PRO-040201

For systemic administrations aiming at longer half-life in circulation, more advanced nano-sized delivery vehicles, encapsulating and protecting small interfering RNA (siRNA), are required. The lipid nanoparticle (LNP) or stable nucleic-acid lipid particle (SNALP) technology is a lipid-based siRNA formulation platform. This delivery vehicle utilizes its small size to passively target its payload in the liver or tumors.

SNALP and ApoB

In the SNALP delivery platform, cationic and helper lipid molecules form lipid bilayer surfaces through self-assembly, which facilitates encapsulation and cellular internalization of the nucleic acid payload. SNALPs also contain a polyethylene glycol (PEG) surface modification for evading the mononuclear phagocyte system and enhancing stability. Studies have demonstrated the ability of SNALPs to systemically deliver apolipoprotein B (ApoB) specific siRNAs in non-human primates. ApoB is an essential protein for the assembly and secretion of very-low-density lipoprotein (VLDL) and low-density lipoprotein (LDL), so inhibition of ApoB by SNALP-formulated siApoB can reduce LDL cholesterol (LDL-C) levels in hypercholesterolemia patients. Currently, there are several SNALP formulations under clinical investigation including ALN-TTR01, ALN-PCS02, PRO-040201, TKM-080301, ALN-VSP02, TKM-100201, ALN-TTR02, Atu027, TKM-100802, siRNA-EphA2-DOPC and so forth.

A graphical illustration of a SNALP. Figure 1. A graphical illustration of a SNALP. (Ho, 2016)

PRO-040201 Introduction

Tekmira Pharmaceuticals Corporation developed a siRNA therapeutic, PRO-040201 (also known as TKM-ApoB) for the treatment of hypercholesterolemia. PRO-040201 is a systemically delivered RNA interference (RNAi) therapeutic incorporated into a SNALP. The siRNA drug is designed to specifically knockdown the expression of ApoB. As LDL transports cholesterol and triglycerides through the bloodstream, ApoB facilitates the uptake of LDL into various cell types and tissues. Thus, inhibition of ApoB by siRNA knockdown is designed to reduce LDL-C levels in hypercholesterolemia patients.

PRO-040201 Phase I Data

Phase I, placebo-controlled, single-blind, single-ascending dose clinical study (NCT00927459) was designed to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of PRO-040201 in hypercholesterolemia patients. Of the 23 subjects, 17 received treatment with a single dose intravenous infusion of the PRO-040201 at seven different dosing levels. Another six subjects received placebo control. The results showed that PRO-040201 was well tolerated with no evidence of liver toxicity. A significant reduction of ApoB and LDL-C was observed. However, the phase I trial was terminated as one patient at the highest dosage level reported flu-like symptoms, which is consistent with immunostimulation caused by siRNA. Tekmira is currently developing the next generation of SNALP-siApoB which is more potent and aims to avoid immunostimulatory side effects.

Please contact us for more information about PRO-040201 and siRNA-based therapeutics in clinical trials.

Reference

  1. Ho, W.; et al. (2016). Biomaterials in siRNA delivery: a comprehensive review. Advanced healthcare materials. 5(21): 2715-2731.
For research use only. Not intended for any clinical use.

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