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.
Level 2 - randomized trial
Randomized, single-blind, placebo-controlled phase 1 trial
PubMed 24094767 · doi:10.1016/S0140-6736(13)61914-5
What was done
In a randomized, single-blind, placebo-controlled, phase 1 dose-escalation trial, 32 healthy adults with baseline serum LDL cholesterol ≥3.00 mmol/L not taking lipid-lowering therapy were randomly assigned (3:1) to a single intravenous dose of ALN-PCS (0.015 to 0.400 mg/kg; n=24) or placebo (n=8). The primary endpoint was safety and tolerability; secondary endpoints were pharmacokinetics and pharmacodynamic changes in circulating PCSK9 and LDL cholesterol analyzed per protocol using ANCOVA.
What was found
Treatment-emergent adverse events occurred in 79% (19/24) of ALN-PCS participants and 88% (7/8) of placebo participants. Drug concentration and area under the curve increased roughly dose-proportionally. At the highest dose of 0.400 mg/kg (n=6), ALN-PCS 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).
Why it matters
This trial provided the initial proof-of-concept that RNA interference targeting PCSK9 synthesis can lower LDL cholesterol in humans.
Limits
The study had a very small sample size (n=32 overall, n=6 at the highest dose), evaluated only a single intravenous dose, was single-blind, and included only healthy volunteers without measuring long-term safety or clinical cardiovascular outcomes.
Cited by
- partial Individuals with loss-of-function variants or lower levels of PCSK9 have naturally lower lifetime LDL levels and lower cardiovascular and all-cause mortality.