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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1984-1993 |
| Number of pages | 10 |
| Journal | Journal of Thrombosis and Haemostasis |
| Volume | 16 |
| Issue number | 10 |
| DOIs | |
| State | Published - Oct 1 2018 |
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Keywords
- blood coagulation
- clinical trial
- factor VIIa
- hemophilia A
- hemophilia B
ASJC Scopus subject areas
- Hematology
Cite this
Phase 1, single-dose escalating study of marzeptacog alfa (activated), a recombinant factor VIIa variant, in patients with severe hemophilia. / the Marzeptacog alfa (activated) Study Group Investigators.
In: Journal of Thrombosis and Haemostasis, Vol. 16, No. 10, 01.10.2018, p. 1984-1993.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Phase 1, single-dose escalating study of marzeptacog alfa (activated), a recombinant factor VIIa variant, in patients with severe hemophilia
AU - the Marzeptacog alfa (activated) Study Group Investigators
AU - Gruppo, R. A.
AU - Malan, D.
AU - Kapocsi, J.
AU - Nemes, L.
AU - Hay, C. R.M.
AU - Boggio, L.
AU - Chowdary, P.
AU - Tagariello, G.
AU - von Drygalski, A.
AU - Hua, F.
AU - Scaramozza, M.
AU - Arkin, S.
AU - Hermans, C. R.J.R.
AU - Claes, C.
AU - Hanes, I.
AU - Huyghe, I.
AU - Kantaridis, C.
AU - da Costa, L. M.
AU - Ndongo, M. N.
AU - Petit, W.
AU - Santagostino, E. M.
AU - Cannavo, A.
AU - Fasulo, M. R.
AU - Mancuso, M. E.
AU - Tosetto, A.
AU - Castaman, G.
AU - Candiotto, L.
AU - Radossi, P.
AU - Scarpa, E.
AU - Smith, M. P.
AU - Dick, A. E.
AU - Robson, R. A.
AU - Waaka, D. S.
AU - Wynne, C. J.
AU - Punt, Z. E.
AU - Kavakli, K. R.
AU - Balkan, C.
AU - Duyu, M.
AU - Goksel, S.
AU - Karapinar, B.
AU - Ozyurek, A. R.
AU - Saydam, G.
AU - Karapinar, D. Y.
AU - Laffan, M.
AU - Millar, C. M.
AU - Suppiah, P. I.
AU - Rizleigh, C. K.
AU - Recht, Michael
AU - Deutsche, Joann
AU - Taylor, Jason
PY - 2018/10/1
Y1 - 2018/10/1
N2 - 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.
AB - 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.
KW - blood coagulation
KW - clinical trial
KW - factor VIIa
KW - hemophilia A
KW - hemophilia B
UR - http://www.scopus.com/inward/record.url?scp=85052841443&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85052841443&partnerID=8YFLogxK
U2 - 10.1111/jth.14247
DO - 10.1111/jth.14247
M3 - Article
C2 - 30151972
AN - SCOPUS:85052841443
VL - 16
SP - 1984
EP - 1993
JO - Journal of Thrombosis and Haemostasis
JF - Journal of Thrombosis and Haemostasis
SN - 1538-7933
IS - 10
ER -