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Preface: From November 5th to 7th, 2022, AHA 2022 will be held online + offline in Chicago as scheduled. Among them, the special research section "The present and future of lipid-lowering treatment" has collected a number of clinical research results of new drugs in the field of lipid-, including the ORION-3 study (PCSK9 siRNA drug Inclisiran), the ARCHES-2 study (ANGPTL3 siRNA drug ARO-ANG3) and the SHASTA-2 study (APOC3 siRNA drug ARO-APOC3).
Inclisiran is the world's first small interfering RNA (siRNA) lipid-lowering drug for . It can block the synthesis of the liver pro-protein converting enzyme subtilisin 9 (PCSK9) protein at the expression level through the RNA interference mechanism, thereby upregulating the liver low-density lipoprotein (LDL) receptor and reducing the circulating low-density lipoprotein cholesterol (LDL-C) level. In the past, multiple global multi-center Phase III lipid reduction studies have been published. The results fully confirm that during the 18-month study period, Inclisiran only needs to two injections a year to achieve the powerful, long-term and stable LDL-C reduction of , with a decrease of more than 50% [1-3]. However, as a new mechanism of small interfering RNA drug, the long-term safety of Inclisiran still needs clinical data support. The ORION-3 study is based on the Phase 2 ORION-1 study. A four-year open-label extension trial was conducted on the original 52 centers, and the long-term efficacy and safety of Inclisiran was explored with .
ORION-3: InclisiranDurable and stable
reduces LDL-C, and has good safety
ORION-3 Study As a multi-center, open-label extension trial, a total of 382 atherosclerotic cardiovascular disease (ASCVD) or ASCVD who have completed the Phase 2 ORION-1 study were included, and were divided into ①Inclisiran treatment group (Inclisiran-only arm, N=290), from the inclisiran treatment group in the original ORION-1 study, continued to receive inclisiran treatment for an additional 4 years; ② The dressing change group (switching arm, N=92), from the placebo group in the original ORION-1 study, was treated with elociumab for 1 year, and then the dressing change was treated with Inclisiran. The main endpoint of the
study was on day 210, and the percentage of changes in LDL-C compared with ORION-1 baseline in the Inclisiran treatment group . The secondary endpoints were the percentage change of LDL-C, PCSK9 and other blood lipid indicators over time and absolute change of ORION-1 baseline in the Inclisiran treatment group. The exploratory endpoint is the efficacy and safety of the dressing change group [4,5].
Figure 1 ORION-3 Study Design
ORION-3 In the end, a total of 233 (80.3%) patients completed a 4-year follow-up, with an average age of 63.3 years, of which 50.0% were ≥65 years old. The mean LDL-C at ORION-1 baseline was 128.9 mg/dL (3.33 mmol/L) [5]. The results of the
Inclisiran-only arm showed that at day 210, the baseline decrease of LDL-C compared with ORION-1 was 47.5% (95% CI: -50.7, -44.3; p <>44.2%, and the decline in lasted and stable ; the average decline in PCSK9 was −62.2% to −77.8%. The results of the switching arm showed that the average reduction of LDL-C compared with ORION-1 baseline was 45.3% [5].
ORION-3 safety analysis showed that during the entire 4-year study period, Inclisiran had good overall safety tolerance and no new adverse reactions were found. main drug-related adverse events is an injection site reaction, all of which are mild to moderate and self-limiting [5].
Figure 2 ORION-3 study LDL-C drop in the Inclisiran treatment group
However, it can achieve such stable clinical efficacy and good safety tolerance in long-term research, which is related to the RNA interference mechanism of and N-acetylgalactosamine (GalNAc) delivery system , which is unique to Inclisiran as a new class of small interfering RNA drugs.
RNA interference: Nobel Prize found that
precisely regulates gene expression
Inclisiran As a class of small interfering RNA drugs, its mechanism of action is to utilize the natural RNA interference phenomenon in the body. RNA interference (RNA interference) was discovered by American scientists Andrew Fire and Craig Mello in 1998. The two won the Nobel Prize in Physiology or Medicine in 2006, opening a new era of small interfering RNA drugs [6].
Simply put, RNA interference is a mechanism that naturally exists in organisms and "learning from the barbarians to control the barbarians", that is, the double-stranded RNA from can specifically induce the degradation of paired mRNA in cells with it [7-8]. Small interfering RNA drugs are such a type of double-stranded RNA. The RNA sequences are designed to specifically recognize and induce mRNA degradation of target proteins, achieving accurate gene expression regulation . Therefore, on the one hand, small interfering RNA drugs can theoretically target any pathogenic gene and interfere with traditional targets that cannot be used in medicine; on the other hand, small interfering RNA drugs are only regulated at the level of cytoplasmic mRNA, and does not affect its original DNA sequence , nor does it affect the expression of other genes [7-8].
