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

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.

• 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
• Journal: Journal of thrombosis and haemostasis : JTH (J Thromb Haemost) Vol. 19 Issue 4 Pg. 967-975 (04 2021) ISSN: 1538-7836 [Electronic] England
• PMID: 33540485 (Publication Type: Clinical Trial, Phase I, Clinical Trial, Phase II, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 International Society on Thrombosis and Haemostasis.

Chemical References

• Recombinant Proteins
• Factor IX

Topics

• Adolescent
• Adult
• Aged
• Blood Coagulation Tests
• Child
• Factor IX
• Half-Life
• Hemophilia A
• Hemophilia B (diagnosis, drug therapy)
• Humans
• Male
• Middle Aged
• Recombinant Proteins
• Young Adult