Novartis : receives EU approval for Leqvio®* (inclisiran), a first-in-class siRNA to lower cholesterol with two doses a year**

• Leqvio^® (inclisiran) is the first and only approved small-interfering RNA (siRNA) low-density lipoprotein cholesterol (LDL-C)lowering treatment in Europe^1-3
  

• Cardiovascular disease causes 3.9 million deaths annually in Europe, and 80% of high-risk patients do not reach guideline-recommended LDL-C targets despite the widespread use of statins^4-7

• Approval is based on a robust clinical development program demonstrating effective and sustained LDL-C reduction of up to 52% in patients with elevated LDL-C despite maximally tolerated statin therapy^1,2

• Novartis is committed to improving population health outcomes in CVD by partnering with European healthcare systems to identify new ways of bringing transformative innovations to patients with atherosclerotic cardiovascular disease who are struggling to reach their LDL-C goals

• Leqvio is currently under review by the U.S. Food and Drug Administration and other health authorities

Basel, December 11, 2020 - Novartis announced today that the European Commission (EC) has approved Leqvio^®* (inclisiran) for the treatment of adults with hypercholesterolemia or mixed dyslipidemia. This approval is based on the results of the robust ORION clinical development program, where Leqvio provided an effective and sustained low-density lipoprotein cholesterol (LDL-C) reduction of up to 52% in patients with elevated LDL-C, despite maximally tolerated statin therapy. With two doses a year, after an initial dose and one at 3 months, Leqvio is expected to support long-term adherence^1-3.

Leqvio is a first-in-class small interfering RNA (siRNA) providing effective and sustained LDL-C reduction for patients with atherosclerotic cardiovascular disease (ASCVD), ASCVD risk equivalent and heterozygous familial hypercholesterolemia (HeFH), which are major drivers of heart attacks, strokes and may ultimately lead to death^1-3.

'Long-term exposure to persistently elevated LDL-C increases the risk of ASCVD⁸, which may lead to a cardiovascular event such as a heart attack or a stroke. As the first and only siRNA providing effective and sustained LDL-C reduction, Leqvio will give an opportunity to change how elevated LDL-C is treated , a highly important modifiable risk factor for ASCVD,' said Professor Ulf Landmesser, M.D., Director of Charité Center for Cardiovascular Diseases, Berlin. 'With only two doses a year administered by a healthcare professional, Leqvio is expected to circumvent the challenges of treatment adherence by improving therapeutic coverage and persistence.'

'Cardiovascular disease remains the leading cause of mortality in Europe⁴, which demonstrates the urgent need for innovative treatments for patients struggling to reach their LDL-C goals. With Leqvio, we're proud to bring a first-in-class treatment delivering effective and sustained LDL-C reduction that has the potential to improve outcomes for people living with ASCVD,' said Marie-France Tschudin, President, Novartis Pharmaceuticals. 'At Novartis, we're committed to reimagining care for cardiovascular disease by working together with healthcare systems and other stakeholders to explore innovative access models and bend the curve of life for patients.'

Leqvio is approved for the treatment of adults with primary hypercholesterolemia (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-C goals with the maximally 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.

The EC marketing authorization is valid in the 27 countries that are members of the EU. Norway, Iceland and Liechtenstein, as members of the European Economic Area (EEA), will take corresponding decisions based on the EC's recommendation.
Leqvio is also under review by the U.S. Food and Drug Administration for adults who have elevated LDL-C while being on a maximally tolerated dose of statin therapy.

*Product and brand name are currently under FDA review.
**After an initial dose and one at 3 months.

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 salt 300 mg, equivalent to 284 mg of inclisiran, administered subcutaneously by a healthcare professional. Starting with an initial dose¹, 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 cholesterol (LDL-C), despite a maximally tolerated dose of LDL-C-lowering therapies (e.g. a statin or ezetimibe). For the primary endpoints of ORION-9, inclisiran delivered mean placebo-adjusted percentage change in LDL-C reductions of 48% (P<.0001)>P<.0001)>1^,9.

ORION-10 was a pivotal Phase III, placebo-controlled, double-blind, randomized study to evaluate the efficacy, safety and tolerability of inclisiran sodium salt 300 mg, equivalent to 284 mg of inclisiran, administered subcutaneously by a healthcare professional. Starting with an initial dose², 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-C, despite a maximally tolerated dose of LDL-C-lowering therapies (e.g. a statin and/or ezetimibe). For the primary endpoints of ORION-10, inclisiran delivered mean placebo-adjusted percentage change in LDL-C reductions of 52% (P<.0001)>P<.0001)>2,⁹.

