November 15, 2021 — Novartis announced results from a pooled post-hoc analysis of Phase III ORION-9, -10 and -11 trials, exploring the impact of body mass index (BMI) levels on the efficacy and safety of twice-yearly inclisiran (Leqvio). At month 17, inclisiran was well-tolerated and provided effective and sustained reduction of approximately 50%, difference from placebo, in low-density lipoprotein cholesterol (LDL-C) when used in addition to other lipid-lowering therapies across all body mass index (BMI) types.1 Results were presented at the American Heart Association Scientific Sessions 2021.
“For patients with vascular disease who have a high BMI, physicians generally recommend weight loss in addition to cholesterol-lowering medication," said Lawrence A. Leiter, M.D., director of the lipid clinic, associate director of the Clinical Nutrition and Risk Factor Modification Centre and associate scientist in the Li Ka Shing Knowledge Institute of St. Michael’s Hospital, Toronto, Canada. “Despite our best efforts, however, weight loss isn’t always achievable. The BMI analysis sheds new light on the potential of inclisiran (Leqvio) in helping patients reduce their LDL-C by up to half with only twice-yearly dosing no matter what their weight.”
Regardless of BMI, Leqvio showed effective and sustained lipid lowering compared to placebo across a range of atherogenic lipids demonstrating that its pharmacology does not appear to be impacted by excessive body weight. In addition to lowering LDL-C levels by approximately 50%, reductions were also seen across triglycerides (~10%), total cholesterol (~33%), non-HDL-C (~45%) and ApolipoproteinB (~40%). The trials included adults with ASCVD, HeFH and ASCVD risk equivalent.1 Inclisiran had a tolerability profile similar to placebo. Serious adverse events increased with BMI levels in both placebo and inclisiran treatment arms. Treatment emergent adverse events (TEAEs) at the injection site were more frequent with inclisiran, but all were mild or moderate.1 The effect ofinclisiran on cardiovascular morbidity and mortality has not been determined.
Product and brand name are currently under FDA review.
ORION Phase III Low-density Lipoprotein Cholesterol (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 300 mg, equivalent to 284 mg, administered subcutaneously by a healthcare professional. Starting with an initial dose5, inclisiran was then administered again at three months and then every six months thereafter in 482 participants with clinical or genetic evidence of heterozygous familial hypercholesterolemia and elevated 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, Leqvio delivered mean placebo-adjusted percentage change in LDL-C reductions of 48% (P<.0001) at 510 days and demonstrated time-adjusted percentage change in LDL-C reductions of 44% (P<.0001) from 90 through 540 days. The international study was conducted at 46 sites in eight countries.5,6
ORION-10 was a pivotal Phase III, placebo-controlled, double-blind, randomized study to evaluate the efficacy, safety and tolerability of inclisiran 300 mg, equivalent to 284 mg of Leqvio, administered subcutaneously by a healthcare professional. Starting with an initial dose7, inclisiran was then administered again at three months and then every six 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, Leqvio delivered mean placebo-adjusted percentage change in LDL-C reductions of 52% (P<.0001) at 510 days and demonstrated time-adjusted percentage change in LDL-C reductions of 54% (P<.0001) from 90 through 540 days. The study was conducted at 145 sites in the U.S.6,7
ORION-11 was a pivotal Phase III, placebo-controlled, double-blind, randomized study to evaluate the efficacy, safety and tolerability of Leqvio 300 mg, equivalent to 284 mg of Leqvio, administered subcutaneously by a healthcare professional. Starting with an initial dose7, Leqvio was then administered again at three months and then every six 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, Leqvio delivered placebo-adjusted change in LDL-C reductions of 50% (P<.0001) at 510 days and demonstrated time-adjusted LDL-C reductions of 49% (P<.0001) from 90 through 540 days. The international study was conducted at 70 sites in seven countries.6,7
The Phase III ORION-9, -10 and -11 trials are part of the larger Leqvio VictORION dynamic evidence generation program.
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.8,9 ASCVD accounts for over 85% of all cardiovascular disease deaths.10 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.11,12 ASCVD risk-equivalent corresponds to conditions that confer a similar risk for an ASCVD event (e.g., diabetes, heterozygous familial hypercholesterolemia).7,13
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.5,7,14 With two doses a year and effective and sustained LDL-C reduction, Leqvio works as a complement to statins.5,7 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 bloodstream.14 Leqvio is dosed initially, again at three months and then once every six months.5,7 In three clinical trials, patients taking Leqvio maintained LDL-C reduction throughout each six-month dosing interval.7,9 Administered in-office as a subcutaneous injection, Leqvio is expected to integrate seamlessly into a patient’s healthcare routine.5,7
In the Phase III trials, Leqvio was well-tolerated. The most common adverse events reported (≥3% of patients treated with Leqvio 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.
Cardiovascular (CV), renal and metabolic diseases are a global health crisis.10,15-17 These chronic, complex and often hereditary diseases are frequently inter-related, and come with healthcare and treatment barriers and a lack of transformative medicines and almost always lead to the same outcome: death due to CV disease.10,15-17
CV disease is the number one killer in the world.10 Taking more lives than all cancers combined, it contributes to one in every three deaths globally.10,18 Of all CV events, 80% can be prevented.19 Patients and their families deserve better, and our society deserves more.
- Leiter LA, Shing LK, Kallend DG, et al. Efficacy and Safety of Inclisiran By Baseline Body Mass Index: A Post Hoc Pooled Analysis Of The ORION-9, ORION-10, ORION-11 Phase III Randomized Controlled Trials. ePoster presentation at: AHA Scientific Sessions; November 2021.
- Society for Vascular Surgery. Hyperlipidemia. Accessed September 2, 2021. Available at https://vascular.org/patient-resources/vascular-conditions/hyperlipidemia.
- Ference B, 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.
- 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.
- Clinicaltrials.gov. ORION -9, -10, -11. Available at https://www.clinicaltrials.gov/ct2/show/NCT03397121, https://clinicaltrials.gov/ct2/show/NCT03399370, https://www.clinicaltrials.gov/ct2/show/NCT03400800 [Last accessed August 2021].
- 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.
- Mayo Clinic Arteriosclerosis / atherosclerosis. Available at https://www.mayoclinic.org/diseases-conditions/arteriosclerosis-atherosclerosis/symptoms-causes/ [Last accessed August 2021].
- 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 at https://www.who.int/news-room/fact-sheets/detail/cardiovascular-diseases-(cvds) [Last accessed October 2021].
- Roger VL, Go AS, Lloyd-Jones DM, et al. Heart disease and stroke Statistics–2012 update: A report from the American Heart Association. 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.
- 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.
- National Kidney Foundation. Global Facts: About Kidney Disease. Available at: https://www.kidney.org/kidneydisease/global-facts-about-kidney-disease. [Last accessed October 2021].
- Levey AS, Atkins R, Coresh J, et al. Chronic kidney disease as a global public health problem: approaches and initiatives – a position statement from Kidney Disease Improving Global Outcomes. Kidney Int. 2007;72(3):247-259.
- World Health Organization. Diabetes. Available at: https://www.who.int/news-room/fact-sheets/detail/diabetes. [Last accessed October 2021].
- American Cancer Society. Global Cancer Facts & Figures 4th Edition. Available at: https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/global-cancer-facts-and-figures/global-cancer-facts-and-figures-4th-edition.pdf. [Last accessed October 2021].
- World Health Organization (WHO). Cardiovascular diseases - Data and statistics. Available at: https://www.euro.who.int/en/health-topics/noncommunicable-diseases/cardiovascular-diseases/data-and-statistics. [Last accessed October 2021].