Subcutaneous engineered factor VIIa marzeptacog alfa (activated) in hemophilia with inhibitors: Phase 2 trial of pharmacokinetics, pharmacodynamics, efficacy, and safety
Abstract Background Marzeptacog alfa (activated) (MarzAA), a novel recombinant activated human factor VII (FVIIa) variant, was developed to provide increased procoagulant activity, subcutaneous (SC) administration, and longer duration of action in people with hemophilia. Objectives To investigate if...
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| Format: | Article |
| Language: | English |
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Elsevier
2021-08-01
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| Series: | Research and Practice in Thrombosis and Haemostasis |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/rth2.12576 |
| _version_ | 1797726386443517952 |
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| author | Johnny Mahlangu Howard Levy Marina V. Kosinova Heghine Khachatryan Bartosz Korczowski Levani Makhaldiani Genadi Iosava Martin Lee Frank Del Greco |
| author_facet | Johnny Mahlangu Howard Levy Marina V. Kosinova Heghine Khachatryan Bartosz Korczowski Levani Makhaldiani Genadi Iosava Martin Lee Frank Del Greco |
| author_sort | Johnny Mahlangu |
| collection | DOAJ |
| description | Abstract Background Marzeptacog alfa (activated) (MarzAA), a novel recombinant activated human factor VII (FVIIa) variant, was developed to provide increased procoagulant activity, subcutaneous (SC) administration, and longer duration of action in people with hemophilia. Objectives To investigate if daily SC administration of MarzAA in subjects with inhibitors can provide effective prophylaxis. Methods This multicenter, open‐label phase 2 trial (NCT03407651) enrolled men with severe congenital hemophilia with an inhibitor. All subjects had a baseline annualized bleeding rate (ABR) of ≥12 events/year. Subjects received a single 18 μg/kg intravenous dose of MarzAA to measure 24‐hour pharmacokinetics (PK) and pharmacodynamics (PD), single 30 μg/kg SC dose to measure 48‐hour PK/PD, then daily SC 30 μg/kg MarzAA for 50 days. If spontaneous bleeding occurred, the dose was sequentially escalated to 60, 90, or 120 μg/kg, with 50 days at the final effective dose without spontaneous bleeding to proceed to a 30‐day follow‐up. The primary end point was reduction in ABR. Secondary end points were safety, tolerability, and antidrug antibody (ADA) formation. Results In the 11 subjects, the mean ABR significantly reduced from 19.8 to 1.6, and the mean proportion of days with bleeding significantly reduced from 12.3% to 0.8%. Of a total of 517 SC doses, six injection site reactions in two subjects were reported. No ADAs were detected. One fatal unrelated serious adverse event occurred: intracerebral hemorrhage due to untreated hypertension. Conclusions The data demonstrated that MarzAA was highly efficacious for prophylactic treatment in patients with inhibitors by significantly decreasing bleed frequency and duration of bleeding episodes. |
| first_indexed | 2024-03-12T10:44:51Z |
| format | Article |
| id | doaj.art-a9322a7798624e72884c4f60d04eb1af |
| institution | Directory Open Access Journal |
| issn | 2475-0379 |
| language | English |
| last_indexed | 2024-03-12T10:44:51Z |
| publishDate | 2021-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Research and Practice in Thrombosis and Haemostasis |
| spelling | doaj.art-a9322a7798624e72884c4f60d04eb1af2023-09-02T07:40:20ZengElsevierResearch and Practice in Thrombosis and Haemostasis2475-03792021-08-0156n/an/a10.1002/rth2.12576Subcutaneous engineered factor VIIa marzeptacog alfa (activated) in hemophilia with inhibitors: Phase 2 trial of pharmacokinetics, pharmacodynamics, efficacy, and safetyJohnny Mahlangu0Howard Levy1Marina V. Kosinova2Heghine Khachatryan3Bartosz Korczowski4Levani Makhaldiani5Genadi Iosava6Martin Lee7Frank Del Greco8Haemophilia Comprehensive Care CenterCharlotte Maxeke Johannesburg Academic HospitalUniversity of the Witwatersrand and NHLS Johannesburg South AfricaCatalyst Biosciences South San Francisco CA USAHematology Kemerovo Regional Clinical Hospital