Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: antihaemorrhagics, blood coagulation factor VIII, ATC code: B02BD02 Mechanism of action
The factor VIII/von Willebrand factor complex consists of two molecules (factor VIII and von Willebrand factor) with different physiological functions. When infused into a haemophiliac patient, factor VIII binds to von Willebrand factor in the patient’s circulation. Activated factor VIII acts as a cofactor for activated factor IX, accelerating the conversion of factor X to activated factor X. Activated factor X converts prothrombin into thrombin. Thrombin then converts fibrinogen into fibrin and a clot can be formed.

Haemophilia A is an X-linked hereditary disorder of blood coagulation due to decreased levels of functional factor VIII:C 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 levels of factor VIII are increased, thereby enabling a temporary correction of the factor deficiency and correction of the bleeding tendencies.

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

ELOCTA (efmoroctocog alfa) is a fully recombinant fusion protein with extended half-life. ELOCTA is comprised of recombinant B-domain deleted human coagulation factor VIII covalently linked to the Fc domain of human immunoglobulin G1. The Fc region of human immunoglobulin G1 binds to the neonatal Fc receptor. This receptor is expressed throughout life and is 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. Efmoroctocog alfa binds to neonatal Fc receptor thereby utilising this same naturally occurring pathway to delay lysosomal degradation and allow for longer plasma half-life than endogenous factor VIII.

Clinical efficacy and safety
The safety, efficacy, and pharmacokinetics of ELOCTA in previously treated patients (PTPs) were evaluated in 2 multinational, open-label, pivotal phase 3 studies, Study I and Study II (see Paediatric population), and an extension study (Study III) with a duration of up to four years. In total 276 PTPs were followed for a total of 80,848 exposure days with a median of 294 (range 1-735) exposure days per patient. In addition, a phase 3 study (Study IV) was performed to evaluate the safety and efficacy of ELOCTA in previously untreated patients (PUPs) (see Paediatric population).

Study I enrolled 165 previously treated male patients (12 to 65 years of age) with severe haemophilia A.
Subjects on prophylaxis regimens prior to entering the study were assigned to the individualised prophylaxis arm. Subjects on on-demand therapy prior to entry either entered the individualised prophylaxis arm or were randomised to the weekly prophylaxis or on-demand arms.

Prophylaxis regimens:
Individualised prophylaxis: 25 to 65 IU/kg every 3 to 5 days.
Weekly prophylaxis: 65 IU/kg

Out of 153 subjects who completed Study I, 150 were enrolled onto Study III (extension study). Median total time on Study I+III was 4.2 years and median number of exposure days was 309.

Individualised prophylaxis: Median annual factor consumption was 4212 IU/kg (min. 2877, max. 7943) in Study I and 4223 IU/kg (min. 2668, max 8317) in Study III. Respective median Annualized Bleed Rate (ABR) was 1.60 (min. 0, max. 18.2) and 0.74 (min. 0, max. 15.6).

Weekly prophylaxis: Median annual factor consumption was 3805 IU/kg (min. 3353, max. 6196) in Study I and 3510 IU/kg (min. 2758, max. 3984) in Study III. Respective median ABR was 3.59 (min. 0, max. 58.0) and 2.24 (min. 0, max. 17.2).

On-demand treatment: Median annual factor consumption was 1039 IU/kg (min. 280, max. 3571) for 23 patients randomised to the on-demand treatment arm in Study I and 671 IU/kg (min. 286, max. 913) for
6 patients remaining on on-demand treatment for at least one year in Study III.

Subjects that switched from on-demand treatment to weekly prophylaxis during Study III had a median ABR of 1.67.

Treatment of bleeding: 2490 bleeding events were treated during Study I and III with a median dose of 43.8 IU/kg (min. 13.0, max. 172.8) to control each bleed. 79.2 % of first injections were rated as excellent or good by the patients.

Perioperative management (surgical prophylaxis): A total of 48 major surgical procedures were performed and assessed in 34 subjects in Study I and Study III. The haemostatic response was rated by the physicians as excellent in 41 and as good in 3 of 44 major surgeries. Median dose to maintain haemostasis during surgery was 60.6 IU/kg (min. 38, max. 158).

