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

K Fitzgerald, M Frank-Kamenetsky, S Shulga-Morskaya et al.

Lancet. Epub ahead of print 1 October 2013. DOI: 10.1016/S0140-6736(13)61914-5.

The enzyme proprotein convertase subtilisin/kexin type 9 (PCSK9) targets low-density lipoprotein receptors (LDL-R) for degradation, reducing their cell surface expression in hepatocytes. Gain-of-function mutations in PCSK9 cause a phenotype identical to familial hypercholesterolaemia, and interestingly, loss-of-function mutations lead to lifelong reductions in LDL cholesterol concentration (LDLc) and reduced cardiovascular risk. PCSK9 inhibition is therefore of great interest to the pharmaceutical industry as a potential means to lower LDLc.

PCSK9 inhibition can be achieved by monoclonal antibodies, and such agents are currently in the late stages of clinical development. This paper describes a novel strategy involving small interfering RNA (siRNA) to block translation of PCSK9 mRNA.

This was a phase 1, placebo-controlled, dose escalation trial of the siRNA ‘ALN-PCS’ in healthy adults with LDLc ≥ 3.0 mmol/L. ALN-PCS was incorporated into lipid nanoparticles and administered intravenously. Of note, participants were premedicated with 8 mg dexamethasone along with H1 and H2 blockers as a standard precaution against infusion reactions. The primary endpoint was safety and tolerability, and key secondary endpoints were reduction in plasma PCSK9 activity and serum LDLc.

Participants (n = 32) received either placebo or ALN-PCS. There was no difference in treatment-emergent adverse events between placebo (88%) and treatment groups (79%). Interestingly, the premedication led to an initial increase in plasma PCSK9 activity, which was overcome by ALN-PCS, with a mean 70% reduction at the highest dose (P < 0.0001). Significant reductions in LDLc were seen, up to 40% at the highest dose compared to placebo (P < 0.0001).

Limitations include small numbers of patients studied, short duration, requirement for intravenous administration, use of corticosteroids which might affect lipid metabolism and smaller reduction in LDLc compared to previously described monoclonal antibodies against PCSK9. Whatever the outcome of future studies of ALN-PCS, this study provides proof of concept of a novel way to target enzymes of therapeutic interest.