PMID- 31444162 OWN - NLM STAT- MEDLINE DCOM- 20200317 LR - 20210202 IS - 1528-0020 (Electronic) IS - 0006-4971 (Print) IS - 0006-4971 (Linking) VI - 134 IP - 22 DP - 2019 Nov 28 TI - Subcutaneous concizumab prophylaxis in hemophilia A and hemophilia A/B with inhibitors: phase 2 trial results. PG - 1973-1982 LID - 10.1182/blood.2019001542 [doi] AB - 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 1+2, 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) ADA+ 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. These trials were registered at www.clinicaltrials.gov as #NCT03196284 and #NCT03196297. CI - (c) 2019 by The American Society of Hematology. FAU - Shapiro, Amy D AU - Shapiro AD AD - Indiana Hemophilia and 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 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, United Kingdom. FAU - Castaman, Giancarlo AU - Castaman G AD - Center for Bleeding Disorders and Coagulation, Department of Oncology, Careggi University Hospital, Florence, Italy. FAU - Chowdary, Pratima AU - Chowdary P AD - Katharine Dormandy Hemophilia Centre and Thrombosis Unit, Royal Free London NHS Foundation Trust, London, United Kingdom. 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 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 AD - Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN. FAU - Young, Guy AU - Young G 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 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; and. 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. LA - eng SI - ClinicalTrials.gov/NCT03196284 SI - ClinicalTrials.gov/NCT03196297 PT - Clinical Trial, Phase II PT - Journal Article PT - Multicenter Study PT - Randomized Controlled Trial PL - United States TA - Blood JT - Blood JID - 7603509 RN - 0 (Antibodies, Monoclonal, Humanized) RN - 0 (Blood Coagulation Factor Inhibitors) RN - 68603V9EAF (concizumab) SB - IM CIN - Blood. 2019 Nov 28;134(22):1885-1887. PMID: 31778542 MH - Adult MH - *Antibodies, Monoclonal, Humanized/administration & dosage/pharmacokinetics MH - Blood Coagulation Factor Inhibitors/*blood MH - Female MH - *Hemophilia A/blood/drug therapy MH - *Hemophilia B/blood/drug therapy MH - *Hemorrhage/blood/prevention & control MH - Humans MH - Injections, Subcutaneous MH - Male MH - Middle Aged PMC - PMC6895373 COIS- Conflict-of-interest disclosure: A.D.S. serves as principal investigator on 3 Novo Nordisk-sponsored research studies. J.A. has received honoraria and consulting fees from Bayer, CSL Behring, Novo Nordisk, Octapharma, Roche, Sobi, Spark, Takeda, and uniQure. G.B. has received grants and personal fees for lectures and consultancy from Bayer, Boehringer Ingelheim, CSL Behring, Novo Nordisk, Pfizer, Shire, and Sobi. G.C. participated in a uniQure advisory board meeting; received fees to act as a speaker from, or to participate in advisory board meetings for, Ablynx, Bayer, CSL Behring, Kedrion, Novo Nordisk, Shire/Takeda, Sobi, Roche, and Werfen; and received research grants from CSL Behring, Pfizer, and Sobi. P.C. has received honoraria from Baxalta/Shire, Biogen Idec, CSL Behring, Novo Nordisk, Pfizer, Roche and Sobi; has served on advisory boards for Bayer, Baxalta/Shire, Biogen Idec, CSL Behring, Chugai, Freeline, Novo Nordisk, Pfizer, Roche, and Sobi; and has received research funding from Bayer, CSL Behring, Novo Nordisk, Pfizer, and Sobi. H.E. has received fees to act as a speaker or consultant from, or to participate in advisory board meetings for, Bayer, CSL Behring, Novo Nordisk, Shire/Takeda, Sobi, and Roche, and has received research grants from Bayer Vital, CSL Behring, and Pfizer. V.J.-Y. has received reimbursement for attending symposia/congresses and/or honoraria for speaking and/or consulting and/or funds for research from Bayer, CSL Behring, Grifols, Novo Nordisk, Octapharma, Pfizer, Roche, Sobi, and Shire. K.K. has participated in advisory board meetings for Bayer, Novo Nordisk, Takeda, Pfizer, and Roche. T.M. has received honoraria from Bayer, Bioverative, Chugai, CSL, KM Biologics, Novo Nordisk, and Shire, and research support from Bayer and Bioverative. L.H.P. has received funding for attending congresses and meetings from Bayer, Novo Nordisk, Pfizer, and Sobi. A.P.W. has participated in advisory board meetings for Biomarin, Novo Nordisk, Octapharma, Shire, and uniQure. G.Y. has received honoraria and consulting fees from Bioverativ/Sanofi, CSL Behring, Genentech/Roche, Grifols, Kedrion, Novo Nordisk, Spark, Takeda, and uniQure. S.Z.-S. has received reimbursement for attending symposia and congresses, and honoraria payment for speaking, from Biogen, Novo Nordisk, Sobi, and Roche. J.O. has received reimbursement for attending symposia/congresses and/or honoraria for speaking and/or consulting and/or funds for research from Bayer, Biogen Idec, Biotest, Chugai, CSL Behring, Grifols, Novo Nordisk, Octapharma, Pfizer, Roche, Taked, and Swedish Orphan Biovitrum. P.A. declares no competing financial interests. EDAT- 2019/08/25 06:00 MHDA- 2020/03/18 06:00 PMCR- 2019/11/28 CRDT- 2019/08/25 06:00 PHST- 2019/05/10 00:00 [received] PHST- 2019/08/06 00:00 [accepted] PHST- 2019/08/25 06:00 [pubmed] PHST- 2020/03/18 06:00 [medline] PHST- 2019/08/25 06:00 [entrez] PHST- 2019/11/28 00:00 [pmc-release] AID - S0006-4971(20)73187-3 [pii] AID - 2019/BLD2019001542 [pii] AID - 10.1182/blood.2019001542 [doi] PST - ppublish SO - Blood. 2019 Nov 28;134(22):1973-1982. doi: 10.1182/blood.2019001542.