Pharmacokinetics, surrogate efficacy, and safety evaluations of a new human plasma-derived fibrinogen concentrate (FIB Grifols) in adult patients with congenital afibrinogenemia

Authors: Ross, CR., Subramanian, S., Navarro-Puerto, J., Subramanian, K., Kalappanavar, N. K., Khayat, CD., Acharya, SS., Peyvandi, F., Rucker, K., Liang, W., Vilardell, D., Trimm, S., and Ayguasanosa, J.

Publication: Thromb. Res.; 199,110-118. January 2021

Affiliations: Department Medicine & Hematology, St. John’s Medical College Hospital, Bangalore, Karnataka, India ; Transfusion Medicine and Immunohematology, St. John’s Medical College Hospital, Bangalore, Karnataka, India; Grifols Bioscience Research Group, Grifols, Barcelona, Spain ; Sahyadri Super Specialty Hospital, Maharashtra, India ; S. S. Institute of Medical Sciences and Research Centre, Davangere, Karnataka, India ; Hotel Dieu de France Hospital Beirut, Saint Joseph University, Lebanon ; Long Island Jewish Medical Center, Northwell Health, New Hyde Park, New York, USA ; Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, UOC Medicina Generale – Emostasi e Trombosi, Fondazione IRCCS CÃ Granda Ospedale Maggiore Policlinico, Milano, Italy; Department of Pathophysiology and Transplantation, Université degli Studi di Milano, Milano, Italy ; Certara Strategic Consulting, Montreal, Canada Abstract:

BACKGROUND AND AIMS: Congenital afibrinogenemia is a rare coagulation disorder resulting from a deficiency in fibrinogen. This study assessed the pharmacokinetics, surrogate efficacy, and safety of FIB Grifols, a new human plasma-derived fibrinogen concentrate, to treat congenital afibrinogenemia. METHODS: Eleven adult patients from a multinational, phase 1-2, prospective, open-label, single-arm, uncontrolled clinical study received a single infusion of FIB Grifols, 70 mg/kg bw. Fibrinogen pharmacokinetics (fibrinogen activity: Clauss method; antigen plasma concentrations: ELISA) and efficacy parameters were determined over 14 days after infusion. Efficacy endpoints were the mean change on plasma maximum clot firmness (MCF) on viscoelastic testing and coagulation tests 1-hour post-infusion, and correlation with fibrinogen levels throughout. Safety parameters were also assessed. RESULTS: For the Clauss method, (mean [standard deviation]) baseline adjusted C(max) was 1.99 (0.40) g/L, reached 1.76 (1.00) h after infusion, and half-life was 76.94 (20.21) h. Using ELISA, C(max) after FIB Grifols infusion was 2.88 (0.86) mg/mL, with a t(max) of 3.06 (2.24) h. Fibrinogen activity and antigen concentrations showed statistically significant correlation of 0.9120 (P < 0.001). Surrogate efficacy was demonstrated by a significant increase of 12.35 (3.85) mm in MCF. Prothrombin time, activated partial thromboplastin time and thrombin time, returned to normal ranges over time, indicating restoration of functionally active fibrinogen. There were no treatment-related adverse events, allergic reactions, serious adverse events, or discontinuations. CONCLUSIONS: The pharmacokinetic profile of functionally active FIB Grifols was established, hemostasis was restored, and FIB Grifols was safe and well tolerated in fibrinogen-deficient patients.