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21 January 2022

Leqvio (inclisiran) for the Treatment of Hypercholesterolaemia

Leqvio® (inclisiran) is the first FDA-approved small interfering RNA (siRNA) indicated for lowering bad cholesterol (LDL-C).
Leqvio (inclisiran) is a first-in-class medication indicated for treating hypercholesterolaemia or mixed dyslipidaemia in adults. Credit: Novartis.
The drug is available as a 284mg clear, colourless to pale yellow injectable solution in a pre-filled syringe. Credit: NICE.
Leqvio is the first and only siRNA treatment used for elevated LDL-C levels via RNA interference (RNAi). Credit: National Centre for Advancing Translational Sciences (NCATS), National Institutes of Health.

Leqvio® (inclisiran) is a first-in-class small interfering ribonucleic acid (siRNA) treatment indicated as an adjunct to diet for the treatment of hypercholesterolaemia or mixed dyslipidaemia in adult patients.

The drug is designed to reduce elevated low-density lipoprotein cholesterol (LDL-C) levels in patients with atherosclerotic cardiovascular disease (ASCVD) or who are at risk of ASCVD, who had previously experienced a cardiovascular event such as a heart attack or stroke. It is the first and only US Food and Drug Administration (FDA) approved siRNA treatment to lower LDL-C.

Inclisiran was originally developed by US-based RNAi therapeutics company Alnylam Pharmaceuticals, which collaborated with The Medicines Company (TMC) in 2013 to advance clinical trials for the drug and support its potential commercialisation.

In January 2020, Swiss pharmaceutical firm Novartis acquired TMC, along with the global rights to develop, manufacture and market Leqvio, under a licence and partnership agreement with Alnylam.

Leqvio is available as a 284mg clear, colourless to pale yellow injectable solution in a pre-filled syringe for subcutaneous administration.

Patients need to be administered with two maintenance doses a year, following an initial dose and another at three months.

Regulatory approvals for Leqvio

In October 2020, Leqvio received a positive opinion from the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) to treat adults with hypercholesterolaemia or mixed dyslipidaemia. The European Commission (EC) granted marketing authorisation for the drug in December 2020.

Around this time, Novartis received a complete response letter (CRL) regarding a new drug application (NDA) submitted for inclisiran to the US Food and Drug Administration (FDA) due to unresolved facility inspection-related conditions at a third-party manufacturing facility.

Novartis resubmitted the NDA to the FDA in July 2021, addressing the CRL. The company’s resubmission included details of its facility at Schaftenau, Austria, where it planned to manufacture the drug.

In December 2021, Leqvio received approval from the FDA review for treating adults with elevated LDL-C who are on a maximally tolerated statin regimen.

In August 2021, Novartis signed a commercial agreement with the UK National Health Service (NHS) to make Leqvio accessible to eligible patients across England through a population health management approach.

Atherosclerotic cardiovascular disease (ASCVD) causes and symptoms

Atherosclerosis is characterised by the accumulation of lipids in the inner lining of the arteries over time, primarily LDL-C. An atherosclerotic cardiovascular event such as a heart attack or stroke can be caused by an unexpected rupture of the atherosclerotic plaque.

Long-term elevated LDL-C is a recognised cause of ASCVD and a significant risk factor for cardiovascular disease.

More than 85% of all cardiovascular disease fatalities are caused by ASCVD, which is the leading cause of mortality in the EU.

Conditions with a comparable risk of ASCVD occurrences, such as diabetes and heterozygous familial hypercholesterolaemia, are referred to as ASCVD risk equivalents.

Leqvio mechanism of action

Leqvio is a cholesterol-reducing, double-stranded siRNA coupled with triantennary N-acetylgalactosamine (GalNAc) on the sense strand to aid hepatocytes uptake.

The drug’s active ingredient, inclisiran, interferes with RNA (genetic material) to inhibit the development of proprotein convertase subtilisin Kexin type 9 (PCSK9), a protein that can raise LDL cholesterol levels. Leqvio reduces LDL cholesterol levels by inhibiting PCSK9 synthesis.

In hepatocytes, inclisiran uses the RNA interference mechanism to guide catalytic mRNA breakdown for PCSK9. The process enhances LDL-C receptor recycling and expression on the hepatocyte cell surface, increasing LDL-C uptake and decreasing LDL-C levels in the blood circulation.

Clinical trials on Leqvio

The FDA’s approval of Leqvio was based on results from a placebo-controlled, double-blind, randomised Phase III clinical trial development programme, which included the ORION-9, ORION-10 and ORION-11 trials.

The global ORION-9 trial was conducted at 46 sites across eight countries. The ORION-10 trial was held at 145 sites in the US, while ORION-11 was carried out at 70 sites across seven countries.

The trials evaluated the efficacy, safety and tolerability of Leqvio sodium salt 300mg, which is equivalent to 284mg of Leqvio when administered subcutaneously by a healthcare professional.

Leqvio showed an effective and sustained decrease in LDL-C level of up to 52% in patients with elevated LDL-C, despite maximally tolerated statin therapy. The drug is expected to support long-term adherence with two doses a year.

In ORION-9, 482 patients with clinical or genetic evidence of heterozygous familial hypercholesterolaemia (HeFH) were recruited. Inclisiran was administered three months after the initial dose, followed by one every six months. This reduced the mean percentage change in LDL-C by 48% compared to placebo at 17 months.

The ORION-10 and ORION-11 trials were conducted in patients with ASCVD and ASCVD risk equivalents.

A total of 1,561 participants with ASCVD were enrolled in ORION-10. In the study, Leqvio demonstrated a mean percentage change in LDL-C reductions of 52% compared to placebo at 17 months, and a time-adjusted percentage change in LDL-C reductions of 54% from three to 18 months.

The ORION-11 study evaluated 1,617 patients with ASCVD or ASCVD risk equivalents, in which Leqvio significantly lowered the mean percentage change in LDL-C by 50% compared to placebo.

The common adverse events reported among the patients treated with Leqvio during the trials were injection site reaction, arthralgia, urinary tract infection, diarrhoea, bronchitis, pain in extremities, and dyspnoea.

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