Pharmacokinetic (PK) Comparison of Two Fibrinogen Concentrates for the Treatment of Congenital Fibrinogen Deficiency

Patients with congenital afibrinogenaemia and hypofibrinogenaemia, experience frequent severe bleeding episodes starting at birth or early childhood. Bleeding may occur after a minor trauma or a small surgical intervention, into the skin, mucosa, muscles, gastrointestinal tract, or the brain. Therapeutic substitution with human fibrinogen concentrate can correct the haemostatic defect and arrest the bleeding in patients with these fibrinogen deficiencies. Octafibrin is plasma derived, highly purified, lyophilized, fibrinogen concentrate, which has been double virus safeguarded using two dedicated virus inactivation/removal steps. In this study, the (PK) profile of this new concentrate is compared to a commercially available product (Haemocomplettan® P/RiaSTAPTM). This ongoing study is a prospective, randomized, open-label, multinational, crossover PK comparison of Octafibrin to an existing marketed product with planned interim data in 9 adult and adolescent patients, including comparison of a surrogate efficacy endpoint Maximum Clot Firmness (MCF) measured by ROTEM®. The study includes a crossover design where both products are given a single dose in a randomized fashion separated by an observation period and washout of any fibrinogen product prior to infusion. Patients are confirmed afibrinogenemic with baseline fibrinogen activity plasma level of < 0.20. All fibrinogen and MCF testing was performed in a central lab using validated methods. Nine patients completed the study until the end of May 2014. There have been no reports of adverse events (AE) related to the infusion of this novel concentrate. Comparable PK profiles between the products were seen but in key parameters, Normalized Aria Under the Curve (AUCnorm) (h·mg/mL/(mg/kg) Octafibrin 0.994, Haemocomplettan® P/RiaSTAPTM 0.731 p-value 0.014) and clearance (mL/h/kg Octafibrin 0.522, Haemocomplettan® P/RiaSTAPTM 0.594 p-value 0.033), significant differences were observed between the groups. Comparable haemostatic efficacy of Octafibrin and Haemocomplettan® P/RiaSTAPTM was demonstrated based on their ability to significantly increase MCF. Mean (± SD) Fibrinogen Levels (g/L) during PK Assessment after Octafibrin and Haemocomplettan® P/RiaSTAPTM Administration, Standardized to 70 mg/kg (PK Population, n=9) ! [Figure 1][1] Figure 1 Ratios of Octafibrin Relative to Haemocomplettan® P/RiaSTAPTM for AUC and AUCnorm (PK Population, N=9) | | Fibrinogen activity | || | Parameter ratio | Mean | 90% CI of mean ratio | p-value | | AUC | 139.11 | 79.25, 246.13 | 0.0173 | | AUCnorm | 139.96 | 80.26, 245.94 | 0.0144 | Table 1 Baseline Characteristics of Patients with and without Cardiac Complications in TTP In conclusion, this study showed in general a comparable PK profile for Octafibrin and Haemocomplettan® P/RiaSTAPTM in patients with congenital fibrinogen deficiency. Octafibrin showed a significantly higher AUCnorm and lower clearance than the comparator. The haemostatic efficacy of Octafibrin, as measured by change in MCF as a surrogate parameter, was similar to that of the licensed comparator used in this study, and there was no related AE or SAE for Octafibrin after single-dose administration. Disclosures Schwartz: Octapharma: Employment. Knaub: Octapharma: Employment. [1]: pending:yes