Safety, Pharmacokinetics and Pharmacodynamics of a Next-Generation Subcutaneously Administered Coagulation Factor IX Variant, Dalcinonacog Alfa, in Previously Treated Hemophilia B Patients.

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 (SQ) for prophylaxis of hemophilia B bleeding episodes. Objectives To investigate the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of DalcA. Methods This multicenter, Phase1/2a study (NCT03186677) was conducted in 11 males aged 12-65 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 SQ 75 IU/kg or 150 IU/kg. Cohort 4 was omitted. Cohort 5 received daily SQ 150 IU/kg DalcA for 6 days and Cohort 6 received IV 75 IU/kg and daily SQ 150 IU/kg DalcA for 9 days. Blood sampling was performed for chemistry, hematology, PK, PD and anti-drug antibody (ADA) measurement. Subjects were monitored for safety endpoints for 30 days post-dosing. Results DalcA demonstrated a 24-fold greater potency over BeneFIX® and longer mean residence time (33.8 hours). SQ bioavailability 8.2-20.3%, beta half-life 53.9-106.9 hours and Tmax 24-48 hours. A median 15.7% FIX activity level [IQR 14.9-16.6%] was reached after 6 daily doses. Neutralizing antibodies to ISU304, but not wt-FIX, occurred in 2 cousins. Conclusions The data demonstrated that DalcA achieved protective FIX activity levels between 11-18%, 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 SQ doses of DalcA was performed.