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Title: Subcutaneous concizumab prophylaxis in hemophilia A and hemophilia A/B with inhibitors: Phase 2 trial results
Authors: Amy D. Shapiro
Pantep Angchaisuksiri
Jan Astermark
Gary Benson
Giancarlo Castaman
Pratima Chowdary
Hermann Eichler
Victor Jiménez-Yuste
Kaan Kavakli
Tadashi Matsushita
Lone Hvitfeldt Poulsen
Allison P. Wheeler
Guy Young
Silva Zupancic-Salek
Johannes Oldenburg
Vanderbilt University Medical Center
Universitäts-Klinikum Bonn und Medizinische Fakultät
Belfast Health and Social Care Trust
Aarhus Universitet
NHS Foundation Trust
Hospital Universitario La Paz
Nagoya University Hospital
Universitätsklinikum des Saarlandes Medizinische Fakultät der Universität des Saarlandes
Ege Üniversitesi
Azienda Ospedaliera Careggi
Josip Juraj Strossmayer University of Osijek
Faculty of Medicine, Ramathibodi Hospital, Mahidol University
Keck School of Medicine of USC
Skånes universitetssjukhus
University of Zagreb School of Medicine
Indiana Hemophilia and Thrombosis Center
Keywords: Biochemistry, Genetics and Molecular Biology;Immunology and Microbiology
Issue Date: 1-Jan-2019
Citation: Blood. Vol.134, No.22 (2019), 1973-1982
Abstract: © 2019 by The American Society of Hematology. Results from the main parts (24 weeks) of 2 concizumab phase 2 trials are presented: explorer4 in hemophilia A (HA) or B (HB) with inhibitors (HAwI/HBwI) and explorer5 in HA. The trials aimed to evaluate the efficacy of daily subcutaneous concizumab prophylaxis (evaluated as annualized bleeding rate [ABR] at last dose level), with secondary objectives being safety and immunogenicity (assessed as number of adverse events [AEs] and antidrug antibodies [ADAs]). Patients received 0.15 mg/kg concizumab, with potential dose escalation to 0.20 and 0.25 mg/kg (if ‡3 spontaneous bleeding episodes within 12 weeks of concizumab treatment). Relevant pharmacokinetic/pharmacodynamic (PK/PD) parameters were assessed. Thirty-six HA, 9 HAwI, and 8 HBwI patients were exposed to concizumab. Most inhibitor patients (15 of 17; 88.2%) did not escalate the dose; all patients chose to continue to the extension phase of the trials. Clinical proof of concept for prevention of bleeding episodes was demonstrated in both trials. Estimated ABRs in HAwI and HBwI were lower vs HA: 3.0 (95% confidence interval [CI], 1.7; 5.3) and 5.9 (95% CI, 4.2; 8.5) vs 7.0 (95% CI, 4.6; 10.7), respectively. PK/PD results were as expected, with no difference between hemophilia subtypes for concizumab exposure, free tissue factor pathway inhibitor, thrombin generation, prothrombin fragment 112, and D-dimers. Concizumab was safe and well tolerated (no severe AEs, AE-related withdrawals, or thromboembolic events). Three patients had (very low to medium titer) ADA1 tests in each trial, with no observed clinical effect. These results support further development of concizumab as a daily prophylactic treatment in all hemophilia patients.
ISSN: 15280020
Appears in Collections:Scopus 2019

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