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FDA approves Novartis Leqvio® (inclisiran), first-in-class siRNA to lower cholesterol and keep it low with two doses a year
Two Phase 3 Trials of Inclisiran in Patients with Elevated LDL Cholesterol
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administered by subcutaneous injection on day 1, day 90, and every 6 months thereafter over a period of 540 days.
It remains to be seen whether inclisiran reduces cardiovascular morbidity and mortality. This is currently being studied in clinical trials, Novartis said.
European regulators had approved inclisiran at the end of 2020.
Notably, inclisiran's approval had been delayed by a year because of FDA's concerns with factory inspection issues.
The siRNA drug will be available in early January 2022 with Novartis manufacturing and commercializing it under a licensing agreement with Alnylam Pharmaceuticals.
The binding of proprotein convertase subtilisin–kexin type 9 (PCSK9) in the circulation by monoclonal antibodies reduces both low-density lipoprotein (LDL) cholesterol levels and the incidence of cardiovascular events.1,2 Inclisiran, a small interfering RNA (siRNA) therapeutic agent, reduces hepatic synthesis of PCSK9. In one trial, the LDL cholesterol level was lowered by 52.6% at 180 days after two doses of 284 mg of inclisiran (equivalent to 300 mg of inclisiran sodium) administered on day 1 and day 90.3 Data from the same trial following the same patients over a period of 360 days suggested that inclisiran might provide sustained reductions in LDL cholesterol levels, with the potential for a dosing schedule of once every 6 months.4
A total of 1561 and 1617 patients underwent randomization in the ORION-10 and ORION-11 trials, respectively. Mean (±SD) LDL cholesterol levels at baseline were 104.7±38.3 mg per deciliter (2.71±0.99 mmol per liter) and 105.5±39.1 mg per deciliter (2.73±1.01 mmol per liter), respectively. At day 510, inclisiran reduced LDL cholesterol levels by 52.3% (95% confidence interval [CI], 48.8 to 55.7) in the ORION-10 trial and by 49.9% (95% CI, 46.6 to 53.1) in the ORION-11 trial, with corresponding time-adjusted reductions of 53.8% (95% CI, 51.3 to 56.2) and 49.2% (95% CI, 46.8 to 51.6) (P<0.001 for all comparisons vs. placebo). Adverse events were generally similar in the inclisiran and placebo groups in each trial, although injection-site adverse events were more frequent with inclisiran than with placebo (2.6% vs. 0.9% in the ORION-10 trial and 4.7% vs. 0.5% in the ORION-11 trial); such reactions were generally mild, and none were severe or persistent.
The use of stable doses of statin treatment was high (89.2% in the ORION-10 trial and 94.7% in the ORION-11 trial), with the majority of patients receiving high-intensity statins (68.0% and 78.6%, respectively). Use of ezetimibe either alone or in combination with statins was low (9.9% in the ORION-10 trial and 7.1% in the ORION-11 trial). The mean (±SD) LDL cholesterol level at baseline was 104.7±38.3 mg per deciliter (2.71±0.99 mmol per liter) and 105.5±39.1 mg per deciliter (2.73±1.01 mmol per liter) in the respective trials (Table 1).
Inclisiran lowered levels of triglycerides and lipoprotein(a) and increased HDL cholesterol levels at day 510 (Table S4A and S4B).
FDA approves Novartis Leqvio® (inclisiran), first-in-class siRNA to lower cholesterol and keep it low with two doses a year
Dec 22, 2021
Ad hoc announcement pursuant to Art. 53 LR
• With two maintenance doses a year, Leqvio is the first and only FDA-approved small interfering RNA (siRNA) therapy for LDL-C (bad cholesterol) reduction1
• Leqvio provides effective and sustained LDL-C reduction of up to 52% vs. placebo for certain people with atherosclerotic cardiovascular disease (ASCVD) on maximally tolerated statin therapy2,3
• Approximately 16 million Americans with ASCVD taking statins to lower cholesterol-including those who have experienced a heart attack or stroke-are not at recommended LDL-C target4,5
Basel, December 22, 2021 - Novartis today announced the US Food and Drug Administration (FDA) approval of Leqvio® (inclisiran), the first and only small interfering RNA (siRNA) therapy to lower low-density lipoprotein cholesterol (also known as bad cholesterol or LDL-C) with two doses a year, after an initial dose and one at three months.
