Efficacy and Safety of Fibrinogen Concentrate for on-Demand Treatment of Acute Bleeding and for Surgical Prophylaxis in Subjects with Congenital Fibrinogen Deficiency — a Phase 3 Study

Introduction: Congenital afibrinogenemia is a rare inherited disorder characterized by an absence of plasma fibrinogen. Affected individuals have a highly variable bleeding tendency, which can be severe and include life-threatening bleeding and spontaneous/trauma-related bleeds. Therapeutic substitution with human fibrinogen concentrate (HFC) can correct the hemostatic defect and arrest bleeding. The FORMA-02 study investigated the hemostatic efficacy of a new plasma-derived, double virus-inactivated HFC (Fibryga, Octapharma) for on-demand treatment of bleeding episodes (BEs) and for surgical prophylaxis in patients with afibrinogenemia.

Methods: FORMA-02 was a prospective, open-label, uncontrolled, multicenter Phase 3 study. A total of 25 patients with congenital afibrinogenemia (≥12 years) received the new HFC for treatment of a BE and/or for surgical prophylaxis. HFC was individually dosed to achieve a recommended target fibrinogen plasma level dependent on the bleeding type or surgery type (minor or major). The primary endpoint was the efficacy of the new HFC for on-demand treatment of the first BE after signed consent was obtained. Secondary endpoints included hemostatic efficacy of the HFC for the treatment of all BEs during the study period and its efficacy in preventing bleeding during and after surgery. Hemostatic efficacy was assessed by investigators and an Independent Data Monitoring and Endpoint Adjudication Committee (IDMEAC) using objective four-point scales, with treatment success defined as a rating of excellent or good. Thromboelastometry maximum clot firmness (MCF) was also investigated as a surrogate marker of efficacy.

Results: A total of 25 patients received the new HFC for treatment of a BE (N=24) and/or surgical prophylaxis (N=9). The mean±SD dose of HFC was 65.51±26.47 mg/kg per BE (89 events) and 40.45±30.78 mg/kg per surgery for surgical prophylaxis (12 events). Hemostatic efficacy for treatment of the first BE (primary endpoint) was rated as excellent or good for all patients by both the investigator and the IDMEAC (Success: 100%; 90% CI 0.89-1.00). When all BEs were evaluated (N=89 BEs in 24 patients), hemostatic efficacy was rated as excellent or good for 96.6% of events by the investigator and 98.9% by the IDMEAC. The first HFC infusion for treatment of the first BE for each patient led to a mean increase in blood fibrinogen concentration of 114.74±25.28 mg/dL 1 hour after administration, while the MCF increased by a mean of 6.48±3.07 mm.

Intraoperative hemostatic efficacy for surgical prophylaxis was rated by the surgeon and the IDMEAC as excellent or good for 100% of the 12 surgeries that were performed (success: 100%; 90%CI 0.82-1.00). Postoperative efficacy was also rated as excellent or good in all cases. The first HFC infusion for each surgery led to a mean increase in blood fibrinogen concentration of 104.55±43.64 mg/dL at 1 hour after administration.

A total of 15 serious adverse events (SAEs) occurred in 5 patients; only one was deemed to be related to the HFC by the investigator. This was a digital ischemia that resolved without sequelae. No inhibitory anti-fibrinogen antibodies were detected and there were no severe allergic or hypersensitivity reactions related to the HFC.

Conclusions: These data indicate that the new HFC was efficacious for on-demand treatment of acute bleeding and for surgical prophylaxis in patients with congenital afibrinogenemia, with hemostatic efficacy rated as 100% in both settings. The HFC showed an acceptable safety profile in this study population.