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 T max 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.

Efficacy and safety of subcutaneous prophylaxis with dalcinonacog alfa in adults with haemophilia B

“…One participant reported their AE to be moderate for the first 2 injections and mild thereafter. 14 No NAb were detected. As NAb typically emerge within 10 exposure days (ED) and the majority within 20 ED, this study reinforces the conclusion of analyses that have collectively found that dalcinonacog alfa is no more immunogenic than wild‐type FIX, but longer periods of observation are desirable.…”

“…As NAb typically emerge within 10 exposure days (ED) and the majority within 20 ED, this study reinforces the conclusion of analyses that have collectively found that dalcinonacog alfa is no more immunogenic than wild‐type FIX, but longer periods of observation are desirable. In the Phase 1/2 trial of 2 participants who received dalcinonacog alfa IV followed by dalcinonacog alfa SQ, both developed NAb (transiently in 1 participant) that did not inhibit BeneFIX and safely returned to wild‐type FIX treatment 14 . The most likely cause was the human leucocyte antigen (HLA) signature of these 2 participants, who were cousins and shared a rare gene mutation of the propeptide region (1 participant had all 3 HLA types predictive for immunogenicity and the other had 1 HLA type) 17…”

“…In the Phase 1/2 trial of 2 participants who received dalcinonacog alfa IV followed by dalcinonacog alfa SQ, both developed NAb (transiently in 1 participant) that did not inhibit BeneFIX and safely returned to wild‐type FIX treatment. 14 The most likely cause was the human leucocyte antigen (HLA) signature of these 2 participants, who were cousins and shared a rare gene mutation of the propeptide region (1 participant had all 3 HLA types predictive for immunogenicity and the other had 1 HLA type). 17…”

“… 11 , 12 Pharmacokinetic (PK) observations in murine models and early clinical studies collectively support that the potency of dalcinonacog alfa is >20‐fold that of recombinant wild‐type FIX dosed at the same mass, thereby allowing for higher activity at equal dosing. 13 , 14 Dalcinonacog alfa was evaluated in a Phase 1/2, open‐label, multicentre, dose‐escalation study in patients with previously treated HB. 14 In a cohort receiving SQ dosing, activity levels after 6 daily doses in 5 participants reached a median of 15.7%, with 4 of these participants having FIX levels >12%.…”

“… 13 , 14 Dalcinonacog alfa was evaluated in a Phase 1/2, open‐label, multicentre, dose‐escalation study in patients with previously treated HB. 14 In a cohort receiving SQ dosing, activity levels after 6 daily doses in 5 participants reached a median of 15.7%, with 4 of these participants having FIX levels >12%. Median half‐life was 63.2 h. Initial IV dosing was also shown to increase SQ dalcinonacog alfa bioavailability by increasing extravascular compartment saturation, resulting in activity levels greater than those expected from simple addition of SQ to IV activity.…”