Effect of an siRNA Therapeutic Targeting PCSK9 on Atherogenic Lipoproteins
| Autor: | Kausik K. Ray, John J.P. Kastelein, Peter L.J. Wijngaard, Lawrence A. Leiter, Robert M. Stoekenbroek, Ulf Landmesser, R. Scott Wright, David Kallend |
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| Rok vydání: | 2018 |
| Předmět: |
Male
Time Factors Cardiac & Cardiovascular Systems STATIN THERAPY Apolipoprotein B LDL-CHOLESTEROL 030204 cardiovascular system & hematology Pharmacology PCSK9 chemistry.chemical_compound 0302 clinical medicine Inclisiran ALN-PCS Medicine 030212 general & internal medicine RNA Small Interfering 1102 Cardiorespiratory Medicine and Haematology RISK biology Middle Aged Lipids Treatment Outcome SAFETY Apolipoprotein B-100 CORONARY-ARTERY-DISEASE Female lipids (amino acids peptides and proteins) Statin therapy Proprotein Convertase 9 Cardiology and Cardiovascular Medicine Life Sciences & Biomedicine inclisiran APOLIPOPROTEIN-B Low density lipoprotein cholesterol Therapeutic targeting 1117 Public Health and Health Services 03 medical and health sciences Double-Blind Method Physiology (medical) Humans CARDIOVASCULAR EVENTS Triglycerides METAANALYSIS Aged Dyslipidemias Science & Technology Apolipoprotein A-I Cholesterol business.industry EVOLOCUMAB proprotein convertases cholesterol 1103 Clinical Sciences REDUCTION Evolocumab RNAi Therapeutics Peripheral Vascular Disease Cardiovascular System & Hematology chemistry Cardiovascular System & Cardiology biology.protein business Biomarkers Lipoprotein(a) |
| Zdroj: | Circulation. 138:1304-1316 |
| ISSN: | 1524-4539 0009-7322 |
| Popis: | Background: The ORION-1 trial (Trial to Evaluate the Effect of ALN-PCSSC Treatment on Low Density Lipoprotein Cholesterol [LDL-C]) demonstrated that inclisiran, an siRNA therapeutic that targets protease proprotein convertase subtilisin/kexin type 9 mRNA within hepatocytes, produces significant low-density lipoprotein cholesterol reduction. The effects of inclisiran on other lipids are less well described. Methods: ORION-1 was a phase 2 trial assessing 6 different inclisiran dosing regimens versus placebo. Participants with elevated low-density lipoprotein cholesterol despite receiving maximally tolerated statin therapy received a single-dose (200, 300, or 500 mg) or 2-dose starting regimen (100, 200, or 300 mg on days 1 and 90) of inclisiran or placebo. This prespecified analysis reports the percentage reductions in non–high-density lipoprotein cholesterol (non–HDL-C), apolipoprotein (apo) B, very-low-density lipoprotein cholesterol, lipoprotein(a), triglycerides, HDL-C, and apo A1 at the primary efficacy time point (day 180) with mixed-effect models for repeated measures. Additional prespecified analyses report time course of changes from baseline at each visit to day 210, interindividual variation in response, and lipid goal attainment. Results: The mean age of the 501 participants was 63 years, 65% were male, 69% had atherosclerotic cardiovascular disease, 73% used statins, and mean low-density lipoprotein cholesterol was 128 mg/dL. A single dose of inclisiran reduced apo B, non–HDL-C, and very-low-density lipoprotein cholesterol over 210 days. A second dose of inclisiran provided additional lowering of these lipids. At day 180, non–HDL-C was lowered dose-dependently: by 25% from 148±43 to 110±45 mg/dL in the 200-mg single-dose group and by 46% from 161±58 to 91±58 mg/dL in the 2-dose 300-mg group. For the same dosing regimens, apo B was reduced by 23% from 101±23 to 78±29 mg/dL and by 41% from 106±31 to 65±33 mg/dL ( P Conclusions: Inclisiran produces significant and prolonged reductions in atherogenic lipoproteins, suggesting that inhibiting the synthesis of protease proprotein convertase subtilisin/kexin type 9 through siRNA may be a viable alternative to other approaches that target protease proprotein convertase subtilisin/kexin type 9. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02597127. |
| Databáze: | OpenAIRE |
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