ALN-PCS02
PCSK9 and siRNA
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a member of the serine protease family. Loss-of-function mutations in PCSK9 have been described in human beings and are associated with reductions in low-density lipoprotein cholesterol (LDL-C) and risk of coronary heart disease. Studies have previously reported the acute, hepatocyte-specific lowering of synthesis and plasma concentrations of PCSK9 by treatment with a PCSK9-specific small interfering RNA (siRNA) formulated in a lipid nanoparticle in several preclinical models. This treatment resulted in a substantial and durable lowering of LDL-C without an effect on high-density lipoprotein cholesterol (HDL-C). Besides, scientists confirmed in these models that the reduction of PCSK9 was based on an RNA interference (RNAi) mechanism and resulted in an increased number of LDL receptors on hepatocyte membranes.
Figure 1. PCSK9 pathway and RNAi synthesis-inhibitor approach. (Fitzgerald, 2014)
ALN-PCS02
ALN-PCS02, a form of RNA (ribonucleic acid) packaged inside tiny, fat-containing lipid nanoparticles, is an intravenous RNAi therapeutic which has completed a phase I trial. This molecule interferes with the action of RNA to reduce the amount of tissue and circulating plasma PCSK9 protein levels as well as the concentration of elevated LDL-C circulating in the blood. ALN-PCS02 targets both extracellular and intracellular PCSK9, thereby phenocopying the human genetics observed in loss of function or null human PCSK9 mutations, without any adverse effects on HDL-C levels.
ALN-PCS02 Pre-Clinical Data
Pre-clinical data from the ALN-PCS02 showed specific silencing of PCSK9 mRNA in the liver, and plasma PCSK9 protein levels up to 90%, with an ED50 (50% effective dose) of approximately 0.06 mg/kg for both mRNA and protein reduction. These studies have also demonstrated a greater than 50% reduction in levels of LDL-C lasting for weeks after a single dose.
ALN-PCS02 Phase I Data
Phase I trial was a randomized, single-blind, placebo-controlled, single ascending dose study in subjects with slightly elevated levels of bad LDL-C. Dosing in the 5 dose cohorts commenced at 0.015 mg/kg and went up to 0.250 mg/kg with each cohort consisting of 3 subjects receiving an intravenous infusion of ALN-PCS02 and 1 receiving placebo. Robust target protein knockdown was observed at the highest dose with a mean 60% reduction in plasma PCSK9 levels presumably 3-5 days after administration. In line with PCSK9 genetics, this type of knockdown entailed a mean 39% reduction in bad LDL-C. Importantly, consistent with the wealth of non-human primate data, this knockdown was sustained for days and weeks. The paper showed that ALN-PCS02 administration resulted in rapid, dose-dependent knockdown of plasma PCSK9 up to 84% relative to baseline and placebo, with a corresponding reduction in serum levels of LDL-C up to 57% relative to baseline and placebo. The knockdown of PCSK9 and lowering of LDL-C were also found to be durable, with effects lasting for weeks after a single dose. ALN-PCS02 was shown to be well tolerated in this phase 1 study and there were no serious adverse events related to study drug administration. For clinical trial information, please refer to NCT01437059.
Reference
- Fitzgerald, K.; et al. (2014). Effect of an RNA interference drug on the synthesis of proprotein convertase subtilisin/kexin type 9 (PCSK9) and the concentration of serum LDL cholesterol in healthy volunteers: a randomized, single-blind, placebo-controlled, phase 1 trial. The Lancet. 383(9911): 60-68.
