Nonclinical Assessment of Bax 604 (FEIBA STAR) - Reduced Volume Reconstitution & Higher Infusion Rate

To support the BAX 604 (FEIBA STAR) clinical study assessing different infusion rates and low volume reconstitution, the following nonclinical program was initiated: Two studies were performed in normal rats and FVIII-inhibited rabbits to evaluate the acute toxicity of FEIBA using different infusion rates. Three further studies were conducted using FEIBA at a reduced reconstitution volume (50% of the currently licensed amount of water for injection, internally identified as BAX 604) to evaluate efficacy, thrombogenicity, and local tolerance in normal and FVIII-inhibited rabbits.

The two acute toxicity studies assessed the effect of administering 100 U/kg FEIBA twice 6 hours apart at infusion rates ranging from 2 to 100 U/kg/min. In rats, an exaggerated pharmacological effect was observed with all rates, the appearance and severity of which did not correlate with infusion rate. In FVIII-inhibited rabbits, the incidence and/or severity of thrombi also did not increase with infusion rate. These results revealed no correlation between an increasing infusion rate and increasing thrombogenicity of FEIBA.

The effect of a reduced reconstitution volume on efficacy and thrombogenicity was assessed in FVIII-inhibited and normal rabbits. Efficacy was tested in a FVIII-inhibitor nail clip model. Each rabbit was treated intravenously with heat-inactivated FVIII-inhibitor goat plasma 45 minutes prior to nail cut. The nail on digit II of the right hind limb was cut and blood was collected. Rabbits were treated intravenously with BAX 604 or FEIBA at doses of 10, 50, or 100 U/kg BW and blood was collected for another 30 minutes. Endpoints included blood loss before and after treatment. No spontaneous deaths or signs of acute toxicity were observed. Treatment with BAX 604 or FEIBA resulted in a dose-related lower relative blood loss (71%, 2%, and 4% for BAX 604; 104%, 3%, and 3% for FEIBA) that was statistically significant (at the 5% level) for doses of 50 or 100 U/kg. The thrombogenic potential of BAX 604 vs. FEIBA was evaluated after a single intravenous administration of 4 U/kg BW, which results in an infusion rate of 16 U/kg/min. Thrombogenicity was determined semi-quantitatively, scoring thrombus formation in the isolated jugular vein on a scale of 0 to 4. The thrombus scores obtained - 1 (n=5), 0.5 (n=1), and 0 (n=2) for BAX 604, and 2 (n=4), 1 (n=2), 0.5 (n=1) and 0 (n=1) for FEIBA - demonstrated that BAX 604 is no more thrombogenic than FEIBA in the rabbit stasis model using an infusion rate of 16 U/kg/min (1.6-fold maximum infusion rate planned for the clinical trial). Based on these results, BAX 604 is considered to be as safe as FEIBA with regard to thrombogenicity.

The local tolerance of BAX 604 and FEIBA was evaluated after intravenous, intra-arterial (2 mL/animal), or paravenous injection (0.5 mL/animal) into rabbits' ears. BAX 604 was well tolerated after intravenous and intra-arterial injection. Following a single paravenous injection, mild local irritation was observed for both products. This effect was slightly more pronounced for BAX 604 than for FEIBA, indicating that misapplication of either product should be avoided.

The results of these nonclinical studies indicate that the efficacy and safety profiles of FEIBA and BAX 604 are comparable. Infusion rates of up to 100 U/kg/min (10-fold the planned clinical infusion rate) of the low reconstitution product did not reveal any concerns with regard to adverse clinical signs. As the infusion is based on U/kg/min (and not ml/kg/min), these studies also support using the low reconstitution volume.

In conclusion, neither a faster infusion rate nor lower reconstitution volume of FEIBA are predicted to pose additional risks to human subjects when tested under the conditions of a clinical study.