CEVENFACTA Powder and solvent for solution for injection Ref.[50508] Active ingredients: Coagulation factor VIIa

Pharmacotherapeutic group: Blood coagulation factors
ATC code: B02BD08

Mechanism of action

In normal conditions, FVIIa is the factor initiating coagulation following its interaction with tissuefactor (TF) at the cell surface. Once the complex is formed, it activates mainly Factor X to Factor Xa and also factor IX to factor IXa. Activation of Factor X to Factor Xa initiates the common pathway of the coagulation cascade in which prothrombin is activated to thrombin, and then converts fibrinogen to fibrin to form a haemostatic plug, thereby achieving clot formation at the site of haemorrhage (haemostasis). This reaction is several-fold amplified in presence of factor VIII and factor IX. In haemophilia A or B patients, factor VIII and factor IX molecules are absent or non-functional preventing coagulation amplification. This leads to debilitating bleeds that can sometimes be life threatening.

In these patients, FVIIa activates coagulation through the natural “TF-dependent” mechanism. However, the therapeutic doses required to reach haemostasis by using FVIIa are much more elevated than the normal FVII circulating concentration. The presence of these supra-natural doses of FVIIa induces two additional coagulation pathways.

A second coagulation pathway “TF-independent” leads similarly than the “TF-dependent” mode of action to the generation of FXa at the surface of activated platelets, without the need of TF to anchor FVIIa at the cell surface and modify its structure. In addition, the use of high-FVIIa doses also alleviates the natural and constant inhibition of FVIIa by the FVII zymogen.

In a third pathway, FVIIa competes with activated protein C (aPC) by binding to the endothelial protein C receptor (EPCR). FVIIa thus down modulates the anticoagulation by limiting the cleavage of Factor Va, the FXa co-factor, by the aPC.

The combination of these three pathways allows FVIIa to bypass the need of FVIIIa or FIXa restoring haemostasis in their absence or even in the presence of inhibitors.

Pharmacodynamic effects

Laboratory assessments of coagulation do not necessarily correlate with or predict the haemostatic effectiveness of this medicinal product.

In the Phase 1b clinical study, this medicinal product demonstrated a dose and concentrationdependent pharmacodynamic effect on the coagulation system, including shortening of aPTT and PT, and increasing the thrombin generation test with platelets (TGT) and the maximum clot firmness (Fibrin-based Thromboelastometry).

Clinical efficacy and safety

The efficacy of this medicinal product was evaluated in three phase 3 clinical studies in a total of 60 male patients with congenital haemophilia A or B with inhibitors. The safety of this medicinal product was evaluated in these three clinical studies and also in the Phase 1b study (15 patients) and in an additional clinical study with a PK assessment as the primary objective (28 patients), in a total of 103 unique male patients with congenital haemophilia A or B with inhibitors.

Efficacy in the treatment of bleedings in adults and adolescents:

PerSept 1 was a Phase 3, multicentre, open-label, randomised, crossover study of two initial dose regimens. The general objectives of this study were to assess the safety and efficacy of two dose regimens of the medicinal product across the full type of severity of bleeding episodes (mild, moderate, and severe), and to assess its pharmacokinetics. Per the study protocol patients ≥12 years of age (up to and including 75 years of age) with congenital haemophilia A or B with inhibitors to FVIII or FIX (positive inhibitor test BU threshold set at 5) were to be included. Patients who met all entry criteria were randomised to start the study with either 75 µg/kg or 225 µg/kg treatment regimen of this medicinal product. Twenty-seven adult and adolescent patients ( ≥12 years to less than 65 years of age) were included and evaluated for the treatment of 468 bleeding episodes with a median of 12 bleeding episodes per patient.

The results of an analysis of the proportion of successfully treated bleeding episodes with a “good” or “excellent” response (using a four-point rating scale), regardless of severity, at 12 hours after initial administration of this medicinal product (primary efficacy endpoint), with missing responses treated as failures are provided in Table 4.

Table 4. Proportion of bleeding episodes with a “Good” or “Excellent” response, regardless of severity, at 12 hours after initial administration of CEVENFACTA (treated population) – Missing responses treated as failures – PerSept 1 study:

Abbreviation: CI = confidence interval.
Notes: Table stratified by actual dose regimen at the time of the bleeding episode. Patients who completed Phase A without any safety concerns began treatment Phase B on the same CEVENFACTA treatment regimen that they were randomised to in Phase A (either 75 µg/kg or 225 µg/kg). Thereafter, the patient was crossed over to the alternate treatment regimen every 12 weeks until the end of the study.
¹ p-value from one-sided normal approximation test of H₀: p≤0.55, where p is the true proportion of successfully treated bleeding episodes at 12 hours, with adjustment for the correlation among bleeding episodes for a given patient. The test was conducted at the 0.0125 level (adjusted from 0.025 to 0.0125 to account for multiplicity of testing).
PerSept : Programme for the evaluation of recombinant factor Seven efficacy by prospective clinical trials.

In addition, at 24 hours, the majority of bleeding episodes was reported with a “good” or “excellent” assessment; the response was 96.7% [93.3%, 100%] and 99.5% [98.6%, 100%] with the 75 µg/kg and 225 µg/kg regimens respectively. The median time to attain a “good” or “excellent” assessment by the patient for a bleeding episode was 5.98 hours for the 75 μg/kg dosing regimen and 3 hours for the 225 μg/kg dosing regimen.

With regard to medicinal product consumption, a median of 1 and 2 injections was needed to treat a bleeding episode with the 225 and 75 µg/kg regimen respectively.