Paediatric population
Study II enrolled a total of 71 previously treated male paediatric patients <12 years of age with severe haemophilia A. Of the 71 enrolled subjects, 69 received at least 1 dose of ELOCTA and were evaluable for efficacy (35 were <6 years of age and 34 were 6 to <12 years of age). The starting prophylactic regimen consisted of 25 IU/kg on the first day followed by 50 IU/kg on the fourth day. Dosing of up to 80 IU/kg and a dosing interval as short as 2 days was allowed and used in a limited number of patients. Out of 67 subjects having completed Study II, 61 enrolled onto Study III (extension study). Median total time on study II+III was 3.4 years and median number of exposure days was 332.

Prophylaxis, age <6 years: Median dose interval was 3.50 days in Study II and Study III. Median annual factor consumption was 5146 IU/kg (min. 3695, max. 8474) in Study II and 5418 IU/kg (min. 3435, max.
9564) in Study III. Respective median Annualized Bleed Rate (ABR) was 0.00 (min. 0, max. 10.5) and 1.18 (min. 0, max. 9.2).

Prophylaxis, age 6 up to 12 years: Median dose interval was 3.49 days in Study II and 3.50 days in Study III.
Median annual factor consumption was 4700 IU/kg (min. 3819, max. 8230 IU/kg) in Study II and 4990 IU/kg (min. 3856, max. 9527) in Study III. Respective median ABR was 2.01 (min. 0, max. 27.2) and
1.59 (min. 0, max. 8.0).

12 adolescent subjects age 12 up to 18 years were included in the adult study population on prophylactic treatment. Median annual factor consumption was 5572 IU/kg (min. 3849, max. 7035) in Study I and 4456 IU/kg (min. 3563, max. 8011) in Study III. Respective median ABR was 1.92 (min. 0, max. 7.1) and
1.25 (min. 0, max. 9.5).

Treatment of bleeding: During Studies II and III, 447 bleeding events were treated with a median dose of 63 IU/kg (min. 28, max. 186) to control each bleed. 90.2 % of first injections were rated as excellent or good by the patients and their caregivers.

Study IV evaluated 103 male previously untreated patients (PUPs) <6 years of age with severe haemophilia A. Patients were followed for a total of 11,255 exposure days with a median of 100 (range 0-649) exposure days per patient. Most subjects started on episodic treatment (N=81) with subsequent transition to prophylaxis (N=69). At any time during the study, 89 PUPs received prophylaxis. The recommended initial dose on prophylaxis was 25–80 IU/kg at 3–5-day intervals. For subjects on prophylaxis, the median average weekly dose was 101.4 IU/kg (range: 28.5-776.3 IU/kg) and the median dosing interval was 3.87 days (range 1.1 to 7 days). Median annual factor consumption was 3971.4 IU/kg. Annualized Bleeding Rate was 1.49 (min. 0.0, max. 18.7).

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

All pharmacokinetic studies with ELOCTA were conducted in previously treated patients with severe haemophilia A. Data presented in this section were obtained by chromogenic and one-stage clotting assays.
The pharmacokinetic parameters from the chromogenic assay data were similar to those derived for the one-stage assay.


Pharmacokinetic properties were evaluated in 28 subjects (≥15 years) receiving ELOCTA (rFVIIIFc).
Following a washout period of at least 96 hours (4 days), the subjects received a single dose of 50 IU/kg of ELOCTA. Pharmacokinetic samples were collected pre-dose and then subsequently at 7 time points up to 120 hours (5 days) post-dose. Pharmacokinetic parameters after 50 IU/kg dose of ELOCTA are presented in Tables 3 and 4.

Table 3: Pharmacokinetic parameters of ELOCTA using the one-stage clotting assay ELOCTA
Pharmacokinetic parameters1                              (95% CI)
N=28
2.24
Incremental Recovery (IU/dL per IU/kg)
(2.11-2.38)
AUC/Dose                                          51.2
(IU*h/dL per IU/kg)                               (45.0-58.4)
108
Cmax (IU/dL)
(101-115)
1.95
CL (mL/h/kg)
(1.71-2.22)
19.0 t½ (h)
(17.0-21.1)
25.2
MRT (h)
(22.7-27.9)
49.1
Vss (mL/kg)
(46.6-51.7)
1
Pharmacokinetic parameters are presented in Geometric Mean (95% CI)
Abbreviations: CI = confidence interval; Cmax = maximum activity; AUC = area under the FVIII activity time curve; t½ = terminal half-life; CL = clearance; Vss = volume of distribution at steady-state; MRT = mean residence time.

