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 Randomised, Single-Blind, Placebo-Controlled, Phase 1 Trial

Study Questions:

What is the safety and efficacy of ALN-PCS, a small interfering RNA that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9) synthesis, in healthy volunteers with raised cholesterol who were not on lipid-lowering treatment?


The investigators conducted a randomized, single-blind, placebo-controlled, phase 1 dose escalation study in healthy adult volunteers with serum low-density lipoprotein (LDL) cholesterol of 3.00 mmol/L or higher. Participants were randomly assigned in a 3:1 ratio by computer algorithm to receive one dose of intravenous ALN-PCS (with doses ranging from 0.015 to 0.400 mg/kg) or placebo. The primary endpoint was safety and tolerability of ALN-PCS. Secondary endpoints were the pharmacokinetic characteristics of ALN-PCS and its pharmacodynamic effects on PCSK9 and LDL cholesterol. Study participants were masked to treatment assignment. Analysis was per protocol, and investigators used ANCOVA to analyze pharmacodynamic endpoint data.


Of 32 participants, 24 were randomly allocated to receive a single dose of ALN-PCS (0.015 mg/kg [n = 3], 0.045 mg/kg [n = 3], 0.090 mg/kg [n = 3], 0.150 mg/kg [n = 3], 0.250 mg/kg [n = 6], or 0.400 mg/kg [n = 6]) and eight to placebo. The proportions of patients affected by treatment-emergent adverse events were similar in the ALN-PCS and placebo groups (19 [79%] vs. seven [88%]). ALN-PCS was rapidly distributed, with peak concentration and area under the curve (0 to last measurement) increasing in a roughly dose-proportional way across the dose range tested. In the group given 0.400 mg/kg of ALN-PCS, treatment resulted in a mean 70% reduction in circulating PCSK9 plasma protein (p < 0.0001) and a mean 40% reduction in LDL cholesterol from baseline relative to placebo (p < 0.0001).


The authors concluded that inhibition of PCSK9 synthesis by RNA interference (RNAi) provides a potentially safe mechanism to reduce LDL cholesterol concentration in healthy individuals with raised cholesterol.


This study reported that ALN-PCS, an RNAi drug designed to inhibit the synthesis of the PCSK9 transcript, was well tolerated and significantly lowered PCSK9 and LDL cholesterol in healthy volunteers with raised cholesterol. This study is the first systemic trial of an RNAi drug to report an effect on a clinically validated endpoint (LDL cholesterol). Future larger, prospective trials are needed to fully assess the benefit and long-term safety of ALN-PCS in various patient populations, including those on statins, those who are statin intolerant, and those with defects in LDL receptor function. Several monoclonal antibodies to PCSK9 are also in later phases of clinical trials (LAPLACE-TIMI 57; ODYSSEY Combo II), and the drug class of PCSK9 inhibitors is likely to become an attractive modality for the treatment of individuals with refractory hypercholesterolemia, statin intolerance, or elevated LDL despite high-dose statins, provided safety and efficacy are confirmed in larger studies.

Clinical Topics: Dyslipidemia, Homozygous Familial Hypercholesterolemia, Lipid Metabolism, Nonstatins, Novel Agents, Statins

Keywords: Healthy Volunteers, Proprotein Convertases, Cholesterol, Biological Markers, Hydroxymethylglutaryl-CoA Reductase Inhibitors, RNA Interference, Hypercholesterolemia, Single-Blind Method

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