Amy D. ShapiroPantep AngchaisuksiriJan AstermarkGary BensonGiancarlo CastamanPratima ChowdaryHermann EichlerVictor Jiménez-YusteKaan KavakliTadashi MatsushitaLone Hvitfeldt PoulsenAllison P. WheelerGuy YoungSilva Zupancic-SalekJohannes OldenburgVanderbilt University Medical CenterUniversitäts-Klinikum Bonn und Medizinische FakultätBelfast Health and Social Care TrustAarhus UniversitetNHS Foundation TrustHospital Universitario La PazNagoya University HospitalUniversitätsklinikum des Saarlandes Medizinische Fakultät der Universität des SaarlandesEge ÜniversitesiAzienda Ospedaliera CareggiJosip Juraj Strossmayer University of OsijekFaculty of Medicine, Ramathibodi Hospital, Mahidol UniversityKeck School of Medicine of USCSkånes universitetssjukhusUniversity of Zagreb School of MedicineIndiana Hemophilia and Thrombosis Center2020-01-272020-01-272019-01-01Blood. Vol.134, No.22 (2019), 1973-198215280020000649712-s2.0-85074346534https://repository.li.mahidol.ac.th/handle/123456789/50412© 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.Mahidol UniversityBiochemistry, Genetics and Molecular BiologyImmunology and MicrobiologyArticleSCOPUS10.1182/blood.2019001542