Nonclinical Safety of SHP 826 (BAX 826), a Next Generation Extended Half-Life Recombinant Factor VIII Product

Hemophilia A is a rare genetic bleeding disorder caused by missing or defective factor VIII (FVIII), a crucial factor in blood coagulation. Baxalta Innovations / Shire is currently developing SHP 826 (BAX 826), as the next generation EHL rFVIII replacement for the treatment of hemophilia A. SHP 826 is the first EHL rFVIII to utilize novel technology in which polysialic acid (PSA) is conjugated to Baxalta's licensed rFVIII product (Advate) to extend the circulation half-life of FVIII.

The potential toxicity of SHP 826 was evaluated in Sprague Dawley rats and cynomolgus monkeys. Acute toxicity was assessed in a dose-escalation study in monkeys that were intravenously administered 350 and 1800 IU rFVIII/kg SHP 826. Repeat dose toxicity was assessed in rats at doses of 80, 350, and 800 IU rFVIII/kg, in monkeys at doses of 800 IU rFVIII/kg every 5 days for 4 weeks, and in monkeys at doses of 80, 350, or 600 IU rFVIII/kg every five days for 31 days. Cardiovascular and respiratory safety was assessed in one of the repeat dose toxicity studies in monkeys. The thrombogenic potential of SHP 826 was evaluated after a single intravenous administration in rabbits (900 rFVIII/kg BW) using a stasis model developed by Wessler et al. (1959). The licensed rFVIII product was used as a comparator in the acute toxicity study and in the Wessler test.

Parameters evaluated included local tolerance at the injection site, body weight, clinical pathology, blood gas analysis, analysis of neutralizing and binding antibodies in plasma, organ weight, necropsy observation, and histopathological evaluation. In addition, seminology (epididymal and testicular sperm) was assessed in rats, and urinalysis, ophthalmic and telemetric cardiovascular examination and respiratory rate measurement was performed in monkeys.

SHP 826 showed a favorable safety/toxicity profile in both species used, with no abnormalities directly caused by test item administration noted in vivo or during clinical or histopathological examination. The NOAEL was set to the highest dose tested in each study (i.e. 800 IU rFVIII/kg BW in rats and 600 IU rFVIII/ kg BW in monkeys). Toxicokinetic evaluation indicated dose proportional PK. Exposure to FVIII decreased after repeated treatments due to appearance of anti-FVIII antibodies in both species. Development of anti-FVIII antibodies is an expected immune response after repeated application of heterologous proteins, and is not predictive of any potential for triggering development of anti-FVIII antibodies in humans.

Safety pharmacology studies with SHP 826 revealed no evidence of thrombogenic potential in rabbits. SHP 826 administered intravenously was well tolerated in conscious telemetered cynomolgous monkeys (part of the repeat dose toxicity study) and did not cause any adverse clinical, cardiovascular, or respiratory effects.

The results of these safety studies indicate sufficient safety margins to support the anticipated maximum clinical dose, and therefore entry into clinical development.