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Phase 1, single‐dose escalating study of marzeptacog alfa (activated), a recombinant factor VII a variant, in patients with severe hemophilia
Author(s) -
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.
Publication year - 2018
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/jth.14247
Subject(s) - medicine , tolerability , pharmacodynamics , adverse effect , pharmacokinetics , immunogenicity , clinical endpoint , pharmacology , factor ix , bolus (digestion) , bioequivalence , clinical trial , anesthesia , immunology , antibody
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) (Marz AA ), a new recombinant activated human factor VII (r FVII a) 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 Marz AA in non‐bleeding patients with congenital hemophilia A or B with or without inhibitors. Methods This international, phase 1, open‐label study ( NCT 01439971) 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 Marz AA 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, Marz AA 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. Marz AA 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 Marz AA 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.