Source: European Medicines Agency (EU) Revision Year: 2022 Publisher: Octapharma AB, Lars Forssells gata 23, 112 75 Stockholm, Sweden
Pharmacotherapeutic group: Antihaemorrhagics, blood coagulation factor VIII
ATC code: B02BD02
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 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 results of accidental or surgical trauma. By replacement therapy the plasma levels of factor VIII are increased, thereby temporarily enabling a correction of the factor VIII deficiency and correction of the bleeding tendencies.
The immunogenicity of Vihuma was evaluated in clinical studies in 190 previously treated patients with severe haemophilia A (129 adult and 61 paediatric patients). None of the patients developed inhibitors.
In a clinical study in 32 adult patients with severe haemophilia A, the median consumption of Vihuma for prophylaxis was 468.7 IU/kg/month.
The median dose to treat break-through bleeding episodes was 33.0 IU/kg in these patients who were on prophylaxis. In another clinical study, 22 adult patients were treated on demand. In total 986 bleeding episodes were treated with a median dose of 30.9 IU/kg. In general, minor bleeds required slightly lower, and more severe bleeds required up to three-fold higher median doses.
Individualised PK-based prophylaxis was evaluated in 66 adult PTPs with severe haemophilia A. Following a 1-3 month standard prophylaxis phase (every other day or 3 times weekly dosing), 44 (67%) patients were switched to a dosing regimen based on their PK assessment, and 40 completed the 6 months of prophylaxis according to the assigned dosing and treatment scheme. Of these patients, 34 (85%) were treated twice weekly or less. 33 (82.5%) patients did not experience any bleeds and 36 (90.0%) patients had no spontaneous bleeds. The mean ± SD annualised bleeding rate was 1.2 ± 3.9 and the mean ± SD dose were 52.2 ± 12.2 IU/kg per injection and 99.7 ± 25.6 IU/kg per week. Of note, annualised bleeding rate (ABR) is not comparable between different factor concentrates and between different clinical studies.
Data have been obtained in 29 previously treated children between 2 and 5 years of age, 31 children between 6 and 12 years of age and one adolescent of 14 years. The median dose per prophylactic infusion was 37.8 IU/kg. Twenty patients used median doses of more than 45 IU/kg. The median consumption of Vihuma for prophylaxis per month was 521.9 IU/kg. A higher median dose of Vihuma was required to treat bleedings in children (43.9 IU/kg) than in adults (33.0 IU/kg), and a higher median dose was required to treat moderate to major than minor bleedings (78.2 IU/kg vs. 41.7 IU/kg). Younger children in general required higher median doses (6-12 years: 43.9 IU/kg; 2-5 years: 52.6 IU/kg). These data were corroborated by a long-term follow-up of 49 of these children who were treated for an additional median period of approximately 30 months (range from 9.5 to 52 months); during this period 45% of children had no spontaneous bleeds.
A prospective open-label clinical study in PUPs with severe haemophilia A (<1% FVIII:C) is ongoing.
The European Medicines Agency has deferred the obligation to submit the results of studies with Vihuma in one or more subsets of the paediatric population in treatment of haemophilia A (congenital factor VIII deficiency) (see section 4.2 for information on paediatric use).
