Preclinical safety, toxicokinetics and metabolism of BIIB131, a novel prothrombolytic agent for acute stroke

BIIB131, a small molecule, is currently in Phase 2 for the treatment of acute ischemic stroke. Safety and metabolism of BIIB131 were evaluated following intravenous administration to rats and monkeys. Exposure increased dose-proportionally in rats up to 60 mg/kg and more than dose-proportionally in monkeys at greater than 10 mg/kg accompanied by prolonged half-life and safety findings. The BIIB131 was poorly metabolized in microsomes with no inhibition of CYPs. BIIB131-glucuronide, formed by UGT1A1, accounted for 21.5% metabolism in human hepatocytes and 28-40% in rat bile. In rats, excretion was primarily via the bile. BIIB131 inhibited the hERG and Nav1.5 cardiac channels by 39% but showed no effect on cardiovascular parameters in monkeys. Toxicology findings were limited to reversable hematuria, changes in urinary parameters and local effects. A MTD of 30 mg/kg was established in monkeys, the most sensitive species, at total plasma Cmax and AUC of 6- and 14-fold, respectively, greater than the NOAEL. The Phase 1 study started with intravenous 0.05 mg/kg and ascended to 6.0 mg/kg which corresponded to safety margins of 147- to 0.9-fold (for Cmax) within the linear drug exposure. Thus, the preclinical profile of BIIB131 has been appropriately characterized and supports its further clinical development.

Automated summary

BIIB131, a small molecule currently in Phase 2 for acute ischemic stroke treatment, was evaluated for its safety and metabolism in rats and monkeys. The exposure of BIIB131 increased dose-proportionally in rats, but more than dose-proportionally in monkeys. The drug showed poor metabolism in microsomes and inhibited cardiac channels without affecting cardiovascular parameters. The toxicity findings were limited to reversible hematuria, changes in urinary parameters, and local effects. A maximum tolerated dose was determined for monkeys, and the Phase 1 study confirmed the linear drug exposure within the safety margins. Overall, the preclinical profile of BIIB131 supports its further clinical development.