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

Jonathan E. Zuckerman, Ismael Gritli, Anthony Tolcher, Jeremy D. Heidel, Dean Lim, Robert Morgan, Bartosz Chmielowski, Antoni Ribas, Mark E. Davis, Yun Yen

Research output: Contribution to journalArticlepeer-review

187 Citations (Scopus)

Abstract

Nanoparticle-based experimental therapeutics are currently being investigated in numerous human clinical trials. CALAA-01 is a targeted, polymer-based nanoparticle containing small interfering RNA (siRNA) and, to our knowledge, was the first RNA interference (RNAi)-based, experimental therapeutic to be administered to cancer patients. Here, we report the results from the initial phase I clinical trial where 24 patients with different cancers were treated with CALAA-01 and compare those results to data obtained from multispecies animal studies to provide a detailed example of translating this class of nanoparticles from animals to humans. The pharmacokinetics of CALAA-01 in mice, rats, monkeys, and humans show fast elimination and reveal that the maximum concentration obtained in the blood after i.v. administration correlates with body weight across all species. The safety profile of CALAA-01 in animals is similarly obtained in humans except that animal kidney toxicities are not observed in humans; this could be due to the use of a predosing hydration protocol used in the clinic. Taken in total, the animal models do appear to predict the behavior of CALAA-01 in humans.

Original languageEnglish
Pages (from-to)11449-11454
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number31
DOIs
Publication statusPublished - Aug 5 2014

Keywords

  • DNA proliferation
  • DNA replication
  • Dose limiting toxicity
  • Maximum tolerance dose
  • Translational medicine

ASJC Scopus subject areas

  • General

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