Table 2. PK parameters for Vihuma (Dose: 50 IU/kg) in adult previously treated patients (age 18-65 years) with severe haemophilia A (n=20):
| PK parameter | Chromogenic assay | |
|---|---|---|
| Mean ± SD | Median (range) | |
| AUC (hr*IU/mL) | 22.6 ± 8.0 | 22.3 (8.4–38.1) |
| T1/2 (hr) | 14.7 ± 10.4 | 12.5 (5.4–55.6) |
| IVR (%/IU/kg) | 2.5 ± 0.4 | 2.5 (1.7–3.2) |
| CL (mL/hr/kg) | 3.0 ± 1.2 | 2.7 (1.5-6.4) |
AUC = Area under the curve (FVIII:C), T1/2 = Terminal half-life,
IVR = Incremental in vivo recovery, CL = Clearance, SD = Standard deviation
Table 3. PK parameters for Vihuma (Dose: 50 IU/kg) in previously treated children aged 6 to 12 years with severe haemophilia A (n=12):
| PK parameter | Chromogenic assay | |
|---|---|---|
| Mean ± SD | Median (range) | |
| AUC (hr*IU/mL) | 13.2 ± 3.4 | 12.8 (7.8–19.1) |
| T1/2 (hr) | 10.0 ± 1.9 | 9.9 (7.6–14.1) |
| IVR (%/IU/kg) | 1.9 ± 0.4 | 1.9 (1.2–2.6) |
| CL (mL/hr/kg) | 4.3 ± 1.2 | 4.2 (2.8–6.9) |
AUC = Area under the curve (FVIII:C), T1/2 = Terminal half-life,
IVR = Incremental in vivo recovery, CL = Clearance, SD = Standard deviation
Table 4. PK parameters for Vihuma (Dose: 50 IU/kg) in previously treated children aged 2 to 5 years with severe haemophilia A (n=13):
| PK parameter | Chromogenic assay | |
|---|---|---|
| Mean ± SD | Median (range) | |
| AUC (hr*IU/mL) | 11.7 ± 5.3 | 10.5 (4.9–23.8) |
| T1/2 (hr) | 9.5 ± 3.3 | 8.2 (4.3–17.3) |
| IVR (%/IU/kg) | 1.9 ± 0.3 | 1.8 (1.5–2.4) |
| CL (mL/hr/kg) | 5.4 ± 2.4 | 5.1 ( 2.3–10.9) |
AUC = Area under the curve (FVIII:C), T1/2 = Terminal half-life,
IVR = Incremental in vivo recovery, CL = Clearance, SD = Standard deviation
As known from the literature, recovery and half-life was lower in young children than in adults and clearance higher, which may be due in part to the known higher plasma volume per kilogram body weight in younger patients. Weight adjusted subgroups
Table 5. Weight-adjusted PK parameters for Vihuma (Dose: 50 IU/kg) in adult previously treated patients (age 18-65 years) with severe haemophilia A (n=20):
| PK parameter | All (n=20) | Normal weight (n=14) | Pre-adipose (n=4) | Adipose (n=2) |
|---|---|---|---|---|
| Chromogenic assay Mean ± SD | ||||
| AUC (hr*IU/mL) | 22.6 ± 8.0 | 20.4 ± 6.9 | 24.9 ± 8.9 | 33.5 ± 6.5 |
| T1/2 (hr) | 14.7 ± 10.4 | 14.7 ± 12.1 | 13.4 ± 5.9 | 17.2 ± 4.8 |
| IVR (%/IU/kg) | 2.5 ± 0.4 | 2.4 ± 0.4 | 2.7 ± 0.4 | 2.8 ± 0.3 |
| CL (mL/hr/kg) | 3.0 ± 1.2 | 3.2 ± 1.3 | 2.6 ± 1.0 | 1.8 ± 0.4 |
| Chromogenic assay Median (range) | ||||
| AUC (hr*IU/mL) | 22.3 (8.4–38.1) | 21.2 (8.4–32.6) | 23.3 (17.4–35.5) | 33.5 (28.9–38.1) |
| T1/2 (hr) | 12.5 (5.4–55.6) | 12.3 (5.4–55.6) | 11.2 (9.3–22.0) | 17.2 (13.8–20.6) |
| IVR (%/IU/kg) | 2.5 (1.7–3.2) | 2.4 (1.7–3.1) | 2.8 (2.3–3.2) | 2.8 (2.6–3.0) |
| CL (mL/hr/kg) | 2.7 (1.5–6.4) | 2.8 (1.7–6.4) | 2.5 (1.6–3.7) | 1.8 (1.5–2.0) |
Normal weight: BMI 18.5-25 kg/m², Pre-adipose: BMI 25-30 kg/m², Adipose: BMI >30 kg/m², SD = Standard deviation
In pre-clinical studies, Vihuma was used to safely and effectively restore haemostasis in dogs with haemophilia. Toxicology studies showed that local intravenous administration and systemic exposure were well tolerated in laboratory animals (rats and cynomolgus monkeys).
Specific studies with long-term repeated administration such as reproduction toxicity, chronic toxicity, and carcinogenicity were not performed with Vihuma due to the immune response to heterologous proteins in all non-human mammalian species.
No studies were performed on the mutagenic potential of Vihuma. Ex vivo evaluations using a commercial assay kit to quantify T cell response to protein therapeutics indicate a low risk of immunogenicity
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