Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties
Pharmacotherapeutic group: antihaemorrhagics, blood coagulation factor IX.
ATC code: B02BD04.

Mechanism of action
Factor IX is a single chain glycoprotein with a molecular mass of about 68,000 Dalton. It is a vitamin- K dependent coagulation factor and it is synthesised in the liver. 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 a sex-linked hereditary disorder of blood coagulation due to decreased levels of factor IX and results in profuse bleeding into joints, muscles or internal organs, either spontaneously or as a result of accidental or surgical trauma. By replacement therapy the plasma levels of factor IX is increased, thereby enabling a temporary correction of the factor deficiency and correction of the bleeding tendencies.

Of note, ABR (annualized bleeding rate) is not comparable between different factor concentrates and between different clinical studies.

Albutrepenonacog alfa is a recombinant coagulation factor IX. Prolongation of the half-life of albutrepenonacog alfa and the enhanced systemic exposure (see section 5.2) are achieved by fusion with recombinant albumin. Albumin is a natural, inert carrier protein in plasma with a half-life of approximately 20 days.
Albutrepenonacog alfa remains intact in the circulation until factor IX is activated, whereupon albumin is cleaved, releasing activated factor IX (FIXa) when it is needed for coagulation.

General information on clinical efficacy and safety
A phase 1/2 study evaluated the treatment efficacy and prevention of bleeding episodes of rIX-FP in 17 subjects (ages 13-46 years), 13 subjects in the prophylaxis arm received weekly prophylaxis with IDELVION for approximately 11 months, and 4 subjects in the on-demand arm received IDELVION upon occurrence of bleeding events. All 85 bleeding episodes were successfully treated with 1 or 2 doses of IDELVION.

The efficacy of IDELVION has been evaluated in the open-label, uncontrolled part of a phase 2/3 study, in which a total of 63 male, previously treated patients (PTPs) between 12 and 61 years of age received IDELVION either for prophylaxis once every 7-, 10- and/or 14-day intervals and/or for the treatment of bleeding episodes on an on-demand basis. All subjects had severe (FIX level <1%) or moderately severe (FIX level ≤ 2%) haemophilia B. Forty PTPs received IDELVION for prophylaxis.

Subjects who received prophylactic treatment started with 35-50 IU/kg once weekly. A subgroup of patients switched to extended treatment intervals (every 10 or 14 days) with a recommended dose of 75 IU/kg and individual adjustments. 21 PTPs remained on the extended 14-day prophylaxis interval for additional treatment duration of 98 to 575 (median 386) days. From those subjects, 8 (38%) experienced at least one bleeding during the 14 day-prophylaxis, while they had no bleeding events during once-weekly prophylaxis. Median Annualised Bleeding Rate (ABR) on 7-day prophylaxis with IDELVION for all bleeds was 0.0 (range 0-6) and on 14 day-prophylaxis it was 1.08 (range 0-9.1).
The long-term efficacy and safety of routine prophylaxis treatment was confirmed in an open-label extension study for up to 5 years. In this study, a total of 59 PTPs ≥12 years (54 adults and 5 
adolescents) received IDELVION either for prophylaxis and/or for the treatment of bleeding episodes on an on-demand basis.
Patients who received prophylactic treatment continued or started with 35-50 IU/kg once weekly. A subgroup of patients switched to extended treatment intervals (every 10, 14 or 21 days) with a recommended dose of 75 IU/kg (10 or 14 days) or 100 IU/kg (21 days). At the end of the study 14 PTPs (24%) were on the 7-day prophylaxis interval, and a total of 11 (19%), 25 (42%) and 9 (15%) PTPs remained on the extended prophylaxis interval of 10, 14 and 21 days, respectively. During the study, 2 PTPs (18%) in the 21-day regimen switched back to a more frequent dosing due to increased bleeding complications. The estimated median Annualised Bleeding Rates (ABRs) on 7-, 14-, and 21- day prophylaxis with IDELVION for all bleeds were 1.3 (range 0-8), 0.9 (range 0-13), and 0.3 (range 0-5), respectively.

Currently available information support extension of treatment intervals for some patients though potentially associated with an increased risk for bleeding compared to a once-weekly regimen.

Prophylaxis and control of bleeding in PTPs below 12 years
The efficacy of IDELVION has been evaluated in a phase 3 study, in which a total of 27 male PTPs between 1 and 10 years (median age 6.0 years) with 12 patients < 6 years, received IDELVION for prophylaxis and control of bleeding episodes. All 27 subjects received weekly prophylaxis treatment with IDELVION for a mean time on study of 13.1 months (9, 18 months).

Of the 106 bleeding episodes, the majority (94; 88.7%) was treated with single injection, 103; 97.2% were treated with 1-2 injections. Haemostatic efficacy at resolution of a bleed was rated excellent or good in 96% of all treated bleeding episodes.

The long-term efficacy and safety of routine prophylaxis treatment was confirmed in an open- label extension study for up to 5 years. In the study, a total of 24 PTPs < 12 years received IDELVION either for prophylaxis and/or for the treatment of bleeding episodes on an on-demand basis.
Patients who received prophylactic treatment continued with 35-50 IU/kg once weekly. A subgroup of patients switched to extended treatment intervals (every 10 or 14 days) with a recommended dose of 75 IU/kg. At the end of the study 17 PTPs (71%) were on the 7 day prophylaxis interval, and a total of 3 (12%), and 4 (17%) PTPs remained on the extended prophylaxis interval of 10 and 14 days, respectively. During the study, 4 PTPs (50%) in the 14- day regimen switched back to a more frequent dosing due to increased bleeding complications.
The estimated median Annualised Bleeding Rates (ABRs) for 7-, and 14-day prophylaxis with IDELVION for all bleeds were 2.0 (range 0-14), and 5.6 (range 0-8), respectively.

