Clinical Pearls & Morning Reports

Published January 4, 2017


How does the mechanism by which inclisiran reduces proprotein convertase subtilisin–kexin type 9 (PCSK9) levels differ from that of anti-PCSK9 antibodies?

Fitzgerald et al. conducted a phase 1 study that assessed the safety, side-effect profile, and pharmacodynamic effects of inclisiran, a long-acting RNA interference therapeutic agent, when it was administered subcutaneously in single or multiple doses in healthy volunteers who had an LDL cholesterol level of at least 100 mg per deciliter. A new Original Article explains.

Clinical Pearls

Q: How does proprotein convertase subtilisin–kexin type 9 (PCSK9) increase circulating LDL cholesterol levels?

A: PCSK9 is a recently identified but well-validated target for LDL cholesterol–lowering therapy. This serine protease, which is expressed and secreted into the bloodstream predominantly by the liver, binds LDL receptors both intracellularly and extracellularly and promotes the lysosomal degradation of these receptors in hepatocytes, thereby increasing the circulating LDL cholesterol levels.

Q: How does the mechanism by which inclisiran reduces PCSK9 levels differ from that of anti-PCSK9 antibodies?

A: Inclisiran differs mechanistically from anti-PCSK9 antibodies. Whereas anti-PCSK9 antibodies bind to extracellular PCSK9 (produced from any tissue) and prevent its interaction with the LDL receptor, inclisiran inhibits the synthesis of PCSK9 protein specifically in the liver. PCSK9-blocking antibodies, administered once or twice monthly, reduce circulating PCSK9 levels and lower LDL cholesterol levels. Preliminary data suggest that long-term treatment with such antibodies is associated with a lower incidence of cardiovascular events than placebo. However, PCSK9 antibodies have a short duration of effect, necessitating frequent subcutaneous injections.

Morning Report Questions

Q: Is inclisiran associated with serious adverse events?

A: In the trial by Fitzgerald et al., all the adverse events were mild or moderate (grade 1 or 2) in severity. There were no treatment discontinuations that were due to adverse events, and no serious adverse events were reported.

Q: How durable are responses to inclisiran with respect to lowering of circulating levels of PCSK9 and LDL cholesterol?

A: In the study by Fitzgerald et al., single doses of inclisiran of 300 mg or more and all the multiple-dose regimens that were studied were associated with reductions of circulating levels of both PCSK9 and LDL cholesterol at 84 days after receipt of the first dose. The authors observed reductions in the PCSK9 level of up to 83.8% and in the LDL cholesterol level of up to 59.7%. The authors also observed lowering of the serum LDL cholesterol level when inclisiran was administered to patients taking stable doses of statin therapy. The effect on the PCSK9 and LDL cholesterol levels persisted for at least 180 days after the initiation of treatment, with little variation over the 6-month period after the receipt of the first dose.

Browse more Clinical Pearls & Morning Reports »

NEJM Knowledge+