PerSept 2 was a Phase 3, global, multicentre, open-label, randomised, crossover study of two initial dose regimens. The general objectives of this study were to assess the safety and efficacy of two dose regimens of the medicinal product across the full type of severity of bleeding episodes (mild, moderate, and severe), and to assess its pharmacokinetics. The study included patients <12 years of age with congenital haemophilia A or B with inhibitors to FVIII or FIX (positive inhibitor test BU threshold set at 5).

Patients who met all entry criteria were randomised to start the study with either 75 µg/kg or 225 µg/kg of this medicinal product.

Twenty-five children (11.3 months to <12 years of age) were included and evaluated for the treatment of 549 bleeding episodes with a median of 17 bleeding episodes per patient.

Results of an analysis of the proportion of successfully treated bleeding episodes with a “good” or “excellent” response (using a four-point rating scale), regardless of severity, at 12 hours after initial administration of this medicinal product (primary efficacy endpoint), with missing responses treated as failures, are provided in Table 5.

Table 5. Proportion of bleeding episodes with a “Good” or “Excellent” response, regardless of severity, at 12 hours after initial administration of CEVENFACTA (treated population) - PerSept 2 study:

Abbreviation: CI = confidence interval.
Notes: Table stratified by actual treatment regimen at the time of the bleeding episode. Patients who completed Phase A without any safety concerns began treatment Phase B on the same treatment regimen that they were randomised to in Phase A (either 75 µg/kg or 225 µg/kg). Thereafter, the patient was crossed over to the alternate treatment regimen every 12 weeks until the end of the study.
¹ p-value from one-sided normal approximation test of H0: p ≤0.55, where p is the true proportion of successfully treated mild/moderate/severe bleeding episodes at 12 hours, with adjustment for the correlation among bleeding episodes for a given patient. The test was conducted at the 0.0125 level (adjusted from 0.025 to 0.0125 to account for multiplicity of testing).
PerSept: Programme for the evaluation of recombinant factor Seven efficacy by prospective clinical trials

The efficacy results are considered inconclusive for PerSept 2: the primary efficacy endpoint was not met (i.e., the Objective Performance Criterion (OPC) was not exceeded). See section 4.2.

Efficacy in the prevention of bleedings in surgery and invasive procedures:

PerSept 3 was a Phase 3, multicentre, open-label, single-arm study that evaluated the safety and efficacy of this medicinal product in patients from ≥6 months to ≤75 years of age, who had haemophilia A or B with inhibitors to FVIII or FIX (positive inhibitor test BU threshold set at 5), and who were scheduled for an elective surgical or other invasive procedure. Twelve patients were enrolled in the study (6 in the minor surgery group and 6 in the major surgery group). For a major surgical/invasive procedure, treatment was administered at an initial bolus dose of 200 μg/kg in a ≤2-minute intravenous injection immediately before the surgical incision or start of the invasive procedure. For a minor elective surgical/invasive procedure, this medicinal product was administered at an initial bolus dose of 75 μg/kg in a ≤2-minute intravenous injection immediately before the surgical incision or start of an invasive procedure. For both minor and major procedures, administration was repeated no more frequently than every 2 hours at a dose of 75 μg/kg during and after the surgical/invasive procedure. The median duration of exposure was 18 days (major procedures) and 2.2 days (minor procedures).

The primary efficacy endpoint was the percentage of surgical or other invasive procedures with a “good” or “excellent” response to treatment 48 (±4) hours after the last administration of this medicinal product as assessed by the investigator. This assessment was based on the totality of assessments performed on the patient at each time point, also taking into consideration the surgeon’s intraoperative haemostatic assessment, the number of (interventions for) bleeding episodes, oozing, blood transfusions, and the amount of medicinal product used. The primary analysis was based on non-missing assessments.

Six adults (up to 56 years old) and 6 paediatric patients (1 adolescent (14 years old) and 5 children (2 to 9 years old)) received this medicinal product for a total of 12 invasive procedures, of which 6 major and 6 minor. Four patients who previously participated in PerSept 1 (2 patients) and PerSept 2 (2 patients) were included in PerSept 3.

Of the 12 surgical procedures performed, 9 (81.8%) procedures were reported by the investigator as successfully treated (“good” or “excellent” response) at 48 hours after the last administration of this medicinal product, 2 (18.2%) were treatment failures (“poor” response), and 1 assessment was missing due to discontinuation of the study (withdrawal of consent) prior to the assessment at 48 hours.

The 2 treatment failures (“poor” response) were in the major surgery group. Response of one of them was imputed as “poor” due to discontinuation of the study following a TEAE leading to death (postprocedural haematoma within 2 days after the last dose of this medicinal product with antihaemorrhagic rescue treatment within 52 hours after the last dose of this medicinal product): this was a patient who experienced 1 day after drug administration post procedural hematoma, then 3 days after drug administration serious gastrointestinal haemorrhage and serious blood loss anaemia, leading to death on the same day. The gastrointestinal haemorrhage and blood loss anaemia were initially reported as unlikely to be related and were subsequently updated to be probably related to the medicinal product by the investigator. Finally, following the independent Data Monitoring Committee (DMC)'s and Sponsor’s reassessment, the causality assessment was considered as “unrelated”. The other treatment failure required rescue treatment at postoperative Day 7 after which time he was determined to be a treatment failure.

The intraoperative haemostatic effect was rated as “excellent” or “good” for all 12 of the minor and major surgeries. The mean estimated actual intraoperative blood loss was lower compared to the mean maximum predicted blood loss (for a patient without a bleeding disorder undergoing the same procedure) for both minor surgeries (2.3 mL for actual intraoperative and 4.2 mL for maximum predicted) and major surgeries (270.0 mL and 350.0 mL, respectively).