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.translational medicine | DNA proliferation | DNA replication | maximum tolerance dose | dose limiting toxicity

Theranostic near-infrared fluorescent nanoplatform for imaging and systemic siRNA delivery to metastatic anaplastic thyroid cancer

“…By improving the in vivo delivery of RNAi agents (e.g., siRNA) to solid tumor tissues through the enhanced permeability and retention (EPR) effect (6), nanotechnology has drastically facilitated the clinical translation of RNAi for cancer therapy (5). However, RNAi nanoparticles (NPs) at the clinical stage for cancer treatment (7,8) may still face challenging obstacles, such as suboptimal systemic delivery of siRNA into target tumor cells. In addition, it has been increasingly recognized that the EPR effect varies substantially among both patients and tumor types and even within the same patient/tumor type over time (9), representing another important challenge for RNAi nanotherapeutics to identify patients most likely to benefit from them.…”

The future of marginal kidney repair in the context of normothermic machine perfusion

“…Although enhanced retention through the conjugation of ligands may not always be effective in systemic delivery, it is in many ways perfectly suited for an isolated NMP setting 6, 33. In the context of an isolated organ, NPs can largely avoid the challenges associated with systemic delivery.…”

“…In addition, NMP is emerging as a platform for the delivery of therapies aimed at reducing the negative effects of ischemic injury. Although attempts to achieve anatomic specificity of systemically administered drugs have been largely unsuccessful in humans, NMP circumvents any systemic side effects via direct delivery to an isolated kidney 4, 5, 6. A number of therapeutic strategies have been tested in this system, mostly addressing singular mechanisms of IRI.…”

RNA Therapeutics in Oncology: Advances, Challenges, and Future Directions

“…47 Unfortunately, these delivery approaches result in limited distribution primarily to the liver and are associated with such intense proinflammatory reactions that prophylactic doses of steroids, histamine antagonists, and NSAIDS are required prior to each administration, and despite these pretreatments, serious infusion reactions are reported in 20% or more of treated patients. [48][49][50][51][52][53][54] However, as mentioned briefly above, a more effective solution to the in vivo delivery of siRNA molecules (at least for the delivery of siRNA to hepatocytes) has been has been the conjugation of double-stranded siRNA molecules (and ASOs) to GalNAc moieties resulting in the active uptake of these conjugates into hepatocytes via Asialoglycoprotein receptors. 43 However, to achieve effective stability and distribution of GalNAcconjugated siRNAs, substantial additional chemical modifications must be incorporated, and thus, most GalNAc-conjugated siRNAs in development contain 10 to 14 PS moieties, 11 to 14 2ʹ-methoxy and 10 to 14 2ʹ-fluoro (2ʹ-F)-modified nucleosides.…”

“…However, several siRNA inhibitors are also currently being evaluated in cancer clinical trials, and in all these trials the siRNA molecules have been formulated into various types of nanoparticles including lipid nanoparticles or liposomes. [47][48][49][50][51][52] Most of these remain at early stages of development, and the data are not yet mature enough to determine their clinical potential. However, evidence of siRNA-mediated target inhibition on systemic delivery for a human solid tumor (melanoma) has been demonstrated, first in a clinical trial with CALAA-01, an siRNA-targeting ribonuclease reductase subunit 2 that is complexed with a cyclodextrin polymer coated with polyethylene glycol and decorated with human transferrin protein on the surface of the particle.…”