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

• Published in: Journal of thrombosis and haemostasis Vol. 19; no. 4; pp. 967 - 975
• Main Authors: You, Chur Woo, Hong, Seung‐Beom, Kim, Suyeong, Shin, Ho‐Jin, Kim, Jin Seok, Han, Jung Woo, Kim, Soo‐Jeong, Kim, Do Young, Lee, Martin, Levy, Howard
• Format: Journal Article
• Language: English
• Published: England Elsevier Limited 01.04.2021
• Subjects: Adolescent; Adult; Aged; Antiplatelet therapy; Bioavailability; blood coagulation; Blood Coagulation Tests; Child; Coagulation factor IX; Coagulation factors; Factor IX; Factor IX deficiency; Half-Life; Hematology; Hemophilia; Hemophilia A; hemophilia B; Hemophilia B - diagnosis; Hemophilia B - drug therapy; Humans; injections; Intravenous administration; Male; Middle Aged; Pharmacodynamics; Pharmacokinetics; Prophylaxis; Recombinant Proteins; Safety; subcutaneous; Young Adult; injections; subcutaneous; recombinant proteins; factor IX; blood coagulation; hemophilia B
• ISSN: 1538-7933; 1538-7836; 1538-7836
• DOI: 10.1111/jth.15259

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.