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Safety, pharmacokinetics, and pharmacodynamics of a next-generation subcutaneously administered coagulation factor IX variant, dalcinonacog alfa, in previously treated hemophilia B patients

Authors
 Chur Woo You  ;  Seung-Beom Hong  ;  Suyeong Kim  ;  Ho-Jin Shin  ;  Jin Seok Kim  ;  Jung Woo Han  ;  Soo-Jeong Kim  ;  Do Young Kim  ;  Martin Lee  ;  Howard Levy 
Citation
 JOURNAL OF THROMBOSIS AND HAEMOSTASIS, Vol.19(4) : 967-975, 2021-04 
Journal Title
JOURNAL OF THROMBOSIS AND HAEMOSTASIS
ISSN
 1538-7933 
Issue Date
2021-04
MeSH
Adolescent ; Adult ; Aged ; Blood Coagulation Tests ; Child ; Factor IX ; Half-Life ; Hemophilia A* ; Hemophilia B* / diagnosis ; Hemophilia B* / drug therapy ; Humans ; Male ; Middle Aged ; Recombinant Proteins ; Young Adult
Keywords
blood coagulation ; factor IX ; hemophilia B ; injections ; recombinant proteins ; subcutaneous
Abstract
Background: Dalcinonacog alfa (DalcA), a next-generation, recombinant human factor IX (FIX) variant, was developed using a rational design approach for increased procoagulant activity and longer duration of action to be administered subcutaneously (SC) for prophylaxis of hemophilia B bleeding episodes.

Objectives: To investigate the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of DalcA.

Methods: This multicenter, phase 1/2a study (NCT03186677) was conducted in 11 males aged 12 to 65 years with severe hemophilia B. In cohort 1, subjects received intravenous (IV) 75 IU/kg BeneFIX and DalcA. Cohorts 2 and 3 had DalcA IV 75 IU/kg and SC 75 IU/kg or 150 IU/kg. Cohort 4 was omitted. Cohort 5 received daily SC 150 IU/kg DalcA for 6 days and cohort 6 received IV 75 IU/kg and daily SC 150 IU/kg DalcA for 9 days. Blood sampling was performed for chemistry, hematology, PK, PD, and anti-drug antibody measurement. Subjects were monitored for safety endpoints for 30 days postdosing.

Results: DalcA demonstrated a 24-fold greater potency over BeneFIX and longer mean residence time (33.8 h). SC bioavailability 8.2% to 20.3%, beta half-life 53.9 to 106.9 h and Tmax 24 to 48 h. A median 15.7% FIX activity level (interquartile range, 14.9%-16.6%) was reached after 6 daily doses. Neutralizing antibodies to ISU304, but not wild-type FIX, occurred in two cousins.

Conclusions: The data demonstrated that DalcA achieved protective FIX activity levels between 11% and 18%, corresponding to a reduced chance of spontaneous bleeds. Based on the results, a phase 2b trial to assess the safety and efficacy of 28 daily SC doses of DalcA was performed.
Full Text
https://onlinelibrary.wiley.com/doi/10.1111/jth.15259
DOI
10.1111/jth.15259
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pediatrics (소아과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Jin Seok(김진석) ORCID logo https://orcid.org/0000-0001-8986-8436
Han, Jung Woo(한정우) ORCID logo https://orcid.org/0000-0001-8936-1205
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/190392
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