Factor IX is a single chain glycoprotein with a molecular mass of about 68,000 Dalton. It is a vitamin-K dependent coagulation factor. Factor IX is activated by factor XIa in the intrinsic coagulation pathway and by the factor VII/tissue factor complex in the extrinsic pathway. Activated factor IX, in combination with activated factor VIII, activates factor X. Activated factor X converts prothrombin into thrombin. Thrombin then converts fibrinogen into fibrin and a clot is formed. Haemophilia B is an X-linked hereditary disorder of blood coagulation due to decreased levels of factor IX and results in bleeding into joints, muscles or internal organs, either spontaneously or as a result of accidental or surgical trauma. By replacement therapy the plasma level of factor IX is increased thereby enabling a temporary correction of the factor deficiency and correction of the bleeding tendencies.
Eftrenonacog alfa is a long-acting, fully recombinant, fusion protein comprising human coagulation factor IX covalently linked to the Fc domain of human immunoglobulin G1, and produced by recombinant DNA technology.
The Fc region of human immunoglobulin G1 binds with the neonatal Fc receptor. This receptor is expressed throughout life as part of a naturally occurring pathway that protects immunoglobulins from lysosomal degradation by cycling these proteins back into circulation, resulting in their long plasma half-life.
All pharmacokinetic studies with eftrenonacog alfa were conducted in previously treated patients with severe haemophilia B. Data presented in this section were obtained by one-stage clotting assay with a silica-based aPTT reagent calibrated against factor IX plasma standards.
Pharmacokinetic properties were evaluated in 22 subjects (≥19 years) receiving eftrenonacog alfa (rFIXFc). Following a washout period of at least 120 hours (5 days), the subjects received a single dose of 50 IU/kg of eftrenonacog alfa. Pharmacokinetic samples were collected pre-dose and then subsequently at 11 time points up to 240 hours (10 days) post-dose. Pharmacokinetic parameters of the non-compartmental analysis after 50 IU/kg dose of eftrenonacog alfa are presented in the following table.
Pharmacokinetic parameters of eftrenonacog alfa (50 IU/kg dose):
| Pharmacokinetic parameters1 | Eftrenonacog alfa (95% CI) |
|---|---|
| N=22 | |
| Incremental Recovery (IU/dL per IU/kg) | 0.92 (0.77-1.10) |
| AUC/Dose (IU*h/dL per IU/kg) | 31.58 (28.46-35.05) |
| Cmax (IU/dl) | 46.10 (38.56-55.11) |
| CL (ml/h/kg) | 3.17 (2.85-3.51) |
| t½ (h) | 77.60 (70.05-85.95) |
| t½α (h)2 | 5.03 (3.20-7.89) |
| t½β (h)2 | 82.12 (71.39-94.46) |
| MRT (h) | 95.82 (88.44-106.2) |
| Vss (ml/kg) | 303.4 (275.1-334.6) |
| Time to 1% (days)2 | 11.22 (10.20-12.35) |
1 Pharmacokinetic parameters are presented in Geometric Mean (95% CI)
2 These pharmacokinetic parameters obtained from the compartmental analysis
Abbreviations: CI = confidence interval; Cmax = maximum activity; AUC = area under the FIX activity time curve; t1/2 = terminal half-life; t1⁄2α =
distribution half-life; t1⁄2β = elimination half-life; CL = clearance; Vss = volume of distribution at steady-state; MRT = mean residence time.
The elimination half-life of eftrenonacog alfa (82 hours) is influenced by the Fc region, which in animal models was shown to be mediated by neonatal Fc receptor cycling pathways.
A population pharmacokinetic model was developed based on FIX activity data from 161 subjects of all ages (2-76 years of age) weighing between 12.5 kg to 186.7 kg in three clinical studies (12 subjects in a phase 1/2a study, 123 subjects in study I and 26 subjects in study II). The estimate of CL of eftrenonacog alfa for a typical 70 kg adult is 2.30 dL/h and steady-state volume of distribution of eftrenonacog alfa is 194.8 dL, respectively. The observed mean (SD) activity time profile following a single dose of eftrenonacog alfa in patients with severe haemophilia B is shown below.
The Observed Mean (SD) FIX activity [IU/dL] following a single dose of eftrenonacog alfa for patients ≥12 years of Age:
| Dose (IU/kg) | 10 mins | 1 h | 3 h | 6 h | 24 h | 48 h | 96 h | 144 h | 168 h | 192 h | 240 h | 288 h |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 50 | 52.9 (30.6) | 34.5 (7.3) | 28.7 (6.7) | 25.1 (5.1) | 15.1 (3.9) | 9.7 (3.0) | 5.0 (1.6) | 3.4 (1.1) | 3.2 (1.9) | 2.6 (1.0) | 2.1 (0.9) | NA |
| 100 | 112 (24) | NA | 77.1 (12.8) | NA | 36.7 (8.0) | 21.8 (4.8) | 10.1 (2.6) | NA | 4.81 (1.67) | NA | 2.86 (0.98) | 2.30 (0.94) |
NA: Not available
Pharmacokinetic parameters of eftrenonacog alfa were determined for adolescents in study I (pharmacokinetic sampling was conducted pre-dose followed by assessment at multiple time points up to 336 hours (14 days) post-dose) and for children in study II (pharmacokinetic sampling was conducted pre-dose followed by assessment at 7 time points up to 168 hours (7 days) post-dose). The following table presents the pharmacokinetic parameters calculated from the paediatric data of 35 subjects less than 18 years of age.
Comparison of PK Parameters of eftrenonacog alfa (rFIXFc) by Age Category:
| PK Parameters1 | Study II | Study I | |
|---|---|---|---|
| <6 years (2, 4) | 6 to <12 years (6, 10) | 12 to <18 years (12, 17) | |
| Ν=11 | Ν=13 | Ν=11 | |
| IR (IU/dl per IU/kg) | 0.5989 (0.5152-0.6752) | 0.7170 (0.6115-0.8407) | 0.8470 (0.6767-1.0600) |
| AUC/Dose (IU*h/dl per IU/kg) | 22.71 (20.32-25.38) | 28.53 (24.47-33.27) | 29.50 (25.13-34.63) |
| t1/2 (h) | 66.49 (55.86-79.14) | 70.34 (60.95-81.17) | 82.22 (72.30-93.50) |
| MRT (h) | 83.65 (71.76-97.51) | 82.46 (72.65-93.60) | 93.46 (81.77-106.81) |
| CL (ml/h/kg) | 4.365 (3.901-4.885) | 3.505 (3.006-4.087) | 3.390 (2.888-3.979) |
| Vss (ml/kg) | 365.1 (316.2-421.6) | 289.0 (236.7-352.9) | 316.8 (267.4-375.5) |
1 PK parameters derived from noncompartmental analysis are presented in Geometric Mean (95% CI)
Abbreviations: CI = confidence interval; IR = incremental recovery; AUC = area under the FIX activity time curve; t1/2 = terminal half-life; MRT = mean residence time; CL = clearance; Vss = volume of distribution at steady-state
Non-clinical data reveal no special hazard for humans based on thrombogenicity test in rabbits (Wessler stasis model) and repeated dose toxicity studies (which included assessment of local toxicity, male reproductive organs and electrocardiographic parameters) in rats and monkeys. Studies to investigate genotoxicity, carcinogenicity, toxicity to reproduction or embryo-foetal development have not been conducted. In a placental transfer study, eftrenonacog alfa has been shown to cross the placenta in small amounts in mice.
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