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Clinical Trial
. 2021 Apr;19(4):967-975.
doi: 10.1111/jth.15259. Epub 2021 Mar 24.

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

Chur Woo You  1 , Seung-Beom Hong  2 , Suyeong Kim  2 , Ho-Jin Shin  3 , Jin Seok Kim  4 , Jung Woo Han  4 , Soo-Jeong Kim  4 , Do Young Kim  3 , Martin Lee  5 , Howard Levy  6
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Free article
Clinical Trial

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

Chur Woo You et al. J Thromb Haemost. 2021 Apr.
Free article

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.

Keywords: blood coagulation; factor IX; hemophilia B; injections; recombinant proteins; subcutaneous.

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References

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