Novartis Leqvio (inclisiran) Demonstrates Effective and Sustained LDL-C Reduction in Two ASCVD Subpopulations

Novartis recently announced at the 2021 European Society of Cardiology (ESC) Congress the results of two pooled analyses from the Phase 3 ORION-9, -10, and -11 trials of the innovative cholesterol-lowering drug Leqvio (inclisiran). The data demonstrated that among two subgroups of patients with atherosclerotic cardiovascular disease (ASCVD)—those with cerebrovascular disease (CeVD) and polyvascular disease (PVD)—twice-yearly treatment with Leqvio effectively and sustainably reduced low-density lipoprotein cholesterol (LDL-C) levels.

LDL-C is one of the most modifiable risk factors for ASCVD; however, despite the widespread use of statins, 80% of patients fail to achieve guideline-recommended LDL-C targets.

The first analysis presented at the meeting showed that, in patients with CeVD, treatment with Leqvio reduced LDL-C by a mean of 55.2% from baseline to Day 510 compared with placebo (p<0.0001). The second analysis showed that, in patients with PVD, treatment with Leqvio reduced LDL-C by a mean of 48.9% from baseline to Day 510 compared with placebo (p<0.0001). Results were similar in patients without PVD, with treatment with Leqvio reducing LDL-C by a mean of 51.5% from baseline to Day 510 compared with placebo (p<0.0001).

In both analyses, Leqvio was well tolerated, with a safety profile similar to that of placebo. The most common mild treatment-emergent adverse events (TEAEs) at the injection site were transient in nature and occurred at a slightly higher incidence, consistent with the findings in the overall pooled population of the combined trials. Treatment-emergent serious adverse events (TESAEs) were more frequent in patients with peripheral vascular disease (PVD), which may be attributable to the greater severity of their underlying condition.

Leqvio is a first-in-class siRNA cholesterol-lowering drug developed by The Medicines Company (TMC). In November 2019, Novartis acquired TMC for $9.4 billion, bringing inclisiran into its portfolio. Currently, inclisiran is also under review by the US FDA.

In December 2020, inclisiran was approved by the European Commission (EC) for marketing in Europe under the trade name Leqvio, as an adjunct to diet for the treatment of adults with primary hypercholesterolemia (heterozygous familial and non-familial) or mixed dyslipidemia, specifically: (1) Leqvio in combination with a statin or a statin and other lipid-lowering therapies for patients who are unable to achieve LDL-C treatment goals on maximally tolerated statin therapy; (2) Leqvio in combination with other lipid-lowering therapies for patients with statin intolerance or for whom statins are contraindicated.

Leqvio is administered via subcutaneous injection. Following initial doses at month 0 and month 3, maintenance dosing is administered every 6 months, requiring only two injections per year. Compared with currently available cholesterol-lowering therapies, Leqvio is expected to significantly improve long-term adherence.

Notably, Leqvio is the world's first and only small interfering RNA (siRNA) therapy for lowering cholesterol (LDL-C). The active ingredient of this drug is inclisiran, a first-in-class siRNA with a novel mechanism of action. Through RNA interference (RNAi), it potently and durably reduces LDL-C levels in patients with atherosclerotic cardiovascular disease (ASCVD), ASCVD risk equivalents, or heterozygous familial hypercholesterolemia (HeFH). These conditions are major drivers of heart attacks and strokes, and may ultimately lead to patient death.

In Europe, cardiovascular disease (CVD) claims 3.9 million lives annually. Despite the widespread use of statins, 80% of high-risk patients fail to achieve guideline-recommended LDL-C targets. Clinical data demonstrate that in patients receiving maximally tolerated lipid-lowering therapy who still have elevated LDL-C, Leqvio effectively and sustainably reduces LDL-C, with a safety profile comparable to placebo. With its unique twice-yearly dosing regimen, Leqvio can be seamlessly integrated into patients’ routine healthcare visits, improving adherence and enhancing patient outcomes.

Inclisiran is the first cholesterol-lowering therapy in the siRNA class, targeting proprotein convertase subtilisin/kexin type 9 (PCSK9), a key mechanism in the human body's regulation of LDL-C. The PCSK9 protein reduces the liver's ability to clear low-density lipoprotein cholesterol (LDL-C) from the bloodstream, and LDL-C is widely recognized as a major risk factor for cardiovascular disease (CVD). Targeting PCSK9 provides a completely novel therapeutic modality to combat LDL-C and is regarded as the most significant advancement in lipid-lowering therapy since statins (e.g., Lipitor).

Inclisiran is a small interfering RNA (siRNA) that utilizes the body's natural RNA interference process to bind to the mRNA encoding the PCSK9 protein. Through RNA interference, it reduces mRNA levels and inhibits hepatic production of the PCSK9 protein, thereby enhancing the liver's ability to clear LDL-C from the bloodstream and ultimately lowering LDL-C levels.

To date, two monoclonal antibody drugs targeting and inhibiting the PCSK9 protein have received marketing approval: Amgen’s Repatha and Sanofi/Regeneron’s Praluent. Unlike monoclonal antibody PCSK9 inhibitors, as an RNAi therapeutic, inclisiran works by directly silencing the production of PCSK9 protein in the liver.

Despite lagging behind other PCSK9 inhibitors, the dosing convenience of inclisiran—requiring only twice-yearly subcutaneous administration during the maintenance phase—provides it with strong market penetration opportunities in the cholesterol-lowering drug market. Credit Suisse previously projected that global annual sales of inclisiran would reach $1.13 billion in 2024.

Note: The original text has been abridged.

Original Source: Novartis Leqvio* (inclisiran) analyses show effective and sustained LDL-C reduction in two sub-populations of patients with ASCVD

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