A future for RNA therapies? Inclisiran: a short interfering RNA for the lowering of LDL cholesterol

The New England Journal of Medicine published results of a phase 1 study investigating a novel method to reduce LDL cholesterol through a small interfering RNA (siRNA) targeting PCSK9 — inclisiran (Alnylam Pharmaceuticals and the Medicines Company). Being a phase 1 study, the safety, side-effect profile and pharmacodynamic effects of this novel therapeutic agent were assessed.

The reason I am reflecting on this study relates to the excitement that is held within the field of cardiology and PCSK9 inhibition. PCSK9 is a well-validated target that has been recently identified as a critical regulator of LDL cholesterol. PCSK9 achieves this by breaking down LDL cholesterol receptors within the liver; the more LDL receptors broken down, the higher the LDL levels within the bloodstream. PCSK9 inhibition therefore results in lower LDL levels. Individuals with raised LDL cholesterol are at risk of major adverse cardiovascular events such as myocardial infarction, and consequently developing therapeutic agents to successfully lower LDL has been a goal for many years. Achieved initially through the development of statins, more recently the FDA approved two monoclonal antibodies that inhibit PCSK9 (alirocumab (Praluent, Sanofi/Regeneron) and evolocumab (Repatha, Amgen)) to lower LDL cholesterol in patients refractory to statin therapy.

What differentiates inclisiran (an siRNA) from the currently FDA approved PCSK9 inhibitors (monoclonal antibodies) is the the mechanism through which PCSK9 inhibition is achieved. To briefly outline these differences: monoclonal antibodies of PCSK9 restrict PCSK9 from binding to LDL receptors across all extracellular tissues across all organs, whilst inclisiran specifically targets PCSK9 inhibition within the liver. This specificity relates to the design of inclisiran, with carbohydrate residues bound to the siRNA combining with a molecule specific to the liver (Asialoglycoprotein receptors), which enables uptake into the liver. Once in the liver, the siRNA binds with an RNA inducing silencing complex that allows the siRNA to interact and disrupt the mRNA that is required for PCSK9 protein production. This unique mechanism of action makes inclisiran a first in class therapeutic.

Inclisiran, administered as a subcutaneous injection, demonstrated no serious adverse events and was reported to provide a sustained reduction in LDL levels (~60% reduction). It will be fascinating to track the progress of inclisiran in subsequent trials — a global phase III trial has been suggested. Some analysts are already suggesting that sales of Inclisiran will reach ~1.3 USD in 2030, despite no cardiovascular outcome trial data.

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