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

Research output: Contribution to journalArticle

3 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)1984-1993
Number of pages10
JournalJournal of Thrombosis and Haemostasis
Volume16
Issue number10
DOIs
StatePublished - Oct 1 2018

Fingerprint

Hemophilia A
Hemophilia B
Factor VIIa
Pharmacokinetics
Safety
Thrombin
Factor IX
Partial Thromboplastin Time
Vital Signs
Prothrombin Time
Factor VIII
Amino Acid Substitution
Half-Life
Electrocardiography
recombinant FVIIa
Clinical Trials
Pharmacology
Therapeutics

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 journalArticle

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title = "Phase 1, single-dose escalating study of marzeptacog alfa (activated), a recombinant factor VIIa variant, in patients with severe hemophilia",
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.",
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author = "{the Marzeptacog alfa (activated) Study Group Investigators} and Gruppo, {R. A.} and D. Malan and J. Kapocsi and L. Nemes and Hay, {C. R.M.} and L. Boggio and P. Chowdary and G. Tagariello and {von Drygalski}, A. and F. Hua and M. Scaramozza and S. Arkin and Hermans, {C. R.J.R.} and C. Claes and I. Hanes and I. Huyghe and C. Kantaridis and {da Costa}, {L. M.} and Ndongo, {M. N.} and W. Petit and Santagostino, {E. M.} and A. Cannavo and Fasulo, {M. R.} and Mancuso, {M. E.} and A. Tosetto and G. Castaman and L. Candiotto and P. Radossi and E. Scarpa and Smith, {M. P.} and Dick, {A. E.} and Robson, {R. A.} and Waaka, {D. S.} and Wynne, {C. J.} and Punt, {Z. E.} and Kavakli, {K. R.} and C. Balkan and M. Duyu and S. Goksel and B. Karapinar and Ozyurek, {A. R.} and G. Saydam and Karapinar, {D. Y.} and M. Laffan and Millar, {C. M.} and Suppiah, {P. I.} and Rizleigh, {C. K.} and Michael Recht and Joann Deutsche and Jason Taylor",
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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

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