PMID- 35290453 OWN - NLM STAT- MEDLINE DCOM- 20220610 LR - 20220720 IS - 2473-9537 (Electronic) IS - 2473-9529 (Print) IS - 2473-9529 (Linking) VI - 6 IP - 11 DP - 2022 Jun 14 TI - Long-term efficacy and safety of subcutaneous concizumab prophylaxis in hemophilia A and hemophilia A/B with inhibitors. PG - 3422-3432 LID - 10.1182/bloodadvances.2021006403 [doi] AB - Despite current therapies, there remains an unmet need for treatment for patients with hemophilia. The main parts of two phase 2 trials established clinical proof-of-concept for once-daily, subcutaneous concizumab prophylaxis in patients with hemophilia A/B with inhibitors (HAwI/HBwI; explorer4) and severe hemophilia A without inhibitors (HA; explorer5). Here, we present results from extension parts of these trials, included to evaluate longer term safety and efficacy. Both trials included main (>/=24 weeks) and extension (52-102 weeks) parts, with patients receiving concizumab 0.15 mg/kg with potential dose escalation to concizumab 0.20 or 0.25 mg/kg if they experienced >/=3 treated spontaneous bleeding episodes within 12 weeks. Endpoints included annualized bleeding rate (ABR), adverse events (AEs), and occurrence of antidrug antibodies. Thromboembolic events were AEs of special interest. Thirty-six patients with HA, 15 with HAwI, and 10 with HBwI were exposed to concizumab. Estimated ABRs during the main + extension parts at last dose level were 4.8 (95% confidence interval [CI], 3.2-7.2) and 6.4 (95% CI, 4.1-9.9) in explorer4 and explorer5, respectively (spontaneous ABRs were 1.8 [95% CI, 1.2-2.6] and 2.1 [95% CI, 1.3-3.3]). Most AEs were mild, with no deaths, events leading to withdrawal, or thromboembolic events. Anti-drug antibodies developed in 25% of patients and were low titer and transient, with no observed clinical effect in most cases. Results of the main + extension parts of these trials were consistent with results of the main parts. Ongoing phase 3 trials will further evaluate concizumab as a once-daily, subcutaneous treatment across hemophilia subtypes. These trials were registered at www.clinicaltrials.gov as #NCT03196284 and #NCT03196297. CI - (c) 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved. FAU - Shapiro, Amy D AU - Shapiro AD AD - Indiana Hemophilia & Thrombosis Center, Indianapolis, IN. FAU - Angchaisuksiri, Pantep AU - Angchaisuksiri P AD - Division of Hematology, Department of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand. FAU - Astermark, Jan AU - Astermark J AUID- ORCID: 0000-0001-8500-2483 AD - Center for Thrombosis and Haemostasis, Lund University, Skane University Hospital, Malmo, Sweden. FAU - Benson, Gary AU - Benson G AD - Department of Hematology, Belfast Health and Social Care Trust, Belfast, Northern Ireland. FAU - Castaman, Giancarlo AU - Castaman G AD - Center for Bleeding Disorders and Coagulation, Department of Oncology, Careggi University Hospital, Florence, Italy. FAU - Eichler, Hermann AU - Eichler H AD - Institute of Clinical Hemostaseology and Transfusion Medicine, Saarland University and University Hospital, Homburg/Saar, Germany. FAU - Jimenez-Yuste, Victor AU - Jimenez-Yuste V AUID- ORCID: 0000-0003-3937-3499 AD - Haematology Department, La Paz University Hospital, Universidad Autonoma Madrid, Madrid, Spain. FAU - Kavakli, Kaan AU - Kavakli K AD - Department of Hematology, Ege University Children's Hospital, Izmir, Turkey. FAU - Matsushita, Tadashi AU - Matsushita T AD - Department of Transfusion Medicine, Nagoya University Hospital, Nagoya, Japan. FAU - Poulsen, Lone Hvitfeldt AU - Poulsen LH AD - The Hemophilia Centre, Department of Haematology, Aarhus University, Aarhus, Denmark. FAU - Wheeler, Allison P AU - Wheeler AP AUID- ORCID: 0000-0003-3967-4873 AD - Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN. FAU - Young, Guy AU - Young G AUID- ORCID: 0000-0001-6013-1254 AD - Hemostasis and Thrombosis Center, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA. FAU - Zupancic-Salek, Silva AU - Zupancic-Salek S AUID- ORCID: 0000-0002-6244-2336 AD - Department of Haematology, and Haemophilia and Thrombosis Unit, University Hospital Centre Zagreb, Zagreb, Croatia. AD - School of Medicine, University of Osijek, Osijek, Croatia. AD - School of Medicine, University of Zagreb, Zagreb, Croatia. FAU - Oldenburg, Johannes AU - Oldenburg J AD - Department of Immunohematology, and. AD - Department of Molecular Hemostasis, Institute of Experimental Hematology and Transfusion Medicine, University Clinic, Bonn, Germany; and. FAU - Chowdary, Pratima AU - Chowdary P AD - Katharine Dormandy Hemophilia Centre and Thrombosis Unit, Royal Free London NHS Foundation Trust, London, United Kingdom. LA - eng SI - ClinicalTrials.gov/NCT03196284 SI - ClinicalTrials.gov/NCT03196297 PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - United States TA - Blood Adv JT - Blood advances JID - 101698425 RN - 0 (Antibodies, Monoclonal, Humanized) RN - 68603V9EAF (concizumab) SB - IM MH - *Antibodies, Monoclonal, Humanized/adverse effects MH - Clinical Trials as Topic MH - *Hemophilia A/drug therapy MH - *Hemophilia B/drug therapy MH - Hemorrhage/chemically induced MH - Humans PMC - PMC9198939 EDAT- 2022/03/16 06:00 MHDA- 2022/06/11 06:00 PMCR- 2022/06/08 CRDT- 2022/03/15 17:19 PHST- 2021/10/21 00:00 [received] PHST- 2022/02/28 00:00 [accepted] PHST- 2022/03/16 06:00 [pubmed] PHST- 2022/06/11 06:00 [medline] PHST- 2022/03/15 17:19 [entrez] PHST- 2022/06/08 00:00 [pmc-release] AID - 484399 [pii] AID - 2022/ADV2021006403 [pii] AID - 10.1182/bloodadvances.2021006403 [doi] PST - ppublish SO - Blood Adv. 2022 Jun 14;6(11):3422-3432. doi: 10.1182/bloodadvances.2021006403.