Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: Bayer AG, 51368, Leverkusen, Germany
Pharmacotherapeutic group: antihemorrhagics: blood coagulation factor VIII
ATC code: B02BD02
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, annualised bleeding rate (ABR) is not comparable between different factor concentrates and between different clinical studies.
Kovaltry does not contain von Willebrand factor.
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.
Two multi-centre, open-label, cross-over, uncontrolled, randomised studies in previously treated adults/adolescents with severe haemophilia A (<1%) and one multi-centre, open-label, uncontrolled study in previously treated children <12 years with severe haemophilia A were conducted.
A total of 204 subjects have been included in the clinical trial program, 153 subjects ≥12 years and 51 subjects <12 years. 140 subjects were treated for at least 12 months, and 55 of these subjects for a median of 24 months.
Table 3. Consumption and overall success rates (patients treated with prophylaxis only):
| Younger children (0 < 6 years) | Older children (6 < 12 years) | Adolescents and adults 12-65 years | Total | |||
|---|---|---|---|---|---|---|
| Study 1 | Study 2 2 x/week dosing | Study 2 3 x/week dosing | ||||
| Study participants | 25 | 26 | 62 | 28 | 31 | 172 |
| Dose/prophylaxis injection, IU/kg BW median (min, max) | 36 IU/kg (21, 58 IU/kg) | 32 IU/kg (22, 50 IU/kg) | 31 IU/kg (21, 43 IU/kg) | 30 IU/kg (21, 34 IU/kg) | 37 IU/kg (30, 42 IU/kg) | 32 IU/kg (21, 58 IU/kg) |
| ABR – all bleeds (median, Q1,Q3) | 2,0 (0,0-6,0) | 0,9 (0,0-5,8) | 1,0 (0,0-5,1) | 4,0 (0,0-8,0) | 2,0 (0,0-4,9) | 2,0 (0,0-6,1) |
| Dose/injection for bleed treatment Median (min; max) | 39 IU/kg (21, 72 IU/kg) | 32 IU/kg (22, 50 IU/kg) | 29 IU/kg (13, 54 IU/kg) | 28 IU/kg (19, 39 IU/kg) | 31 IU/kg (21, 49 IU/kg) | 31 IU/kg (13, 72 IU/kg) |
| Success rate* | 92,4% | 86,7% | 86,3% | 95,0% | 97,7% | 91,4% |
ABR annualised bleed rate
Q1 first quartile; Q3 third quartile
BW: Body weight
* Success rate defined as % of bleeds treated successfully with ≤2 infusions
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 factor VIII 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 N=109 | 12-<18 years N=23 | 6-<12 years N=27 | 0-<6 years 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 Median; (Q1; Q3) (IU/dL / IU/kg) | 2.3 (1.8; 2.6) |
| One-stage assay results Median; (Q1; Q3) (IU/dL / IU/kg) | 2.2 (1.8; 2.4) |
Non-clinical data reveal no special risk for humans based on safety pharmacology, in vitro genotoxicity, and short term repeat-dose toxicity studies. Repeat-dose toxicity studies longer than 5 days, reproductive toxicity studies, and carcinogenicity studies, have not been performed. Such studies are not considered meaningful due to the production of antibodies against the heterologous human protein in animals. Also factor VIII is an intrinsic protein and not known to cause any reproductive or carcinogenic effects.
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