ORION-11 was a pivotal Phase III, placebo-controlled, double-blind, randomized study to evaluate the efficacy, safety and tolerability of inclisiran sodium salt 300 mg, equivalent to 284 mg of inclisiran, administered subcutaneously by a healthcare professional. Starting with an initial dose²,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-C 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-C reductions of 50% (P<.0001)>P<.0001)>2,⁹.

About Atherosclerotic Cardiovascular Disease (ASCVD)
Atherosclerosis corresponds to the accumulation of lipids over time mainly low-density lipoprotein cholesterol (LDL-C) in the inner lining of the arteries. Unexpected rupture of the atherosclerotic plaque can cause an atherosclerotic cardiovascular event such as a heart attack or stroke^10,11. ASCVD accounts for over 85% of all cardiovascular disease deaths¹². ASCVD is the primary cause of death in the European Union and its burden in the United States is greater than that from any other chronic diseases^13,14. ASCVD risk equivalent corresponds to conditions that confer a similar risk for an ASCVD event (e.g. diabetes, heterozygous familial hypercholesterolemia)^2,15.

About Leqvio (inclisiran)
Leqvio (inclisiran, KJX839) is the first and only small interfering RNA (siRNA) therapy to reduce low-density lipoprotein cholesterol (LDL-C) levels via an RNA interference (RNAi) mechanism of action and could help improve outcomes for patients with atherosclerotic cardiovascular disease (ASCVD), a deadly form of cardiovascular disease^1-3. With two doses a year and effective and sustained LDL-C reduction, Leqvio works as a complement to statins^1,2. Leqvio works differently from other therapies by preventing the production of the target protein in the liver, increasing hepatic uptake of LDL-C and clearing it from the bloodstream³. Leqvio is dosed initially, again at 3 months and then once every 6 months^1,2. In three clinical trials, patients taking Leqvio maintained LDL-C reduction throughout each 6-month dosing interval^1,2. Administered in-office as a subcutaneous injection, Leqvio is expected to integrate seamlessly into a patient's healthcare routine^1,2.

In the Phase III trials, inclisiran was well-tolerated. The most common adverse events reported (≥3% of patients treated with inclisiran and occurring more frequently than placebo) were injection site reaction, arthralgia, urinary tract infection, diarrhea, bronchitis, pain in extremity and dyspnea. Among those, injection site reactions were the most frequent ones. Those were generally mild and none were severe or persistent.

Novartis has obtained global rights to develop, manufacture and commercialize Leqvio under a license and collaboration agreement with Alnylam Pharmaceuticals, a leader in RNAi therapeutics.

About Novartis in Cardiovascular-Renal-Metabolism
Bending the curve of life requires addressing some of society's biggest public health concerns. Novartis has an established and expanding presence in diseases covering the heart, kidney and metabolic system. In addition to essential treatment Entresto^® (sacubitril/valsartan), Novartis has a growing pipeline of potentially first-in-class molecules addressing cardiovascular, metabolic and renal diseases.

Disclaimer
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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 nearly 800 million people globally and we are finding innovative ways to expand access to our latest treatments. About 110,000 people of more than 140 nationalities work at Novartis around the world. Find out more at https://www.novartis.com.

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References

1. Raal F, Kallend D, Ray K, et al. Inclisiran for Heterozygous Familial Hypercholesterolemia. N Engl J Med. 2020;382(16):1520-1530.
2. Ray K, Wright R, Kallend D, et al. Two Phase 3 Trials of Inclisiran in Patients with Elevated LDL Cholesterol. N Engl J Med. 2020;382(16):1507-1519.
3. Stoekenbroek RM, Kallend D, Wijngaard PL, et al. Inclisiran for the treatment of cardiovascular disease: the ORION clinical development program. Future Cardiol. 2018;14(6):433-442.
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7. Wong ND, Young D, Zhao Y, et al. Prevalence of the American College of Cardiology/American Heart Association statin eligibility groups, statin use, and low-density lipoprotein cholesterol control in US adults using the National Health and Nutrition Examination Survey 2011-2012. J Clin Lipidol. 2016;10(5):1109-1118.
8. Ference BA, Graham I, Tokgozoglu L, Catapano AL. Impact of Lipids on Cardiovascular Health: JACC Health Promotion Series. J Am Coll Cardiol. 2018;72(10):1141-1156.
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