ALN-VSP02
Small interfering RNA (siRNA) is a member of a family of non-coding RNAs that affect and regulate gene, RNA and protein function. siRNA-based therapeutic technologies represent a rapidly expanding class of therapeutic opportunities with the power to modulate cellular biology in ways never before possible. With siRNA-targeted therapeutics, inhibitors of previously undruggable proteins, gene expression modulators, and even therapeutic proteins can be rationally designed based on sequence information alone, something that is not possible with other therapeutic modalities.
Figure 1. Turning siRNA into drugs.
ALN-VSP02
The ALN-VSP02 is an Alnylam Pharmaceutics lipid nanoparticle formulation containing two siRNAs directed against the kinesin spindle protein (KSP) and vascular endothelial growth factor-A (VEGF-A). Both siRNAs were chemically modified to reduce their immunostimulatory potential. ALN-VSP02 has a particle diameter of 80-100 nm and is essentially uncharged with a zeta potential of less than 6 mV at pH 7.4. Consistent with other liposomes of a similar size, ALN-VSP02 distributes primarily to the liver and spleen following parenteral administration due to the fenestrated endothelium in those organs. Distribution to tumors with leaky microvasculature containing endothelial pores is thought to occur through the enhanced permeability and retention (EPR) mechanism described for liposomes and other nanoparticles.
- Clinical Trials
ALN-VSP02, produced through the Tekmira's SNALP technology, entered in a phase I dose-escalation trial. The study was completed, and a total of 41 patients were enrolled between Mar 2009 and Aug 2011, including 30 patients of the dose-escalation phase treated at 0.1 to 1.5 mg/kg (administered by IV infusion) and 11 of the expansion phase treated at 1.0 or 1.25 mg/kg. Based on the molecular analysis of biopsy samples from patients, the study confirmed the presence of residual siRNAs and mRNAs cleavage products at the site of actions. The drug was well tolerated at the highest dose, and then an expansion study has been initiated and completed.
Seven patients from the first study were treated for an average of 11.3 months (between Jul 2010 and Aug 2012), in order to further evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of the drug. Even if the efficacy of the drug was not tested during the phase I clinical trial, it is worth noting that one patient (of seven) with endometrial cancer showed a complete response (full tumor regression) and remained in remission and completed treatment after receiving 50 doses over 26 months. Three other patients have shown stable disease, having received 17-36 doses over 8-18 months.
Reference
- Gulnihal, O.; et al. (2015). Preclinical and clinical development of siRNA-based therapeutics. Advanced Drug Delivery Reviews. 87: 108-119.
