Activity measurements of dalcinonacog alfa

Williams, Stella; Gray, Elaine

doi:10.1111/hae.13949

Cited by 5 publications

(11 citation statements)

References 22 publications

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“…Although this study initially used a chromogenic activity assay, we subsequently learned that the activity of dalcinonacog alfa is best determined by a onestage assay. 25,26 Last, only patients aged 12 to 65 years were enrolled in this study. 27,28 These data demonstrated that DalcA may be efficacious for the treatment of hemophilia B (with the ab-…”

Section: Discussionmentioning

confidence: 99%

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

You

Hong²,

Kim³

et al. 2021

Journal of Thrombosis and Haemostasis

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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.

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Section: Discussionmentioning

confidence: 99%

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

You

Hong²,

Kim³

et al. 2021

Journal of Thrombosis and Haemostasis

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“…Additional studies are required to monitor immunogenicity to dalcinonacog alfa. Although this study initially utilized a chromogenic activity assay, we subsequently learned that the activity of dalcinonacog alfa is best determined by a one-stage assay [ 44 , 53 ] Results presented in Fig 3D thus represent those of the one-stage clotting assay. Interestingly, a significant correction in the WBCT and aPTT was observed within the first 24 hours after the first dose of 300 IU/kg dalcinonacog alfa, whereas the observable plasma levels of FIX activity were approximately 5% and negligible antigen was detected.…”

Section: Discussionmentioning

confidence: 99%

“…The concentration of rFIX antigen in canine plasma samples was determined using an ELISA (Asserachrom IX:Ag, Diagnostica Stago, cat no 00943). Baseline antigen levels were undetectable [ 44 ]. FIX activity was assessed at Haematologic Technologies using an activated partial thromboplastin time (aPTT) Factor IX one-stage clotting assay on an ACL-TOP instrument (Instrumentation Laboratories) using the recommended HemosIL ® or SynthasIL ® reagents and calibrators.…”

Section: Methodsmentioning

confidence: 99%

Preclinical evaluation of a next-generation, subcutaneously administered, coagulation factor IX variant, dalcinonacog alfa

et al. 2020

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Introduction The rapid clearance of factor IX necessitates frequent intravenous administrations to achieve effective prophylaxis for patients with hemophilia B. Subcutaneous administration has historically been limited by low bioavailability and potency. Dalcinonacog alfa was developed using a rational design approach to be a subcutaneously administered, next-generation coagulation prophylactic factor IX therapy. Aim This study aimed to investigate the pharmacokinetic, pharmacodynamic, and safety profile of dalcinonacog alfa administered subcutaneously in hemophilia B dogs. Methods Two hemophilia B dogs received single-dose daily subcutaneous dalcinonacog alfa injections for six days. Factor IX antigen and activity, whole blood clotting time, and activated partial thromboplastin time were measured at various time points. Additionally, safety assessments for clinical adverse events and evaluations of laboratory test results were conducted. Results There was an increase in plasma factor IX antigen with daily subcutaneous dalcinonacog alfa. Bioavailability of subcutaneous dalcinonacog alfa was 10.3% in hemophilia B dogs. Daily subcutaneous dosing of dalcinonacog alfa demonstrated the effects of bioavailability, time to maximal concentration, and half-life by reaching a steady-state activity sufficient to correct severe hemophilia to normal, after four days. Conclusion The increased potency of dalcinonacog alfa facilitated the initiation and completion of the Phase 1/2 subcutaneous dosing study in individuals with hemophilia B.

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“…Dalcinonacog alfa activity measurement variability between platforms and reagents has been published, including data that the chromogenic assay should not be used. 15 FIX activity was assayed at Haemtech Biopharma Services (Essex Junction, Vermont, USA), with an activated partial thromboplastin time (aPTT) FIX one‐stage clotting assay on an ACL‐TOP instrument (Instrumentation Laboratory) applying the recommended SynthASil ® (Instrumentation Laboratory) reagents and calibrators. Clearance, volume of distribution at steady‐state and half‐life (t 1/2 ) (alpha and beta phase) were determined from day 28 and subsequent samples during washout.…”

Section: Methodsmentioning

confidence: 99%

“…Dalcinonacog alfa activity measurement variability between platforms and reagents has been published, including data that the chromogenic assay should not be used. 15 (Siemens Enzygnost TAT kit) were performed at the central laboratory. Anti-drug antibodies (ADA) to dalcinonacog alfa and BeneFIX were detected through a direct binding enzyme-linked immunosorbent assay (ELISA).…”

Section: Assessmentsmentioning

confidence: 99%

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

et al. 2021

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Aim Phase 2b study to assess efficacy, safety, thrombogenicity, immunogenicity and tolerability with 28 days of daily dosing of subcutaneous (SQ) dalcinonacog alfa as prophylaxis for haemophilia B (HB). Methods Adult males with a confirmed diagnosis of congenital HB (factor IX [FIX] activity <2%) received daily dalcinonacog alfa 100 IU/kg SQ until day 28. The primary efficacy endpoint was the number of participants who achieved a steady‐state FIX activity level ≥12%. Tolerability, thrombogenicity and immunogenicity were study safety endpoints. Results Of 6 participants who received study drug, one discontinued the study on day 7 due to injection‐site reactions (ISR). Of the 5 participants completing the study, FIX activity level exceeded 12% in 3 participants at day 7, increasing to 4 participants on days 14, 21 and 28 and all 5 at day 29. Pharmacokinetic findings (including mean alpha and beta half‐life of 5.3 days and 3.9 days, respectively, and mean residence time of 6.2 days) supported prolonged effects. Thrombogenicity markers remained normal throughout prophylactic injections or showed some initial increases followed by decreases with continued dosing. Two participants had anti‐drug antibodies to dalcinonacog alfa at study end, none had neutralizing antibody. Two participants had ISR, both resolved. Reports of redness, swelling, tenderness or pain among the first 3 participants prompted dose‐splitting for the last 3 participants, leading to fewer ISR. Conclusion Subcutaneous dalcinonacog alfa is effective in raising FIX levels into the mild haemophilia range, comparable to intravenous extended half‐life FIX clotting factors.

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Activity measurements of dalcinonacog alfa

Cited by 5 publications

References 22 publications

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

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

Preclinical evaluation of a next-generation, subcutaneously administered, coagulation factor IX variant, dalcinonacog alfa

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

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