Kemerovo RussiaR.H. Yeolyan Hemophilia and Thrombophilia Center Yerevan Republic of ArmeniaInstitute of Medical Sciences College of Medical Sciences of the University of Rzeszow, University of Rzeszow Rzeszow PolandK. Eristavi National Center of Experimental and Clinical Surgery Tbilisi GeorgiaInstitute of Hematology and Transfusiology Tbilisi GeorgiaFielding School of Public Health University of California Los Angeles Los Angeles CA USACatalyst Biosciences South San Francisco CA USAAbstract Background Marzeptacog alfa (activated) (MarzAA), a novel recombinant activated human factor VII (FVIIa) variant, was developed to provide increased procoagulant activity, subcutaneous (SC) administration, and longer duration of action in people with hemophilia. Objectives To investigate if daily SC administration of MarzAA in subjects with inhibitors can provide effective prophylaxis. Methods This multicenter, open‐label phase 2 trial (NCT03407651) enrolled men with severe congenital hemophilia with an inhibitor. All subjects had a baseline annualized bleeding rate (ABR) of ≥12 events/year. Subjects received a single 18 μg/kg intravenous dose of MarzAA to measure 24‐hour pharmacokinetics (PK) and pharmacodynamics (PD), single 30 μg/kg SC dose to measure 48‐hour PK/PD, then daily SC 30 μg/kg MarzAA for 50 days. If spontaneous bleeding occurred, the dose was sequentially escalated to 60, 90, or 120 μg/kg, with 50 days at the final effective dose without spontaneous bleeding to proceed to a 30‐day follow‐up. The primary end point was reduction in ABR. Secondary end points were safety, tolerability, and antidrug antibody (ADA) formation. Results In the 11 subjects, the mean ABR significantly reduced from 19.8 to 1.6, and the mean proportion of days with bleeding significantly reduced from 12.3% to 0.8%. Of a total of 517 SC doses, six injection site reactions in two subjects were reported. No ADAs were detected. One fatal unrelated serious adverse event occurred: intracerebral hemorrhage due to untreated hypertension. Conclusions The data demonstrated that MarzAA was highly efficacious for prophylactic treatment in patients with inhibitors by significantly decreasing bleed frequency and duration of bleeding episodes.https://doi.org/10.1002/rth2.12576hemophiliamarzeptacog alfa (activated)prophylaxisrecombinant FVIIasubcutaneous injection |
| spellingShingle | Johnny Mahlangu Howard Levy Marina V. Kosinova Heghine Khachatryan Bartosz Korczowski Levani Makhaldiani Genadi Iosava Martin Lee Frank Del Greco Subcutaneous engineered factor VIIa marzeptacog alfa (activated) in hemophilia with inhibitors: Phase 2 trial of pharmacokinetics, pharmacodynamics, efficacy, and safety Research and Practice in Thrombosis and Haemostasis hemophilia marzeptacog alfa (activated) prophylaxis recombinant FVIIa subcutaneous injection |
| title | Subcutaneous engineered factor VIIa marzeptacog alfa (activated) in hemophilia with inhibitors: Phase 2 trial of pharmacokinetics, pharmacodynamics, efficacy, and safety |
| title_full | Subcutaneous engineered factor VIIa marzeptacog alfa (activated) in hemophilia with inhibitors: Phase 2 trial of pharmacokinetics, pharmacodynamics, efficacy, and safety |
| title_fullStr | Subcutaneous engineered factor VIIa marzeptacog alfa (activated) in hemophilia with inhibitors: Phase 2 trial of pharmacokinetics, pharmacodynamics, efficacy, and safety |
| title_full_unstemmed | Subcutaneous engineered factor VIIa marzeptacog alfa (activated) in hemophilia with inhibitors: Phase 2 trial of pharmacokinetics, pharmacodynamics, efficacy, and safety |
| title_short | Subcutaneous engineered factor VIIa marzeptacog alfa (activated) in hemophilia with inhibitors: Phase 2 trial of pharmacokinetics, pharmacodynamics, efficacy, and safety |
| title_sort | subcutaneous engineered factor viia marzeptacog alfa activated in hemophilia with inhibitors phase 2 trial of pharmacokinetics pharmacodynamics efficacy and safety |
| topic | hemophilia marzeptacog alfa (activated) prophylaxis recombinant FVIIa subcutaneous injection |
| url | https://doi.org/10.1002/rth2.12576 |
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