Effect of an siRNA Therapeutic Targeting PCSK9 on Atherogenic Lipoproteins

Kausik K. Ray, Robert M. Stoekenbroek, David Kallend, Lawrence A. Leiter, Ulf Landmesser, R. Scott Wright, Peter Wijngaard, John J.P. Kastelein

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

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<0.001 for all groups versus placebo). In the 300-mg 2-dose group, all individuals experienced apo B and non-HDL-C reductions. There was larger interindividual variation in very-low-density lipoprotein cholesterol, triglycerides, and lipoprotein(a) reductions. In the 300-mg 2-dose group, the percentages of patients achieving guideline-recommended apo B goals for high- and very-high-risk patients at day 180 were 78% and 90%; 68% and 83% of participants achieved non-HDL-C <100 and <130 mg/dL.

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.

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.

Original languageEnglish (US)
Pages (from-to)1304-1316
Number of pages13
JournalCirculation
Volume138
Issue number13
DOIs
StatePublished - Sep 25 2018

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Apolipoproteins B
Therapeutic Uses
Small Interfering RNA
Lipoproteins
VLDL Cholesterol
LDL Cholesterol
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Lipoprotein(a)
Peptide Hydrolases
Placebos
Lipids
Apolipoprotein A-I
Hepatocytes
Triglycerides
Cardiovascular Diseases
Therapeutics
Clinical Trials
Guidelines
Messenger RNA
lipoprotein cholesterol

Keywords

  • ALN-PCS
  • cholesterol
  • proprotein convertases

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Ray, K. K., Stoekenbroek, R. M., Kallend, D., Leiter, L. A., Landmesser, U., Wright, R. S., ... Kastelein, J. J. P. (2018). Effect of an siRNA Therapeutic Targeting PCSK9 on Atherogenic Lipoproteins. Circulation, 138(13), 1304-1316. https://doi.org/10.1161/CIRCULATIONAHA.118.034710

Effect of an siRNA Therapeutic Targeting PCSK9 on Atherogenic Lipoproteins. / Ray, Kausik K.; Stoekenbroek, Robert M.; Kallend, David; Leiter, Lawrence A.; Landmesser, Ulf; Wright, R. Scott; Wijngaard, Peter; Kastelein, John J.P.

In: Circulation, Vol. 138, No. 13, 25.09.2018, p. 1304-1316.

Research output: Contribution to journalArticle

Ray, KK, Stoekenbroek, RM, Kallend, D, Leiter, LA, Landmesser, U, Wright, RS, Wijngaard, P & Kastelein, JJP 2018, 'Effect of an siRNA Therapeutic Targeting PCSK9 on Atherogenic Lipoproteins', Circulation, vol. 138, no. 13, pp. 1304-1316. https://doi.org/10.1161/CIRCULATIONAHA.118.034710
Ray KK, Stoekenbroek RM, Kallend D, Leiter LA, Landmesser U, Wright RS et al. Effect of an siRNA Therapeutic Targeting PCSK9 on Atherogenic Lipoproteins. Circulation. 2018 Sep 25;138(13):1304-1316. https://doi.org/10.1161/CIRCULATIONAHA.118.034710
Ray, Kausik K. ; Stoekenbroek, Robert M. ; Kallend, David ; Leiter, Lawrence A. ; Landmesser, Ulf ; Wright, R. Scott ; Wijngaard, Peter ; Kastelein, John J.P. / Effect of an siRNA Therapeutic Targeting PCSK9 on Atherogenic Lipoproteins. In: Circulation. 2018 ; Vol. 138, No. 13. pp. 1304-1316.
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T1 - Effect of an siRNA Therapeutic Targeting PCSK9 on Atherogenic Lipoproteins

AU - Ray, Kausik K.

AU - Stoekenbroek, Robert M.

AU - Kallend, David

AU - Leiter, Lawrence A.

AU - Landmesser, Ulf

AU - Wright, R. Scott

AU - Wijngaard, Peter

AU - Kastelein, John J.P.

PY - 2018/9/25

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N2 - 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<0.001 for all groups versus placebo). In the 300-mg 2-dose group, all individuals experienced apo B and non-HDL-C reductions. There was larger interindividual variation in very-low-density lipoprotein cholesterol, triglycerides, and lipoprotein(a) reductions. In the 300-mg 2-dose group, the percentages of patients achieving guideline-recommended apo B goals for high- and very-high-risk patients at day 180 were 78% and 90%; 68% and 83% of participants achieved non-HDL-C <100 and <130 mg/dL.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.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.

AB - 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<0.001 for all groups versus placebo). In the 300-mg 2-dose group, all individuals experienced apo B and non-HDL-C reductions. There was larger interindividual variation in very-low-density lipoprotein cholesterol, triglycerides, and lipoprotein(a) reductions. In the 300-mg 2-dose group, the percentages of patients achieving guideline-recommended apo B goals for high- and very-high-risk patients at day 180 were 78% and 90%; 68% and 83% of participants achieved non-HDL-C <100 and <130 mg/dL.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.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.

KW - ALN-PCS

KW - cholesterol

KW - proprotein convertases

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