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The toxicological study effects of rFVIIIFc were measured through observations of in-life parameters (clinical observations, body weight, food consumption, and ophthalmic examination), laboratory evaluations (hematology, serum chemistry, and coagulation parameters), and post-mortem evaluation (gross necropsy, organ weights, and histopathology) in all studies. Cardiovascular evaluations were also performed for monkeys in the repeat-dose toxicology study. Electrocardiograms (ECGs) were recorded for all monkeys prior to dosing and on Day 23, as well as in the week prior to the scheduled core cohort necropsy (Day 26) and all recovery monkeys during the week prior (Day 54) to the recovery cohort necropsy; ECGs were analyzed qualitatively by a board-certified veterinary cardiologist. Heart rates were calculated from the ECG tracings. Local tolerance was evaluated through gross and microscopic evaluation of the intravenous infusion site in the repeat-dose studies in both rats and monkeys.
For the repeat-dose studies, assessments of in-life parameters, clinical pathology, and post-mortem evaluations were analyzed statistically when the number of animals was 3 or greater. Data were analyzed for effects of rFVIIIFc through an analysis of variance. For data with variances that were homogeneous across test groups, as determined by Bartlett’s test for homogeneity at the 0.05 level, tests for differences between experimental and control groups were made using Dunnett’s test. For non-homogenous data, tests for pair-wise differences between experimental and control groups were made using Cochran and Cox’s modified 2-sample t test. Statistical significance was set at the 0.05 level for all comparisons.
Rats and monkeys were pharmacologically relevant species for toxicological study, as the coagulation cascade is well conserved across species and rFVIIIFc is able to bind to FcRn in both species (unpublished data). The route of administration (intravenous) and formulations of rFVIIIFc used in this study were consistent with those used in clinical studies; the lyophilized formulation used in the repeat-dose monkey study was representative of the formulation intended for commercial use. Dosing frequency in the repeat-dose studies (every other day) was based on an elimination half-life of approximately 13 hours in both species. The doses of rFVIIIFc used in these studies (50-1000 IU/kg in the repeat-dose studies and 3000-20,000 IU/kg in the high-dose study) were greater than those indicated for use in humans.
rFVIIIFc was well tolerated in 2 relevant animal species, rats and monkeys. An adequate safety margin of 10-fold was demonstrated, based on a NOAEL of 1000 IU/kg in the repeat-dose toxicology studies compared with a highest anticipated clinical dose of 100 IU/kg. The nonclinical safety profile of rFVIIIFc shown here supported the observed clinical safety profile of rFVIIIFc  and. Furthermore, the A-LONG phase 3 clinical study demonstrated that rFVIIIFc was well tolerated and efficacious for the prevention and treatment of bleeding episodes in previously treated subjects with severe hemophilia.