Correlating animal and human phase Ia/Ib clinical data with CALAA-01, a targeted, polymer-based nanoparticle containing siRNA

摘要

Nanoparticle-based experimental therapeutics are currently beingudinvestigated in numerous human clinical trials. CALAA-01 is a targeted,udpolymer-based nanoparticle containing small interferingudRNA (siRNA) and, to our knowledge, was the first RNA interferenceud(RNAi)–based, experimental therapeutic to be administeredudto cancer patients. Here, we report the results from the initialudphase I clinical trial where 24 patients with different cancers wereudtreated with CALAA-01 and compare those results to data obtainedudfrom multispecies animal studies to provide a detailed exampleudof translating this class of nanoparticles from animals toudhumans. The pharmacokinetics of CALAA-01 in mice, rats, monkeys,udand humans show fast elimination and reveal that the maximumudconcentration obtained in the blood after i.v. administrationudcorrelates with body weight across all species. The safety profile ofudCALAA-01 in animals is similarly obtained in humans except thatudanimal kidney toxicities are not observed in humans; this could beuddue to the use of a predosing hydration protocol used in the clinic.udTaken in total, the animal models do appear to predict the behaviorudof CALAA-01 in humans.