European Commission grants licence for inclisiran (Leqvio® ▼), a first-in-class siRNA cholesterol-lowering treatment

• Cardiovascular disease (CVD) causes more than a quarter of all deaths in the UK; claiming nearly 170,000 lives each year.¹

• Inclisiran is the first and only small interfering RNA (siRNA) to treat primary hypercholesterolaemia (heterozygous familial and non-familial) or mixed dyslipidaemia,² two common forms of elevated cholesterol linked to increased risk of cardiovascular disease.^3,4 The medicine is indicated in these patient populations as an adjunct to diet, in combination with a statin, or statin with other lipid-lowering therapies for those not reaching their low-density lipoprotein (LDL) cholesterol target 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.²

• The licence follows the announcement in early 2020 that the UK will pioneer an innovative population health model, expected to make inclisiran available through a population-level agreement in a first of its kind approach to reducing the risk of heart disease.^5,6

London, UK. 11 Dec 2020 Novartis today announced that the European Commission (EC) has granted a licence for the use of inclisiran (Leqvio^®▼) for the treatment of adults with primary hypercholesterolemia (heterozygous familial and non-familial) or mixed dyslipidaemia,² two common forms of elevated cholesterol.^3,4 The medicine is indicated in these patient populations as an adjunct to diet, in combination with a statin, or statin with other lipid-lowering therapies for those not reaching their low-density lipoprotein (LDL) cholesterol  target 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.²

Inclisiran is a first-in-class, small interfering RNA (siRNA) cholesterol-lowering treatment administered as a single injection initially, at 3 months and then at 6-month intervals. Using a novel mechanism of action, the treatment has been shown to deliver effective and sustained LDL cholesterol reduction in patients with atherosclerotic cardiovascular disease (ASCVD).^2,9,10

Following the granting of this marketing authorisation by the EC - and pending further approval from the National Institute for Health and Care Excellence (NICE) - Novartis and the NHS will continue pioneering an innovative population health model announced earlier this year, which is expected to make the medicine available through a population-level agreement in a first of its kind approach to reducing the risk of heart disease. This collaboration also includes the creation of an industry and academic consortium to improve the efficiency in which the UK can manufacture this form of treatment.^5,6

In the UK, heart and circulatory diseases cause more than a quarter (27%) of all deaths each year, and 7.4 million people are living with these diseases every day.¹ The NHS has recognised cardiovascular disease as a clinical priority, identifying this as the single biggest area in which lives can be saved over the next ten years, and made a long-term commitment to prevent over 150,000 heart attacks, strokes and dementia cases, over the next ten years.⁷

Commenting on the benefits of providing a cholesterol-lowering population health approach to tackling cardiovascular disease at the primary care level, Dr Tracey J. Vell MBE, GP for the Manchester Local Medical Committee, said: “In the area of cholesterol management, Health Innovation Manchester and the Greater Manchester system have been delighted to apply a population health management methodology to the implementation of this new medicine. It allows us to identify at risk groups digitally, and then deliver innovative long acting cholesterol lowering therapy alongside other holistic care objectives. Through this we are hoping to deliver better outcomes for those at risk of cardiovascular disease as well as care close to their home and community.”  

Patients with established ASCVD are increasingly falling short of achieving and maintaining guideline-recommended LDL cholesterol goals, leaving them at high cardiovascular risk.⁸ This highlights the current need for greater utilisation of non-statin LDL cholesterol–lowering therapies, particularly for patients at highest CVD risk.⁸

“Inclisiran has shown considerable and significant improvements in the reduction of cholesterol levels, which could really help in our ongoing battle to tackle the growing burden of cardiovascular disease in the UK. This new treatment, with a novel mechanism of action, could also help address two major barriers to improving population health. Namely, achieving even lower cholesterol levels for those most at risk, above that of maximally tolerated statins, and the challenge of long term non-adherence commonly encountered with current treatments, which require frequent dosing.” said Professor Kausik Ray, Prof of Public Health, Imperial College London and Honorary Consultant Cardiologist at the Imperial College NHS Trust.

“There is a real and pressing need for new, innovative treatments that can help people manage high cholesterol levels – alongside other medication, healthy eating and lifestyle changes – to prevent the associated risks of cardiovascular disease. HEART UK welcomes this authorisation which marks a big step forward in our ability to help people prevent heart disease, heart attacks and stroke in the UK.” comments Jules Payne, Chief Executive at cholesterol charity HEART UK.

“At Novartis, our purpose is to reimagine medicine. I am proud to say that inclisiran, thanks to this licence, could now be part of this journey. As the first and only treatment of its kind, inclisiran embodies our commitment to develop innovative therapies that expand the frontiers of cardiovascular medicine. I am confident that our pioneering and ongoing collaboration with NHS England could help ensure the benefits of this innovation can truly be realised for hundreds of thousands of patients across the UK.” said Chinmay Bhatt, Managing Director UK, Ireland & Nordics for Novartis Pharmaceuticals.

The granting of marketing authorisation by the EC was based on results from the Novartis ORION clinical research programme, including phase 3 trials ORION-9, ORION-10 and ORION-11, which involved over 3,600 patients and assessed the safety, efficacy and tolerability of inclisiran.^9,10

In ORION-9, significant reductions in LDL cholesterol levels were seen in patients with all genotypes of heterozygous familial hypercholesterolemia, who were already taking a maximally tolerated statin dose.⁹ In ORION-10 and ORION-11, patients with ASCVD (& at risk equivalents in ORION-11) who were already taking a maximally tolerated statin dose, achieved ≥50% reduction in mean placebo-adjusted LDL cholesterol at month 17. A time-averaged LDL cholesterol reduction of 52% and 49% respectively, was observed from month 3 to 18, vs. placebo.¹⁰ Across these trials, the safety profile between the inclisiran and placebo groups were similar, apart from injection-site adverse events being more common within the inclisiran treatment group, with the events graded as mild or moderate, with none being severe or persistent.^9,10

Following granting of this marketing authorisation by the EC, Novartis is continuing to work with relevant stakeholders within health agencies to ensure implementation can be provided to secondary prevention ASCVD patients, subject to further NICE approval.

