilia Center, Rush University Medical Center, Chicago, IL, USA. 7. KD Haemophilia and Thrombosis Centre, Royal Free Hospital, London, UK. 8. Department of Medicine, Hemophilia Center, Castelfranco Veneto Hospital, Castelfranco, Italy. 9. University of California San Diego, San Diego, CA, USA. 10. Applied BioMath, Concord, MA, USA. 11. Early Clinical Development, Pfizer Worldwide R&D, Pfizer Inc., Cambridge, MA, USA. 12. Rare Disease Research Unit, Pfizer Inc., Cambridge, MA, USA.
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.
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 hemophiliapatients 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-bleedingpatients 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.
Authors: C Hermans; P L F Giangrande; B O'Mahony; P de Kleijn; M Bedford; A Batorova; J Blatný; K Jansone Journal: Orphanet J Rare Dis Date: 2020-08-24 Impact factor: 4.123
Authors: Hans H Brackmann; Wolfgang Schramm; Johannes Oldenburg; Viridiana Cano; Peter L Turecek; Claude Négrier Journal: Hamostaseologie Date: 2020-07-27 Impact factor: 2.145