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

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 Cmax 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, Cmax after FIB Grifols infusion was 2.88 (0.86) mg/mL, with a tmax 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.

Comparing the incidence of bone tumors in rats chronically exposed to the selective PTH type 1 receptor agonist abaloparatide or PTH(1-34).

Prolonged treatment with human parathyroid hormone (hPTH) in rats results in development of bone tumors, though this finding has not been supported by clinical experience. The PTH type 1 receptor agonist abaloparatide, selected for its bone anabolic activity, is under clinical development to treat postmenopausal women with osteoporosis. To determine the carcinogenic potential of abaloparatide, Fischer (F344) rats were administered SC daily abaloparatide at doses of 0, 10, 25, and 50 µg/kg or 30 µg/kg hPTH(1-34) as a positive control for up to 2 years. Robust increases in bone density were achieved at all abaloparatide doses and with hPTH(1-34). Comprehensive histopathological analysis reflected a comparable continuum of proliferative changes in bone, mostly osteosarcoma, in both abaloparatide and hPTH(1-34) treated rats. Comparing the effects of abaloparatide and hPTH(1-34) at the 25 and 30 µg/kg respective doses, representing similar exposure multiples to the human therapeutic doses, revealed similar osteosarcoma-associated mortality, tumor incidence, age at first occurrence, and metastatic potential. There were no increases in the incidence of non-bone tumors with abaloparatide compared to vehicle. Thus, near life-long treatment with abaloparatide in rats resulted in dose and time dependent formation of osteosarcomas, with a comparable response to hPTH(1-34) at similar exposure.