Safety of Baxter’s Longer Acting rFVIII (BAX 855) After Repeated Application in Rats and Cynomolgus Monkeys

Abstract 4345

Baxter and Nektar have developed BAX 855, a PEGylated form of Baxter’s recombinant FVIII (rFVIII) product based on the ADVATE™ manufacturing process. The objective of this preclinical study program was to evaluate the safety of BAX 855 in different species. The systemic toxic potential of BAX 855 was tested in rats and cynomolgus monkeys. The product was given intravenously at 350 or 700 U/kg to rats every other day for 28 days. Monkeys were treated at doses of 150, 350 or 700 U/kg every five days for one month. To demonstrate consistent safety between different batches, two lots of BAX 855 were used in each study. Assessment of toxicity was based on mortality, clinical observations, ophthalmic examination, clinical pathology, assessment on male fertility in rats, organ weights and pathology evaluations. In addition to safety endpoints, toxicokinetics and the formation of anti-product antibodies were assessed. In rats, no drug-related changes with respect to body weight, food consumption, ophthalmoscopy, hematology cellular variables, clinical chemistry, urinalysis, seminology or organ weights were noted. In addition, there were no treatment-related adverse effects on the coagulation markers. Macroscopic as well as microscopic examination and organ weights revealed no test-item related adverse effects.

In monkeys, there were no signs of toxicity or mortalities throughout the experimental period at any dose level. Minor findings in red blood cell variables as well as a corresponding increase in reticulocyte counts together with bloody emesis or hematoma in single animals and a prolonged APTT in all animals treated with BAX 855 were noted during the last week of dosing. These observations were likely caused by the development of cross-reactive neutralizing anti-FVIII antibodies against endogenous FVIII which probably caused a partial reduction in cynomolgus monkey FVIII activity. A partial recovery for APTT was noted until day 12 of the recovery phase. The formation of binding and neutralizing antibodies was also reflected in a statistically significant decrease in exposure observed during toxicokinetic analysis at the study end. The formation of antibodies against BAX 855 is an expected immune reaction after repeated application of heterologous human proteins to animals, which is also well known for non-PEGylated FVIII products.

In conclusion, intravenous administration of BAX 855 for 28 days did not result in any evidence of systemic effect. Therefore, 700 U/kg was considered the No Observed Adverse Effect level (NOAEL) in these studies. The good safety profile of BAX 855 during the preclinical program provides the basis for proceeding with human trials.