Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: Swedish Orphan Biovitrum AB (publ), SE-112 76 Stockholm, Sweden
Pharmacotherapeutic group: antihaemorrhagics, blood coagulation factor IX
ATC code: B02BD04
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.
ALPROLIX (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.
The safety, efficacy, and pharmacokinetics of ALPROLIX were evaluated in 2 multinational, open-label, pivotal studies; a phase 3 study in adults and adolescents, referred to as study I and a phase 3 paediatric study, referred to as study II (see Paediatric population).
Study I compared the efficacy of each of 2 prophylactic treatment regimens (fixed weekly interval with dosing of 50 IU/kg, and individualised interval with 100 IU/kg starting every 10 days) to on demand treatment. The study enrolled a total of 123 previously treated male patients (12 to 71 years of age) with severe haemophilia B (≤2% endogenous FIX activity). All patients received treatment with ALPROLIX and were followed for up to 77 weeks.
Out of 123 subjects who completed Study I, 93 were enrolled in Study III (extension study) with median total follow-up time of 6.5 years.
Median weekly dose for subjects in the fixed weekly arm was 45.17 IU/kg (interquartile range (IQR) 38.1-53.7) in Study I. The corresponding median Annualised Bleeding Rates (ABR) in subjects evaluable for efficacy were 2.95 (IQR: 1.01-4.35) and remained similar throughout Study III (1.85 (IQR: 0.76-4.0)). Subjects had a median of 0.38 (IQR: 0.00-1.43) spontaneous joint bleeds in Study III.
For subjects in the individualised interval arm, the median dosing interval was 12.53 days (IQR: 10.4-13.4) in Study I. The corresponding median ABR was 1.38 (IQR: 0.00-3.43) and remained similar throughout Study III (1.85 (IQR: 0.76-4.0)). Dosing intervals and factor consumption remained similar in Study III (extension study) compared to Study I for both prophylactic regimens.
No bleeding episodes were experienced in 42% of subjects while on individualised prophylaxis and in 23% of subjects while on weekly prophylaxis. There was a lower proportion of subjects in individualised interval prophylaxis with ≥1 target joint at baseline than in weekly prophylaxis (27.6% and 57.1%, respectively). Of note, ABR is not comparable between different factor concentrates and between different clinical studies.
Of the 636 bleeding events observed during study I, 90.4% were controlled with 1 injection and overall 97.3% with 2 or fewer injections. The median average dose per injection to treat a bleeding episode was 46.07 (IQR: 32.86-57.03) IU/kg. The median overall dose to treat a bleeding episode was 51.47 IU/kg (IQR: 35.21-61.73) in the weekly prophylaxis arm, 49.62 IU/kg (IQR: 35.71-94.82) in the individualised interval prophylaxis arm and 46.58 IU/kg (IQR: 33. 33-59.41) in the on demand treatment arm.
A total of 35 major surgical procedures were performed and assessed in 22 subjects (21 adults and adolescents, and 1 paediatric patient <12 years of age) in Study I and Study III. Of the 35 major surgeries, 28 surgeries (80.0%) required a single pre-operative dose to maintain haemostasis during surgery. The median average dose per injection to maintain hemostasis during surgery was 94.7 IU/kg (range: 49 to 152 IU/kg). The total dose on the day of surgery ranged from 49 to 341 IU/kg and the total dose in the 14 day perioperative period ranged from 60 to 1947 IU/kg.
The haemostatic response was rated as excellent or good in 100% of major surgeries.
Study II enrolled a total of 30 previously treated male paediatric patients with severe hemophilia B (≤2% endogenous FIX activity). Patients were less than 12 years of age (15 were <6 years of age and 15 were 6 to <12 years of age). All patients received treatment with ALPROLIX and were followed for up to 52 weeks.
All of the 30 patients were treated with ALPROLIX on a prophylactic dosing regimen starting with 50-60 IU/kg every 7 days, with adjustment of dose to a maximum of 100 IU/kg and dosing interval to a minimum of once weekly and a maximum of twice weekly. Out of 30 patients having completed Study II, 27 enrolled to Study III (extension study). The median time on Study II+III was 2.88 years and median number of exposure days was 166.
The median average weekly dose of ALPROLIX was 59.40 IU/kg (interquartile range, 52.95 to 64.78 IU/kg) for subjects <6 years of age and 57.78 IU/kg (interquartile range, 51.67 to 65.01 IU/kg) for subjects 6 to <12 years of age. The median dosing interval overall was 6.99 day (interquartile range, 6.94 to 7.03) with no difference in the median dosing interval between age cohorts. With the exception of one patient whose last prescribed dose was 100 IU/kg every 5 days, the other 29 patients last prescribed doses were up to 70 IU/kg every 7 days. No bleeding episodes were experienced in 33% of paediatric subjects. Dosing intervals and factor consumption remained similar in Study III compared to Study II.
Median annualised bleeding rates in subjects <12 years of age evaluable for efficacy were 1.97 (interquartile range 0.00-3.13) in Study II and remained similar throughout Study III (extension study).
Of the 60 bleeding events observed during study II, 75% were controlled with 1 injection, and overall 91.7% of bleeding episodes were controlled with 2 or fewer injections. The median average dose per injection to treat a bleeding episode was 63.51 (interquartile range, 48.92- 99.44) IU/kg. The median overall dose to treat a bleeding episode was 68.22 IU/kg (interquartile range, 50.89-126.19).
All pharmacokinetic studies with ALPROLIX 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 ALPROLIX (rFIXFc). Following a washout period of at least 120 hours (5 days), the subjects received a single dose of 50 IU/kg of ALPROLIX. 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 ALPROLIX are presented in Table 3.
Table 3. Pharmacokinetic parameters of ALPROLIX (50 IU/kg dose):
| Pharmacokinetic parameters1 | ALPROLIX (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 ALPROLIX (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 ALPROLIX for a typical 70 kg adult is 2.30 dL/h and steady-state volume of distribution of ALPROLIX is 194.8 dL, respectively. The observed mean (SD) activity time profile following a single dose of ALPROLIX in patients with severe haemophilia B is shown below (see Table 4).
Table 4. The Observed Mean (SD) FIX activity [IU/dL] following a single dose of ALPROLIX1 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) |
1 See section 4.2; NA: Not available
Pharmacokinetic parameters of ALPROLIX 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). Table 5 presents the pharmacokinetic parameters calculated from the paediatric data of 35 subjects less than 18 years of age.
Table 5. Comparison of PK Parameters of ALPROLIX (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, ALPROLIX has been shown to cross the placenta in small amounts in mice.
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