Octapharma USA, Paramus, NJ, USA, New Jersey, United States
Background/Case Studies: Fibrinogen is essential for hemostasis; fibrinogen deficiency can lead to inadequate blood clot formation, resulting in excessive bleeding, and it can be congenital, or acquired through blood loss, consumption or dilution. Fibrinogen supplementation may be achieved with human fibrinogen concentrate (HFC) or cryoprecipitate. Cryoprecipitate is widely used in the US but HFC has advantages of viral reduction processing, known fibrinogen concentration, and can be administered immediately after reconstitution. The pharmacokinetics (PK), efficacy and safety of HFC (Fibryga, Octapharma) were assessed in two Phase 2 and three Phase 3 studies in patients with congenital (CFD) or acquired (AFD) fibrinogen deficiency.
Study
Design/Methods: FORMA-01 compared the PK of the investigational HFC to a comparator (RiaSTAP) in adults with CFD (Table 1). Efficacy and safety of HFC were investigated 1) in patients with CFD in the FORMA-02 and FORMA-04 uncontrolled studies, and 2) vs. cryoprecipitate in bleeding surgical patients with AFD in the FORMA-05 and FIBRES studies. Plasma fibrinogen level was assessed via Clauss assay before and after treatment. Hemostatic efficacy was assessed in FORMA-02, -04 and -05 by the Independent Data Monitoring & Endpoint Adjudication Committee (IDMEAC) using objective 4-point scales with treatment success defined as good/excellent. Safety was assessed by monitoring adverse events.
Results/Findings: PK was assessed in 21 patients with CFD in FORMA-01. The primary PK endpoint, activity-based ratio of geometric means for area under the curve normalized to dose administered (AUCnorm) for the investigational HFC vs. the comparator, was 1.196 (90% CI, 1.117, 1.281). Bioequivalence could not be demonstrated as the upper 90% CI was >1.25 (i.e., >125%), due to higher AUCnorm with HFC vs. the comparator.
Across all five studies, HFC increased mean fibrinogen level (Table 1). This coincided with hemostatic effectiveness, demonstrated by 100% of patients achieving hemostatic efficacy rated by the IDMEAC as ‘success’ (Table 1) as per primary endpoints of FORMA-02, -04 and -05. In FIBRES, HFC was non-inferior to cryoprecipitate for the primary endpoint; mean (±SD) number of allogeneic blood products transfused during the first 24 h after termination of cardiopulmonary bypass (p< 0.0001 for non-inferiority; Table 1).
All five studies demonstrated HFC had a favorable safety profile.
Conclusions: Five Phase 2/Phase 3 trials demonstrated that HFC was effective in increasing plasma fibrinogen level in patients with CFD or AFD, and was hemostatically efficacious. Moreover, HFC had a favorable safety profile. Together with other advantages of HFC over cryoprecipitate, including viral reduction, results advocate the use of HFC in patients with CFD or AFD.
