Inclisiran in patients at high cardiovascular risk with elevated LDL cholesterol

Kausik K. Ray, Ulf Landmesser, Lawrence A. Leiter, David Kallend, Robert Dufour, Mahir Karakas, Tim Hall, Roland P.T. Troquay, Traci Turner, Frank L.J. Visseren, Peter Wijngaard, R. Scott Wright, John J.P. Kastelein

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Abstract

BACKGROUND In a previous study, a single injection of inclisiran, a chemically synthesized small interfering RNA designed to target PCSK9 messenger RNA, was found to produce sustained reductions in low-density lipoprotein (LDL) cholesterol levels over the course of 84 days in healthy volunteers. METHODS We conducted a phase 2, multicenter, double-blind, placebo-controlled, multipleascending- dose trial of inclisiran administered as a subcutaneous injection in patients at high risk for cardiovascular disease who had elevated LDL cholesterol levels. Patients were randomly assigned to receive a single dose of placebo or 200, 300, or 500 mg of inclisiran or two doses (at days 1 and 90) of placebo or 100, 200, or 300 mg of inclisiran. The primary end point was the change from baseline in LDL cholesterol level at 180 days. Safety data were available through day 210, and data on LDL cholesterol and proprotein convertase subtilisin-kexin type 9 (PCSK9) levels were available through day 240. RESULTS A total of 501 patients underwent randomization. Patients who received inclisiran had dose-dependent reductions in PCSK9 and LDL cholesterol levels. At day 180, the least-squares mean reductions in LDL cholesterol levels were 27.9 to 41.9% after a single dose of inclisiran and 35.5 to 52.6% after two doses (P<0.001 for all comparisons vs. placebo). The two-dose 300-mg inclisiran regimen produced the greatest reduction in LDL cholesterol levels: 48% of the patients who received the regimen had an LDL cholesterol level below 50 mg per deciliter (1.3 mmol per liter) at day 180. At day 240, PCSK9 and LDL cholesterol levels remained significantly lower than at baseline in association with all inclisiran regimens. Serious adverse events occurred in 11% of the patients who received inclisiran and in 8% of the patients who received placebo. Injection-site reactions occurred in 5% of the patients who received injections of inclisiran. CONCLUSIONS In our trial, inclisiran was found to lower PCSK9 and LDL cholesterol levels among patients at high cardiovascular risk who had elevated LDL cholesterol levels.

Original languageEnglish (US)
Pages (from-to)1430-1440
Number of pages11
JournalNew England Journal of Medicine
Volume376
Issue number15
DOIs
StatePublished - Apr 13 2017

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LDL Cholesterol
Placebos
Injections
Subcutaneous Injections
Random Allocation
Least-Squares Analysis
Small Interfering RNA
Healthy Volunteers
Cardiovascular Diseases
Proprotein Convertase 9
Safety
Messenger RNA

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Ray, K. K., Landmesser, U., Leiter, L. A., Kallend, D., Dufour, R., Karakas, M., ... Kastelein, J. J. P. (2017). Inclisiran in patients at high cardiovascular risk with elevated LDL cholesterol. New England Journal of Medicine, 376(15), 1430-1440. https://doi.org/10.1056/NEJMoa1615758

Inclisiran in patients at high cardiovascular risk with elevated LDL cholesterol. / Ray, Kausik K.; Landmesser, Ulf; Leiter, Lawrence A.; Kallend, David; Dufour, Robert; Karakas, Mahir; Hall, Tim; Troquay, Roland P.T.; Turner, Traci; Visseren, Frank L.J.; Wijngaard, Peter; Wright, R. Scott; Kastelein, John J.P.

In: New England Journal of Medicine, Vol. 376, No. 15, 13.04.2017, p. 1430-1440.