Perioperative management
The safety and efficacy in the perioperative setting was evaluated in two pivotal Phase 3 studies and a long-term extension study. The per-protocol efficacy analysis includes 30 surgeries performed in 21 patients between 5 and 58 years undergoing major or minor surgical, dental or other surgical invasive procedures. Dosing was individualized based on the subject’s PK and clinical response to treatment. A single preoperative bolus ranging from 14 to 163 IU/kg was used in 96.7% (n=29) of surgeries. Haemostatic efficacy was rated as excellent or good in all of the assessed procedures. During the 14-day postoperative period, patients received between 0 and 11 infusions and total doses ranging from 0 to 444 IU/kg.

Previously untreated patients (PUP)
Safety and efficacy of IDELVION were evaluated in a multicenter open-label clinical study with 12 previously untreated paediatric patients (PUPs) with hemophilia B (≤2% endogenous FIX activity), of whom 11 were in the age-range of 0 to 1 years. The median number of exposure days (EDs) was 50 (range 22 to 146 EDs), and 8 PUPs achieved ≥50 EDs during on-demand, prophylaxis, surgical and PK periods.
All 12 PUPs received routine prophylaxis with 11 receiving the 7-day regimen. The overall median time on prophylaxis was 11.5 months (range: 3.1 to 32.3 months). In the 9 PUPs on the 7-day prophylaxis regimen who reached > 6 months of treatment, median annualized bleeding rate (ABR) was 1.16 (range 0 to 3.1). Five of the 9 PUPs had an ABR of 0. The median monthly dose was 195.9 IU/kg (range 171.8 to 215.6 IU/kg) IU/kg for the 7-day prophylaxis regimen (N = 9).
Five subjects received on-demand treatment over varying periods prior to prophylaxis, with the number of EDs ranging from 1 to 4.
Of the 37 bleeding events observed in 10 PUPs across all study periods, 94% were successfully controlled with 1 or 2 infusions.

Pharmacokinetic Properties

5.2     Pharmacokinetic properties

Adult population
The pharmacokinetics (PK) of IDELVION were evaluated following an intravenous injection of a single dose of 25, 50 and 75 IU/kg. The PK parameters following a single injection of 50 IU/kg IDELVION (see table below) were based on plasma factor IX activity measured by the one-stage clotting assay. The mean factor IX activity at day 7 and day 14 was 13.76% and 6.10%, respectively, after a single dose of 50 IU/kg IDELVION. Repeat PK assessment for up to 30 weeks demonstrated a stable pharmacokinetic profile and incremental recovery was consistent over time.
Trough levels of 5-10% have been targeted in clinical studies for achieving bleeding control while on prophylaxis. PK simulations suggest the time to reach 5% plasma FIX activity following a single injection of 50 IU/kg IDELVION to be 12.5 days for adults.

Pharmacokinetic parameters for subjects with severe haemophilia (Median (min, max)) following a single injection of IDELVION in adults

50 IU/kg
PK parameters
(N=22)

IR a
1.18 (0.86, 1.86)
(IU/dl)/(IU/kg)
Cmax a
62.7 (40.5, 87.0)
(IU/dl)
AUC0-inf
6638 (2810, 9921)
(h*IU/dl)
Elimination t1/2
95.3 (51.5, 135.7)
(h)
CL
0.875 (0.748, 1.294)
(ml/h/kg) a = corrected for baseline levels
IR = incremental recovery; AUC = area under the factor IX activity time curve; CL = body weight adjusted clearance; Elimination t1/2 = Elimination half-life

Paediatric population
Pharmacokinetic parameters of IDELVION were evaluated in adolescents (12 to <18 years of age) and infants and children (1 to <12 years of age) following an intravenous injection of a single dose of 50 IU/kg. PK parameters (presented below) were estimated based on the plasma factor IX activity over time profile measured by the one-stage clotting assay.


Comparison of pharmacokinetic parameters of IDELVION in children (Median (min, max)) following a single injection of 50 IU/kg IDELVION
1 to <6 years     6 to <12 years     12 to <18 years
PK parameters
(N=12)             (N=15)              (N=5)
IRa
(IU/dl)/(IU/kg)              0.968 (0.660, 1.280)          1.07 (0.70, 1.47)          1.11 (0.84, 1.61) Cmaxa
(IU/dl)                        48.2 (33.0, 64.0)           50.5 (34.9, 73.6)          55.3 (40.5, 80.3) AUC0-inf
(h*IU/dl)                     4301 (2900, 8263)           4718 (3212, 7720)          4804 (2810, 9595) Elimination t1/2
(h)                           86.2 (72.6, 105.8)          89.3 (62.1, 123.0)         88.8 (51.5, 130.0) CL
(ml/h/kg)                      1.16 (0.61, 1.72)           1.06 (0.65, 1.56)          1.04 (0.52, 1.67) a = corrected for baseline levels
IR = incremental recovery; AUC = area under the factor IX activity time curve; CL = body weight adjusted clearance; Elimination t1/2 = Elimination half-life

Trough levels of 5-10% have been targeted in clinical studies for achieving bleeding control while on prophylaxis. PK simulations suggest the time to reach 5% plasma FIX activity following a single injection of 50 IU/kg IDELVION to be 7 days for 1-<6 years, 9 days for 6-<12 years and 11 days for 12-<18 years of age).