Novartis receives positive CHMP opinion for Leqvio?* (inclisiran), a potential first-in-class siRNA for the treatment of high cholesterol
Basel,?October?16, 2020?? Novartis announced today that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a positive opinion and recommended granting marketing authorization of Leqvio?*?(inclisiran) for the treatment of adults with hypercholesterolemia or mixed dyslipidemia, marking an important milestone towards it becoming available in the EU.
Inclisiran is a potential first-in-class small interfering RNA (siRNA) with a new mechanism of action which delivers effective and sustained low-density lipoprotein cholesterol (LDL-C) reduction for patients with atherosclerotic cardiovascular disease (ASCVD), ASCVD risk equivalent and heterozygous familial hypercholesterolemia (HeFH) a major driver of heart attacks, strokes and deaths1.
?This investigational medicine could significantly change how high LDL-C is treated6,7,? said Professor Ulf Landmesser, M.D., Director of Charit? Center for Cardiovascular Diseases, Berlin. ?Many patients struggle to keep their LDL-C at recommended levels, and long-term exposure to high LDL-C is a major driver of ASCVD4,8,9. The unique mechanism of action of inclisiran provides effective and sustained LDL-C reduction, a causal factor of atherosclerotic disease progression. With only two doses a year, and as an injection administered by healthcare professionals, it is anticipated to remove adherence challenges commonly encountered with self-administered treatments1,6,7,10-13.?
?LDL-C reduction remains a major public health issue, with 80% of high-risk patients in Europe not achieving guideline-recommended LDL-C targets despite available current standard of care treatments. These patients remain at risk of ASCVD events, such as strokes or heart attacks3-5?, said John Tsai, Head Global Drug Development and Chief Medical Officer, Novartis. ?This encouraging positive CHMP opinion is a significant step in our journey of reimagining medicine with this transformational treatment, which has the potential to bring new hope to the millions of people in Europe currently unable to reach their LDL-C goals3-5.?
This CHMP opinion is based on results from the ORION clinical research program including Phase III trials, which involved more than 3,600 patients on a maximally tolerated statin dose and assessed the safety, efficacy and tolerability of inclisiran6,7. Inclisiran demonstrated effective and sustained LDL-C reduction of up to 52% (P<0.0001) with two doses per year, after an initial dose and one at 3 months, in adults with ASCVD, ASCVD risk equivalent and/or HeFH6,7. Further, the reduction in LDL-C achieved with inclisiran was sustained through 17 months, with a safety and tolerability profile similar to placebo6,7. Additional post hoc analysis showed low variability among the patients treated with inclisiran: 88% of them reached guideline recommended targets at any timepoint during the study (observed values)14.
The CHMP recommended granting inclisiran marketing authorization for the treatment of?adults with primary hypercholesterolemia (heterozygous familial and non-familial) or mixed dyslipidemia, as an adjunct to diet:
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- 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.
- 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.
- European Heart Network.?European Cardiovascular Disease Statistics 2017 edition. Available from:?http://www.ehnheart.org/cvd-statistics/cvd-statistics-2017?[Last accessed: October 2020].
- Bruckert E, Parhofer KG, Gonzalez-Juanatey JR, et al. Proportion of High-Risk/Very High-Risk Patients in Europe with Low-Density Lipoprotein Cholesterol at Target According to European Guidelines: A Systematic Review.?Adv?Ther. 2020;37(5):1724?1736.
- Lansberg P, Lee A, Lee ZV, et al. Nonadherence to statins: Individualized intervention strategies outside the pill box.?Vasc?Health Risk?Manag. 2018;14:91?102.
- 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.
- Raal F, Kallend D, Ray K, et al. Inclisiran for Heterozygous Familial Hypercholesterolemia.?N?Engl?J Med.?2020;382(16):1520?1530.
- 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.
- Brandts J, Ray KK. Low Density Lipoprotein Cholesterol-Lowering Strategies and Population Health: Time to Move to a Cumulative Exposure Model.?Circulation. 2020;141(11):873?876.
- Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS Guidelines for the Management of Dyslipidaemias: Lipid Modification to Reduce Cardiovascular Risk. Eur Heart J. 2020;1(41):111?188.
- Farnier M, Colhoun HM, Sasiela WJ, et al. Long-term treatment adherence to the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab in 6 ODYSSEY Phase III clinical studies with treatment duration of 1 to 2 years.?J Clin?Lipidol. 2017;11(4):986?997.
- Saborowski M, D?lle M, Manns MP, et al. Lipid-lowering therapy with PCSK9-inhibitors in the management of cardiovascular high-risk patients: Effectiveness, therapy adherence and safety in a real world cohort.?Cardiol?J. 2018;25(1):32?41.
- Kosmas CE, Silverio D, Ovalle J, et al. Patient adherence, compliance, and perspectives on evolocumab for the management of resistant hypercholesterolemia.?Patient Prefer Adherence. 2018;12:2263?2266.
- Hlatky MA, Kazi DS. PCSK9 Inhibitors: Economics and Policy.?J Am Coll?Cardiol. 2017;70(21):2677?2687.
- Scott Wright R. ORION-10 and ORION-11, Interindividual variability in LDL-C reductions with inclisiran. Date presented at the European Society of Cardiology Annual Congress; August 29?September 01, 2020.
- Mayo Clinic.?Arteriosclerosis / atherosclerosis. Available from:?https://www.mayoclinic.org/diseases-conditions/arteriosclerosis-atherosclerosis/symptoms-causes/?[Last accessed: October 2020].
- Goldstein J, Brown M. A century of cholesterol and coronaries: from plaques to genes to statins.?Cell. 2015;161(1):161?172.
- World Health Organization.?Cardiovascular diseases (CVDs).?Available from:?https://www.who.int/news-room/fact-sheets/detail/cardiovascular-diseases-(cvds)?[Last accessed: October 2020].
- Roger VL, Go AS, Lloyd-Jones DM, et al. Heart disease and stroke Statistics?2012 update.?Circulation. 2012;125(1):e2?e220.
- Kim H, Kim S, Han S, et al. Prevalence and incidence of atherosclerotic cardiovascular disease and its risk factors in Korea: a nationwide population-based study.?BMC Public Health. 2019;19(1):1112.
- National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report.?Circulation. 2002;106(25):3143?3421.
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