Figure 3 Small interfering RNA drugs achieve accurate gene expression regulation at the mRNA level
GalNAc delivery system:
targets the liver, safe and reliable
Inclisiran-coupled GalNAc structure can assist it to target the liver accurately. GalNAc is a widely used small interfering RNA delivery system that acts as a class of carbohydrate chemical groups that bind only to the assialic glycoprotein receptor (ASGPR) highly expressed on the surface of hepatocytes [9-11]. Therefore, with the GalNAc structure, Inclisiran can achieve targeted in the liver, reduce the potential exposure risk of other organs, and achieve precise intervention of liver PCSK9 protein.
Figure 4 GalNAc tag makes it possible to target the liver of small interfering RNA
Summary
Inclisiran As a new class of small interfering RNA lipid-lowering drugs, previous studies have fully confirmed its clinical efficacy in reducing LDL-C levels by two injections a year in dangerous people such as ASCVD and ASCVD. The ORION-3 study, released by the 2022 Annual Meeting of the American Heart Association Science Conference (AHA), is its first long-term study for prospective follow-up, further expanding this conclusion from 1.5 years to 4 years. At the same time, the ORION-3 study also filled the data gap in the long-term safety of small interfering RNA drugs in the field of lipid-lowering, enriching the experience of small interfering RNA in the field of chronic diseases. Finally, we also look forward to the good compliance brought by its two injections a year to bring new treatment opportunities to Chinese ASCVD patients in the future.
Peng Daoquan Professor/Chief Physician
Director of the Cardiovascular Disease Research Office of Xiangya Second Hospital of Central South University, Director of the Institute of Lipid and Atherosclerosis of Central South University, Professor, Chief Physician, Doctoral Supervisor;
Currently a member of the Standing Committee of the Professional Committee of Cardiology Prevention and Control of the Chinese Preventive Medicine Association, China Healthcare International Exchange Promotion Association Standing Committee of the Preventive Thrombosis Prevention and Control Branch, Deputy Chairman of the Hunan Cardiovascular Disease Professional Committee, Deputy Chairman of the Professional Committee of the Hunan Preventive Medicine Association, Deputy Chairman of the Professional Committee of Cardiology Prevention and Control of the Hunan Pathophysiology Association, Deputy Chairman of the Professional Committee of the Cardiovascular Professional Committee of the Hunan Pathophysiology Association;
"Lipid and Cardiovascular Professional Committee" Editorial board member of Research magazine and Chinese Cardiovascular Magazine, and expert in reviewing a number of international magazines. Mainly engaged in research on blood lipids, inflammation and atherosclerosis. He has been postdoctoral research for 4 years at the University of Calgary, Canada and Cleveland Clinical Center in the United States. He has obtained more than 10 scientific research projects such as the American Heart Association Foundation (1 item), the National Natural Science Foundation (5 items), and the Ministry of Health’s key clinical projects (1 item). Published SCI papers in journals such as Nat Med, Eur Heart J. During his time in the United States, he won 2 patent innovation awards. It has won 54 Science and Technology Achievements Awards from the Ministry of Education, the Ministry of Health, the Provincial Science and Technology Commission and other science and technology achievements. He edited 2 monographs and participated in the editing of 7 monographs.
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References:
[1]Ray Kausik K, et al. N Engl J Med. 2020 Apr 16;382(16):1507-1519.
[2]Raal Frederick J, et al. N Engl J Med. 2020 Apr 16;382(16):1520-1530.
[3]Wright R Scott, et al. 2021 Mar 9;77(9):1182-1193.
[4]https://clinicaltrials.gov/ct2/show/NCT03060577?term=NCT03060577draw=2rank=1
[5]https://eppro02.ativ.me/src/EventPilot/php/express/web/planner.php?id=AHA22
[6]The Nobel Prize in Physiology or Medicine 2006. https://www.nobelprize.org/prizes/medicine/2006/summary/
[7]RNA Interference Pubmed MeSH. https://www.ncbi.nlm.nih.gov/mesh/68034622.
[8]Stanley T Crooke, et al. Cell Metab. 2018 Apr 3;27(4): 714-739.
[9]Rose Q Do, et al. Curr Cardiol Rep. 2013 Mar;15(3):345.
[10]Khvorova Anastasia. N Engl J Med. 2017 Jan 5;376(1):4-7.
[11]Lancellotti Patrizio, et al. N Engl J Med. 2017 May 4;376(18):e38.
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