"Leqvio is a revolutionary approach to lower LDL-C, and creates new possibilities for how healthcare systems can impact cardiovascular disease, a defining public health challenge of our time," said Vas Narasimhan, Novartis CEO. "We now have the opportunity, working together with partners, to provide this first-ever approved LDL-C–lowering siRNA-based therapy to tackle ASCVD at scale across the United States."
Leqvio is indicated in the United States 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. The effect of Leqvio on cardiovascular morbidity and mortality is being explored in clinical trials currently underway.
"ASCVD is a substantial public health burden affecting 30 million Americans," said Norman Lepor, MD, a Los Angeles based cardiologist and a clinical investigator in the Phase III clinical program for Leqvio. "As a first-of-its-kind siRNA therapy, Leqvio works differently than other cholesterol treatments, with twice-yearly dosing that makes it a compelling option for the millions of people with ASCVD already on cholesterol-lowering medications struggling to reach their LDL-C target."
Leqvio reduces the amount of LDL-C in the bloodstream by improving the liver's natural ability to prevent the production of a protein that plays a role in keeping circulating cholesterol levels high6,7. It is a subcutaneous injection given by a healthcare provider with an initial dose, then again at three months, and then every six months1. This approach may help those who have trouble sticking to medicines that are self-administered and have greater dosing frequency. Leqvio will be available in early January 2022.
"People with ASCVD have most likely experienced a heart attack or stroke from high cholesterol, causing a burden on the family and having a negative impact on lives," said Andrea Baer, Executive Director of The Mended Hearts, Inc. "One of the first steps to improving patients' health is to manage high cholesterol and we're encouraged that this new twice-a-year treatment offers a new option."
The FDA approval was based on results from the comprehensive Phase III ORION-9, -10 and -11 clinical trials, in which all 3,457 participants with ASCVD or HeFH had elevated LDL-C while receiving a maximally tolerated dose of statin therapy2,3. In the Phase III trials at month 17, Leqvio delivered effective and sustained LDL-C reduction of up to 52% vs. placebo and was reported to be well-tolerated with a safety profile shown to be comparable to placebo2,3. The most common side effects were mild to moderate injection site reaction (including pain, redness and rash), joint pain, urinary tract infection, diarrhea, chest cold, pain in legs or arms and shortness of breath2,3.
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.
1. Leqvio prescribing information. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2021.
2. Ray KK, Wright RS, 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. doi:10.1056/NEJMoa1912387
3. Raal FJ, Kallend D, Ray KK, et al. Inclisiran for heterozygous familial hypercholesterolemia. N Engl J Med. 2020;382(16):1520-1530. doi:10.1056/NEJMoa1913805
4. 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. doi: 10.1016/j.jacl.2016.06.011
5. Grundy MS, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/ AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019;139:e1082–e1143. doi: 10.1161/CIR.0000000000000625
6. Khvorova A. Oligonucleotide therapeutics-a new class of cholesterol-lowering drugs. N Engl J Med. 2017;376(1):4-7. doi: 10.1056/NEJMp1614154
7. Kosmas CE, Muñoz Estrella A, Sourlas A, et al. Inclisiran: a new promising agent in the management of hypercholesterolemia. Diseases. 2018;6(3):63. doi: 10.3390/diseases6030063
8. World Health Organization. Cardiovascular diseases (CVDs). June 11, 2021. Accessed November 23, 2021. https://www.who.int/news-room/fact-sheets/detail/cardiovascular-diseases-(cvds)
9. National Kidney Foundation. Global Facts: About Kidney Disease. Accessed November 23, 2021. https://www.kidney.org/kidneydisease/global-facts-about-kidney-disease
10. 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. doi: 10.1038/sj.ki.5002343
11. World Health Organization. Diabetes. November 10, 2021. Accessed November 23, 2021. https://www.who.int/news-room/fact-sheets/detail/diabetes
12. American Cancer Society. Global Cancer Facts & Figures 4th Edition. Atlanta, GA: American Cancer Society; 2018. Accessed November 23, 2021. 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
13. World Health Organization. Cardiovascular diseases: Data and statistics. Accessed November 23, 2021. https://www.euro.who.int/en/health-topics/noncommunicable-diseases/cardiovascular-diseases/data-and-statistics

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