Putting the I Back in the Lipid Lowering Team

Volume 8, Issue 2

Cardiovascular disease remains a leading cause of mortality across the developing and developed world, and hyperlipidemia is a steady, silent contributor. Recent advances in the management of residual hyperlipidemia have significant disadvantages.

Ezetimibe is a once daily pill but has only modest reductions in LDL. The currently available PCSK9 inhibitors provide robust reductions in serum LDL but are expensive and must be administered 1-2 times per month.

In this week’s issue of Talking Therapeutics, we expose inclisirin, and discuss whether this novel agent holds the key to lowering residual cardiovascular risk.

Point 1: Inclisirin Interferes With Lipid Synthesis

Inclisiran works by targeting the PCSK9 enzyme; however, as opposed to PCSK9 inhibitors, which are antibodies that inhibit circulating PCSK9, inclisiran is a chemically synthesized small interfering RNA (siRNA) molecule that reduces the production of PCSK9 through gene silencing. It consists of two nucleotide strands conjugated to the ligand, triantennary N-acetylgalactosamine (GaINAc).

This ligand targets the drug to the liver by binding specifically to the asialoglycoprotein receptors (ASGPR), which are almost exclusively expressed on hepatocytes. Once bound, inclisiran is rapidly taken in by the cell where it then binds to the RNA-induced silencing complex (RISC) as well as the mRNA encoding PCSK9. The siRNA RISC complex cleaves the PCSK9 mRNA, preventing the synthesis of the PCSK9 protein, which ultimately lowers LDL.

The major advantage of this medication is that it is administered as a twice-yearly subcutaneous injection. Some preliminary data even suggest that once yearly may be sufficient, which means inclisirin could come like a LDL flu shot, one that patients visit their providers twice yearly for prevention of CVD events.

Point 2: Early Data Is Promising, but Road Blocks Persist

In a pooled analysis of 3660 high-risk patients in ORION 9, 10 and 11 treated with maximally tolerated statin therapy, 68% of those who received inclisirin had LDL levels reduced to less than 70 mg/dL compared with just 12.4% of statin-treated patients. Overall, 80.2% of those treated in the pooled ORION analysis achieved LDL cholesterol less than 100 mg/dL and 61.5% achieved a more than 50% reduction in LDL-cholesterol levels from baseline. 

A large cardiovascular outcomes study, ORION-4, is ongoing, but it will be several more years before results from that 15,000-patient study will be ready.

While already approved in Europe, inclisirin hit some snags in the US related to overseas manufacturing processes.

Once approved in the US, the million-dollar question (pun intended) is how much the drug will cost, as price has been a barrier to more widespread adoption of the currently available PCSK9 inhibitors.

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