Table 4: Pharmacokinetic parameters of ELOCTA using the chromogenic assay ELOCTA
Pharmacokinetic parameters1
(95% CI)
N=27
2.49
Incremental Recovery (IU/dL per IU/kg)
(2.28-2.73)
AUC/Dose                                          47.5
(IU*h/dL per IU/kg)                               (41.6-54.2)
131
Cmax (IU/dL)
(104-165)
2.11
CL (mL/h/kg)
(1.85-2.41)
20.9 t½ (h)
(18.2-23.9)
25.0
MRT (h)
(22.4-27.8)
52.6
Vss (mL/kg)
(47.4-58.3)
1
Pharmacokinetic parameters are presented in Geometric Mean (95% CI)
Abbreviations: CI = confidence interval; Cmax = maximum activity; AUC = area under the FVIII activity time curve; t½ = terminal half-life; CL = clearance; Vss = volume of distribution at steady-state; MRT = mean residence time.

The PK data demonstrate that ELOCTA has a prolonged circulating half-life.

Paediatric population
Pharmacokinetic parameters of ELOCTA were determined for adolescents in study I (pharmacokinetic sampling was conducted pre-dose followed by assessment at multiple time points up to 120 hours (5 days) post-dose) and for children in study II (pharmacokinetic sampling was conducted pre-dose followed by assessment at multiple time points up to 72 hours (3 days) post-dose). Tables 5 and 6 present the pharmacokinetic parameters calculated from the paediatric data of subjects less than 18 years of age.

Table 5: Pharmacokinetic parameters of ELOCTA for paediatrics using the one-stage clotting assay Study II                               Study I*
Pharmacokinetic                <6 years                6 to <12 years           12 to <18 years parameters1
N = 23                    N = 31                    N = 11
Incremental Recovery                1.90                      2.30                      1.81 (IU/dL per IU/kg)             (1.79-2.02)               (2.04-2.59)               (1.56-2.09) AUC/Dose                      28.9                      38.4                      38.2 (IU*h/dL per IU/kg)            (25.6-32.7)               (33.2-44.4)               (34.0-42.9) t½ (h)                     12.3                      13.5                      16.0 (11.0-13.7)               (11.4-15.8)               (13.9-18.5)
MRT (h)                      16.8                      19.0                      22.7 (15.1-18.6)               (16.2-22.3)               (19.7-26.1)
CL (mL/h/kg)                    3.46                      2.61                      2.62 (3.06-3.91)               (2.26-3.01)               (2.33-2.95)
Vss (mL/kg)                   57.9                   49.5                          59.4 (54.1-62.0)           (44.1-55.6)                   (52.7-67.0)
1
Pharmacokinetic parameters are presented in Geometric Mean (95% CI)
Abbreviations: CI = confidence interval; AUC = area under the FVIII activity time curve; t½ = terminal half-life;
CL = clearance; MRT = mean residence time; Vss = volume of distribution at steady-state *Pharmacokinetic parameters in 12 to <18 years included subjects from all the arms in Study I with different sampling schemes


Table 6: Pharmacokinetic parameters of ELOCTA for paediatrics using the chromogenic assay Study II                                  Study I*
Pharmacokinetic               <6 years                6 to <12 years             12 to <18 years parameters1
N = 24                    N = 27                       N = 11
Incremental Recovery              1.88                      2.08                        1.91 (IU/dL per IU/kg)           (1.73-2.05)               (1.91-2.25)                 (1.61-2.27) AUC/Dose                     25.9                      32.8                        40.8 (IU*h/dL per IU/kg)           (23.4-28.7)               (28.2-38.2)                 (29.3-56.7) t½ (h)                    14.3                      15.9                        17.5 (12.6-16.2)               (13.8-18.2)                 (12.7-24.0)
MRT (h)                     17.2                      20.7                        23.5 (15.4-19.3)               (18.0-23.8)                 (17.0-32.4)
CL (mL/h/kg)                   3.86                      3.05                        2.45 (3.48-4.28)               (2.62-3.55)                 (1.76-3.41)
Vss (mL/kg)                 66.5                   63.1                          57.6 (59.8-73.9)            (56.3-70.9)                   (50.2-65.9)
1
Pharmacokinetic parameters are presented in Geometric Mean (95% CI)
Abbreviations: CI = confidence interval; AUC = area under the FVIII activity time curve; t½ = terminal half-life;
CL = clearance; MRT = mean residence time; Vss = volume of distribution at steady-state * Pharmacokinetic parameters in 12 to <18 years included subjects from all the arms in Study I with different sampling schemes

In comparison with adolescents and adults, children less than 12 years of age may have a higher clearance and a shorter half-life which is consistent with observations of other coagulation factors. These differences should be taken into account when dosing.