FDA approves Novartis Leqvio® (inclisiran), first-in-class siRNA to lower cholesterol and keep it low with two doses a year

Posted on Dec 23, 2021

After a rejection in December 2020 due to “unresolved facility inspection-related conditions,” the FDA has now approved Novartis’ Leqvio (Inclisiran) as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with clinical atherosclerotic cardiovascular disease (ASCVD) or heterozygous familial hypercholesterolemia (HeFH) who require additional lowering of LDL-C.

This is the first new approval of a lipid lowering therapeutic in the US since Nexletol and Nexlizet (Bempedoic Acid) in February 2020, and the decision was based on positive cholesterol lowering outcomes data in the Phase 3 ORION-9, ORION-10 and ORION-11 trials. Leqvio is an siRNA-based drug that reduces levels of the cholesterol-raising PCSK9 protein, and requires twice-yearly administration. It is this reduction in cholesterol that is anticipated to lower the risk of adverse cardiovascular events such as heart attacks and strokes, although actual cardiovascular outcome clinical trial data is not yet available.

The ORION-4 trial, investigating the effect of Leqvio for the prevention of recurrent adverse cardiovascular events is ongoing and will conclude in 2026. Another trial, ORION-17, is planned, which will collect data on cardiovascular outcomes of Leqvio-treated participants who have not experienced a cardiovascular event.


Leqvio's target, PCSK9, is also targeted by the drugs Repatha and Praluent, which are administered every two to four weeks, and have seen low uptake due to factors such as high annual list prices leading to unfavourable cost effectiveness analyses from organisations such as the Institute for Clinical and Economic Review (ICER).

Consequently, insurance providers in the US required that patients fail to reach cholesterol goals on multiple first-line drugs (statins) before they were eligible for treatment with PCSK9 inhibitors, even after 60% reductions in the list prices of these drugs. To counteract this, in early September 2021, Leqvio was provided by Novartis to the UK’s National Health Service (NHS) at an undisclosed discount.

Following the price reduction, Leqvio received approval by the National Institute for Health and Care Excellence (NICE) for the treatment of elevated cholesterol in adults with primary hypercholesterolaemia (heterozygous familial and non-familial) or mixed dyslipidemia, as an adjunct to diet in combination with a statin or statin with other lipid-lowering therapies in patients unable to reach LDL-cholesterol goals with the maximum tolerated dose of a statin or, alone or in combination with other lipid-lowering therapies in patients who are statin-intolerant, or for whom a statin is contraindicated. NICE’s analysis also specifically found Leqvio to be the most cost-effective drug in direct head-to-head comparisons with Praluent and Repatha.

Subsequently, new NHS Guidelines for lipid management for prevention of cardiovascular disease in the UK published in December recommended the use of Leqvio in the same patient population to prevent recurrent adverse cardiovascular events.

Airfinity analysis

Airfinity estimates that by 2027, approximately 12 million patients in the US will not reach cholesterol goals despite treatment with the widely-used statins for prevention of recurrent cardiovascular events, and will require additional intensification of cholesterol lowering with Leqvio or other PCSK9-targeting drugs.

Leqvio benefits from a multiple factors that favourably position it relative to its competitors, including lower pricing and direct head-to-head cost-effectiveness comparisons to its competitors in the UK, a novel sales approach in the US, a more favourable twice-yearly dosing regimen, and new guideline updates clarifying its role and position in patient treatment pathways in preventing recurrent adverse cardiovascular events.

Multiple patient registries have outlined low cholesterol goal attainment on first line therapies, as well as low uptake of Praluent and Repatha due to economic and regulatory factors worldwide. This suggests that Leqvio could potentially establish itself as the second line of therapy for cholesterol lowering in the years to come.

For more information about Airfinity's analytics and predictive capabilities in Lipid Lowering Therapies, contact the team here.

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