 About the ORION Phase III LDL-C-lowering Studies

ORION-9 was a pivotal Phase III, placebo-controlled, double-blind, randomized study to evaluate the efficacy, safety and tolerability of inclisiran sodium 300 mg, equivalent to 284 mg of inclisiran, administered subcutaneously by a healthcare professional starting with an initial dose.⁹ After the initial dose, inclisiran was then administered again at 3 months and then every 6 months thereafter, in 482 participants with clinical or genetic evidence of heterozygous familial hypercholesterolemia (HeFH) and elevated low-density lipoprotein (LDL) cholesterol, despite a maximally tolerated dose of LDL cholesterol lowering therapies (e.g. a statin and/or ezetimibe). For the primary endpoints of ORION-9, inclisiran delivered mean placebo-adjusted percentage change in LDL cholesterol reductions of 48% (P<0.001) at 17 months and demonstrated time-adjusted percentage change in LDL cholesterol reductions of 44% (P<0.001) from 3 through 18 months. The international study was conducted at 46 sites in eight countries. The safety profile between the inclisiran and placebo groups were similar, apart from injection-site adverse events being more common within the inclisiran treatment group, with the events graded as mild or moderate, with none being severe or persistent.⁹

ORION-10 was a pivotal Phase III, placebo-controlled, double-blind, randomised study to evaluate the efficacy, safety and tolerability of inclisiran sodium 300 mg, equivalent to 284 mg of inclisiran, administered subcutaneously by a healthcare professional starting with an initial dose.¹⁰ After the initial dose, inclisiran was then administered again at 3 months and then every 6 months thereafter in 1,561 participants with atherosclerotic cardiovascular disease (ASCVD) and elevated LDL cholesterol, despite a maximally tolerated dose of statin therapy (with or without ezetimibe). For the primary endpoints of ORION-10, inclisiran delivered mean placebo-adjusted percentage change in LDL cholesterol reductions of 52% (P<0.001) at 17 months and demonstrated time-adjusted percentage change in LDL cholesterol reductions of 54% (P<0.001) from 3 through 18 months. The study was conducted at 145 sites in the United States. The safety profile between the inclisiran and placebo groups were similar, apart from injection-site adverse events being more common within the inclisiran treatment group, with the events graded as mild or moderate, with none being severe or persistent.¹⁰

ORION-11 was a pivotal Phase III, placebo-controlled, double-blind, randomised study to evaluate the efficacy, safety and tolerability of inclisiran sodium 300 mg, equivalent to 284 mg of inclisiran, administered subcutaneously by a healthcare professional starting with an initial dose.¹⁰ After the initial dose, inclisiran was then administered again at 3 months and then every 6 months thereafter in 1,617 patients with ASCVD or ASCVD-risk equivalents and elevated LDL cholesterol despite a maximally tolerated dose of statin therapy (with or without ezetimibe). For the primary endpoints of ORION-11, inclisiran delivered placebo-adjusted change in LDL cholesterol reductions of 50% (P<0.001) at 17 months and demonstrated time-adjusted LDL cholesterol reductions of 49% (P<0.001) from 3 through 18 months. The international study was conducted at 70 sites in seven countries. The safety profiles between inclisiran and placebo treatment groups were similar, apart from injection-site adverse reactions being more common within the inclisiran treatment group, with the events graded as mild or moderate, with none being severe or persistent.¹⁰

About Atherosclerotic Cardiovascular Disease (ASCVD)

Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of morbidity and mortality worldwide.^11,12 ASCVD results from a thickening and loss of elasticity in the arterial wall. It is a severe disorder and the leading cause of morbidity (sickness) and mortality (death) in most developed countries. High levels of LDL cholesterol build up on the walls of blood vessels. This build up is called “plaque.” As blood vessels build up plaque over time, the insides of the vessels narrow; this process is called atherosclerosis.¹⁴ This narrowing blocks blood flow to and from the heart and other organs and eventually causes heart disease or stroke.^13,14

About inclisiran

Inclisiran, the first cholesterol-lowering therapy in the siRNA (small-interfering RNA) class, is a twice-yearly therapy, following initial and three-month doses. As an siRNA, inclisiran harnesses the body’s process of RNA interference through a novel mechanism of action to prevent production of the target protein in the liver. This enhances the liver’s ability to remove LDL cholesterol from the bloodstream, thereby lowering LDL cholesterol levels.² Inclisiran has been granted marketing authorisation by the European Commission,² and is not yet approved by the FDA or other regulatory authorities.

About Novartis 

Novartis is reimagining medicine to improve and extend people’s lives. As a leading global medicines company, we use innovative science and digital technologies to create transformative treatments in areas of great medical need. In our quest to find new medicines, we consistently rank among the world’s top companies investing in research and development. Novartis products reach more than 750 million people globally and we are finding innovative ways to expand access to our latest treatments. About 105 000 people of more than 140 nationalities work at Novartis around the world. Find out more at www.novartis.com. 

In 2018, Novartis supported a total of 17,458 UK jobs, of which it directly employed 1,268 full time equivalent workers to serve healthcare needs across the whole of the UK, as well as supporting the global operations of Novartis. Since 2014, Novartis has invested over £200 million in R&D and is the single largest industry sponsor of clinical trials in the UK. For more information, please visit www.novartis.co.uk