Correlating animal and human phase Ia/Ib clinical data with CALAA-01, a targeted, polymer-based nanoparticle containing siRNA
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.
Additional Information
Copyright © 2014 National Academy of Sciences. Freely available online through the PNAS open access option. Contributed by Mark E. Davis, June 20, 2014 (sent for review May 29, 2014) We thank the patients who participated in the clinical trials. The clinical trial was sponsored by Calando Pharmaceuticals. J.E.Z. is supported by National Institutes of Health National Institute of General Medical Sciences Training Grant GM08042 and the University of California at Los Angeles–Caltech Medical Scientist Training Program. Author contributions: A.T., A.R., and Y.Y. designed research; A.T., D.L., R.M., B.C., A.R., and Y.Y. performed research; J.E.Z., I.G., J.D.H., M.E.D., and Y.Y. analyzed data; A.T., A.R., and Y.Y. directed clinical site; A.T., D.L., R.M., B.C., A.R., and Y.Y. recruited patients; and J.E.Z., I.G., M.E.D., and Y.Y. wrote the paper. The authors declare no conflict of interest. This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1411393111/-/DCSupplemental.Attached Files
Published - 11449.full.pdf
Supplemental Material - PNAS-2014-Zuckerman-1411393111.pdf
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Additional details
- PMCID
- PMC4128111
- Eprint ID
- 47295
- Resolver ID
- CaltechAUTHORS:20140717-114522722
- Calando Pharmaceuticals
- NIH
- GM08042
- UCLA-Caltech Medical Scientist Training Program
- Created
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2014-07-21Created from EPrint's datestamp field
- Updated
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2021-11-10Created from EPrint's last_modified field