Subcutaneous concizumab prophylaxis in hemophilia A and hemophilia A/B with inhibitors: Phase 2 trial results

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  • Amy D. Shapiro, Indiana Hemophilia and Thrombosis Center
  • ,
  • Pantep Angchaisuksiri, Mahidol University
  • ,
  • Jan Astermark, Lund University
  • ,
  • Gary Benson, Belfast Health and Social Care Trust
  • ,
  • Giancarlo Castaman, University Hospital of Careggi
  • ,
  • Pratima Chowdary, The National Institute for Health Research Collaboration for Leadership in Applied Health Research and Care West (NIHR CLAHRC West) at University Hospitals Bristol NHS Foundation Trust
  • ,
  • Hermann Eichler, Universitatsklinikum des Saarlandes Medizinische Fakultat der Universitat des Saarlandes
  • ,
  • Victor Jiménez-Yuste, Universidad Autónoma de Madrid
  • ,
  • Kaan Kavakli, Ege University
  • ,
  • Tadashi Matsushita, Nagoya University
  • ,
  • Lone Hvitfeldt Poulsen
  • Allison P. Wheeler, Vanderbilt University Medical Center
  • ,
  • Guy Young, University of Southern California
  • ,
  • Silva Zupancic-Salek, School of Medicine and University Hospital Centre, University of Zagreb, Josip Juraj Strossmayer University of Osijek
  • ,
  • Johannes Oldenburg, University Hospital Bonn

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.

OriginalsprogEngelsk
TidsskriftBlood
Vol/bind134
Nummer22
Sider (fra-til)1973-1982
Antal sider10
ISSN0006-4971
DOI
StatusUdgivet - 1 jan. 2019

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