Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: antihemorrhagics: blood coagulation factor VIII, ATC code B02BD02.


Mechanism of action

The factor VIII/von Willebrand factor (vWF) complex consists of two molecules (factor VIII and vWF) with different physiological functions. When infused into a haemophiliac patient, factor VIII binds to vWF 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 a sex-linked hereditary disorder of blood coagulation due to decreased levels of factor VIII:C 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 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.

Kovaltry does not contain von Willebrand factor.

Pharmacodynamic effects
The activated partial thromboplastin time (aPTT) is prolonged in people with haemophilia.
Determination of aPTT is a conventional in vitro assay for biological activity of factor VIII. Treatment with rFVIII normalizes the aPTT similar to that achieved with plasma-derived factor VIII.

Clinical efficacy and safety

Control and Prevention of Bleeding
Two multi-centre, open-label, cross-over, uncontrolled, randomized studies in previously treated adults/adolescents with severe haemophilia A (< 1%) and one multicentre, open label, uncontrolled study in PTPs< 12 years of age (Part A) and PUPs/MTPs <6 years of age (Part B) with severe haemophilia A were conducted.

A total of 247 subjects (204 PTPs and 43 PUPs/MTPs) have been exposed in the clinical trial program, 153 subjects ≥ 12 years and 94 subjects < 12 years. Two-hundred and eight (208) subjects (174 PTPs, 34 PUPs/MTPs) were treated for at least 360 days, and 98 of these subjects (78 PTPs, 20 PUPs/MTPs) for at least 720 days.


Paediatric population <12 years
Part A: The paediatric trial enrolled 51 PTPs with severe haemophilia A, 26 subjects in the age group 6-12 years and 25 subjects in the age group <6 years having accumulated a median number of 73 EDs (range: 37 to 103 EDs). Subjects were treated with 2 or 3 injections per week or up to every other day at a dose of 25 to 50 IU/kg. Consumption for prophylaxis and treatment of bleeds, annualised bleed rates and success rate for bleed treatment are presented in Table 3.

Part B: A total of 43 PUPs/MTPs were enrolled and accumulated a median of 46 EDs (range 1 to 55 EDs). The median dose for treatment of bleeds in all PUPs/MTPs was 40.5 IU/kg and 78.1% of the bleeds were successfully treated with ≤ 2 infusions.
The most frequently reported adverse reaction in PUPs/MTPs was Factor VIII inhibitor (see section 4.8). FVIII inhibitors were detected in 23 of 42 patients with a median (range) of 9 (4 – 42) EDs at the time of the first positive inhibitor test. Of these, 6 patients had low-titre inhibitors (≤ 5.0 BU) and 17 patients had high-titre inhibitors.

Extension: Of the 94 treated subjects, 82 subjects entered the Leopold Kids extension study, 79 patients received treatment with Kovaltry and 67 patients received Kovaltry as prophylaxis treatment. The median time in the extension study was 3.1 years (range 0.3 to 6.4 years), the median total time in entire study (main plus extension study) was 3.8 years (range 0.8 to 6.7 years).
During the extension study, 67 of 82 subjects received Kovaltry as prophylaxis treatment. Amongst the 67 subjects, a total of 472 bleeds were treated with Kovaltry, requiring 1-2 infusions for the majority of bleeds (83.5%), and response to treatment was good or excellent in most (87.9%) of the cases.

Immune Tolerance Induction (ITI)
Data on ITI has been collected in patients with haemophilia A. 11 subjects with high titer inhibitors received ITI with various treatment regimens of three times per week up to twice daily. 5 subjects completed ITI with a negative inhibitor result at the end of the study, and 1 subject had a low titer (1.2 BU/mL) at time of discontinuation.


Table 3: Consumption and overall success rates (patients treated with prophylaxis only) Younger        Older             Adolescents and adults                        Total children     children                   12-65 years
(0 <6       (6 <12 years)      years)
Study 1        Study 2     Study 2

2 x/week       3 x/week dosing         dosing
Study                      25           26              62           28             31             172 participants


Dose/prophylaxis       36 IU/kg     32 IU/kg       31 IU/kg       30 IU/kg       37 IU/kg       32 IU/kg injection, IU/kg          (21;         (22;           (21;           (21;           (30;           (21; BW                     58 IU/kg)    50 IU/kg)      43 IU/kg)      34 IU/kg)      42 IU/kg)      58 IU/kg) median (min,
max)


ABR – all bleeds          2.0           0.9           1.0            4.0            2.0            2.0 (median, Q1,Q3)        (0.0; 6.0)    (0.0; 5.8)    (0.0; 5.1)     (0.0; 8.0)     (0.0; 4.9)     (0.0; 6.1) 

Dose/injection for      39 IU/kg    32 IU/kg       29 IU/kg       28 IU/kg       31 IU/kg       31 IU/kg bleed treatment        (21;72 IU       (22;           (13;           (19;           (21;           (13; Median (min;              /kg)      50 IU/kg)      54 IU/kg)      39 IU/kg)      49 IU/kg)      72 IU/kg) max)
Success rate*            92.4%        86.7%            86.3%        95.0%          97.7%          91.4% 
ABR annualized bleed rate
Q1 first quartile; Q3 third quartile
BW: Body weight
*Success rate defined as % of bleeds treated successfully with < 2 infusions 

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

The pharmacokinetic (PK) profile of Kovaltry was evaluated in PTPs with severe haemophilia A following 50 IU/kg in 21 subjects ≥ 18 years, 5 subjects ≥ 12 years and < 18 years and 19 subjects < 12 years of age.

A population PK model was developed based on all available FVIII measurements (from dense PK sampling and all recovery samples) throughout the 3 clinical studies allowing calculation of PK 
parameters for subjects in the various studies. The table 4 below provides PK parameters based on the population PK model.

Table 4: PK parameters (geometric mean (%CV)) based on chromogenic assay. * PK parameter         ≥ 18 years      12-<18 years     6-<12 years        0-<6 years N=109             N=23             N=27              N=24
T1/2 (h)           14.8 (34)        13.3 (24)        14.1 (31)         13.3 (24) AUC (IU.h/dL)**       1,858 (38)       1,523 (27)       1,242 (35)         970 (25) CL (dL/h/kg)         0.03 (38)        0.03 (27)        0.04 (35)         0.05 (25) Vss (dL/kg)         0.56 (14)        0.61 (14)        0.77 (15)         0.92 (11) * Based on population PK estimates
**AUC calculated for a dose of 50 IU/kg

Repeated PK measurements after 6 to 12 months of prophylaxis treatment with Kovaltry did not indicate any relevant changes in PK characteristics after long-term treatment.

In an international study involving 41 clinical laboratories, the performance of Kovaltry in FVIII:C assays was evaluated and compared to a marketed full length rFVIII product. Consistent results were determined for both products. The FVIII:C of Kovaltry can be measured in plasma with a one-stage coagulation assay as well as with a chromogenic assay using the routine methods of the laboratory.

The analysis of all recorded incremental recoveries in previously treated patients demonstrated a median rise of > 2% (> 2 IU/dL) per IU/kg body weight for Kovaltry. This result is similar to the reported values for factor VIII derived from human plasma. There was no relevant change over the 6-12 months treatment period.

Table 5: Phase III incremental recovery results
Study participants                                                         N=115 Chromogenic assay results                                               2.3 (1.8; 2.6) Median; (Q1; Q3) (IU/dL / IU/kg)
One-stage assay results                                                 2.2 (1.8; 2.4) Median; (Q1; Q3) (IU/dL / IU/kg)