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Harnessing RNA Interference for Cholesterol Lowering: The Bench-to-Bedside Story of Inclisiran
Michael J Wilkinson1, Archna Bajaj2, Margaret E Brousseau3
1Division of Cardiovascular Medicine, Department of Medicine Cardiovascular Institute, University of California San Diego San Diego CA USA.
Insights
Inclisiran, an RNA interference therapy, significantly lowers low-density lipoprotein cholesterol (LDL-C) by approximately 50% with twice-yearly dosing. This offers a new option for patients with atherosclerotic cardiovascular disease not meeting LDL-C goals.
Area of Science:
- Biochemistry and Molecular Biology
- Cardiovascular Medicine
- Pharmacology
Background:
- Lowering low-density lipoprotein cholesterol (LDL-C) is crucial for preventing atherosclerotic cardiovascular disease (ASCVD).
- Existing non-statin therapies for LDL-C reduction are underutilized due to various barriers, leaving many patients below guideline-recommended goals.
- Increasing ASCVD mortality necessitates novel therapeutic strategies for effective LDL-C lowering.
Purpose of the Study:
- To review the development of inclisiran, a novel RNA interference therapeutic targeting proprotein convertase subtilisin/kexin type 9 (PCSK9).
- To discuss the clinical trial program, characteristics, and practical application of inclisiran for LDL-C reduction.
- To highlight inclisiran's journey from discovery to its approval as a treatment for hyperlipidemia and ASCVD prevention.
Main Methods:
- Inclisiran utilizes RNA interference to inhibit hepatic PCSK9 synthesis, a key regulator of LDL receptors.
- The therapeutic regimen involves initial loading doses followed by maintenance subcutaneous injections twice yearly.
- Clinical trials assessed the efficacy, safety, and tolerability of inclisiran, particularly when added to maximally tolerated statin therapy.
Main Results:
- Inclisiran demonstrated a sustained reduction in circulating LDL-C levels by approximately 50% compared to placebo.
- The twice-yearly dosing regimen proved effective in significantly lowering LDL-C in patients with established ASCVD or familial hypercholesterolemia.
- Long-term safety and tolerability data are being collected, with ongoing studies evaluating cardiovascular outcomes.
Conclusions:
- Inclisiran represents a significant advancement in LDL-C lowering therapy, offering a novel mechanism of action via RNA interference.
- Its convenient dosing schedule addresses adherence challenges associated with previous non-statin therapies.
- Inclisiran provides a valuable new option for managing hyperlipidemia and preventing atherosclerotic cardiovascular disease.
Abstract:
Lowering low-density lipoprotein cholesterol (LDL-C) is a cornerstone of reducing risk for atherosclerotic cardiovascular disease. Despite the approval of nonstatin therapies for LDL-C lowering over the past 2 decades, these medications are underused, and most patients are still not at guideline-recommended LDL-C goals. Barriers include poor adherence, clinical inertia, concern for side effects, cost, and complex prior authorization processes. With atherosclerotic cardiovascular disease-related mortality increasing globally, there remains a need for additional therapeutic options for lowering LDL-C as part of an atherosclerotic cardiovascular disease prevention strategy. Following the identification of PCSK9 (proprotein convertase subtilisin/kexin type 9) as a promising therapeutic target, inclisiran was developed using the natural process of RNA interference for robust, sustained prevention of hepatic PCSK9 synthesis. Twice-yearly maintenance subcutaneous inclisiran (following initial loading doses at Day 1 and Day 90) reduces circulating LDL-C levels by ≈50% versus placebo when added to maximally tolerated statins. Long-term safety and tolerability of inclisiran have been assessed, with studies underway to evaluate the effects of inclisiran on cardiovascular outcomes and to provide additional safety and effectiveness data. In 2021, <20 years after the discovery of PCSK9, inclisiran became the first RNA interference therapeutic approved in the United States for LDL-C lowering in patients with established atherosclerotic cardiovascular disease or familial hypercholesterolemia and has since been approved for use in patients with primary hyperlipidemia. This article reviews the journey of inclisiran from bench to bedside, including early development, the clinical trial program, key characteristics of inclisiran, and practical points for its use in the clinic.
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