Research output: Contribution to journalArticle

Ray, KK, Landmesser, U, Leiter, LA, Kallend, D, Dufour, R, Karakas, M, Hall, T, Troquay, RPT, Turner, T, Visseren, FLJ, Wijngaard, P, Wright, RS & Kastelein, JJP 2017, 'Inclisiran in patients at high cardiovascular risk with elevated LDL cholesterol', New England Journal of Medicine, vol. 376, no. 15, pp. 1430-1440. https://doi.org/10.1056/NEJMoa1615758
Ray KK, Landmesser U, Leiter LA, Kallend D, Dufour R, Karakas M et al. Inclisiran in patients at high cardiovascular risk with elevated LDL cholesterol. New England Journal of Medicine. 2017 Apr 13;376(15):1430-1440. https://doi.org/10.1056/NEJMoa1615758
Ray, Kausik K. ; Landmesser, Ulf ; Leiter, Lawrence A. ; Kallend, David ; Dufour, Robert ; Karakas, Mahir ; Hall, Tim ; Troquay, Roland P.T. ; Turner, Traci ; Visseren, Frank L.J. ; Wijngaard, Peter ; Wright, R. Scott ; Kastelein, John J.P. / Inclisiran in patients at high cardiovascular risk with elevated LDL cholesterol. In: New England Journal of Medicine. 2017 ; Vol. 376, No. 15. pp. 1430-1440.
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abstract = "BACKGROUND In a previous study, a single injection of inclisiran, a chemically synthesized small interfering RNA designed to target PCSK9 messenger RNA, was found to produce sustained reductions in low-density lipoprotein (LDL) cholesterol levels over the course of 84 days in healthy volunteers. METHODS We conducted a phase 2, multicenter, double-blind, placebo-controlled, multipleascending- dose trial of inclisiran administered as a subcutaneous injection in patients at high risk for cardiovascular disease who had elevated LDL cholesterol levels. Patients were randomly assigned to receive a single dose of placebo or 200, 300, or 500 mg of inclisiran or two doses (at days 1 and 90) of placebo or 100, 200, or 300 mg of inclisiran. The primary end point was the change from baseline in LDL cholesterol level at 180 days. Safety data were available through day 210, and data on LDL cholesterol and proprotein convertase subtilisin-kexin type 9 (PCSK9) levels were available through day 240. RESULTS A total of 501 patients underwent randomization. Patients who received inclisiran had dose-dependent reductions in PCSK9 and LDL cholesterol levels. At day 180, the least-squares mean reductions in LDL cholesterol levels were 27.9 to 41.9{\%} after a single dose of inclisiran and 35.5 to 52.6{\%} after two doses (P<0.001 for all comparisons vs. placebo). The two-dose 300-mg inclisiran regimen produced the greatest reduction in LDL cholesterol levels: 48{\%} of the patients who received the regimen had an LDL cholesterol level below 50 mg per deciliter (1.3 mmol per liter) at day 180. At day 240, PCSK9 and LDL cholesterol levels remained significantly lower than at baseline in association with all inclisiran regimens. Serious adverse events occurred in 11{\%} of the patients who received inclisiran and in 8{\%} of the patients who received placebo. Injection-site reactions occurred in 5{\%} of the patients who received injections of inclisiran. CONCLUSIONS In our trial, inclisiran was found to lower PCSK9 and LDL cholesterol levels among patients at high cardiovascular risk who had elevated LDL cholesterol levels.",
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AU - Landmesser, Ulf

AU - Leiter, Lawrence A.

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AU - Dufour, Robert

AU - Karakas, Mahir

AU - Hall, Tim

AU - Troquay, Roland P.T.

AU - Turner, Traci

AU - Visseren, Frank L.J.

AU - Wijngaard, Peter

AU - Wright, R. Scott

AU - Kastelein, John J.P.

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N2 - BACKGROUND In a previous study, a single injection of inclisiran, a chemically synthesized small interfering RNA designed to target PCSK9 messenger RNA, was found to produce sustained reductions in low-density lipoprotein (LDL) cholesterol levels over the course of 84 days in healthy volunteers. METHODS We conducted a phase 2, multicenter, double-blind, placebo-controlled, multipleascending- dose trial of inclisiran administered as a subcutaneous injection in patients at high risk for cardiovascular disease who had elevated LDL cholesterol levels. Patients were randomly assigned to receive a single dose of placebo or 200, 300, or 500 mg of inclisiran or two doses (at days 1 and 90) of placebo or 100, 200, or 300 mg of inclisiran. The primary end point was the change from baseline in LDL cholesterol level at 180 days. Safety data were available through day 210, and data on LDL cholesterol and proprotein convertase subtilisin-kexin type 9 (PCSK9) levels were available through day 240. RESULTS A total of 501 patients underwent randomization. Patients who received inclisiran had dose-dependent reductions in PCSK9 and LDL cholesterol levels. At day 180, the least-squares mean reductions in LDL cholesterol levels were 27.9 to 41.9% after a single dose of inclisiran and 35.5 to 52.6% after two doses (P<0.001 for all comparisons vs. placebo). The two-dose 300-mg inclisiran regimen produced the greatest reduction in LDL cholesterol levels: 48% of the patients who received the regimen had an LDL cholesterol level below 50 mg per deciliter (1.3 mmol per liter) at day 180. At day 240, PCSK9 and LDL cholesterol levels remained significantly lower than at baseline in association with all inclisiran regimens. Serious adverse events occurred in 11% of the patients who received inclisiran and in 8% of the patients who received placebo. Injection-site reactions occurred in 5% of the patients who received injections of inclisiran. CONCLUSIONS In our trial, inclisiran was found to lower PCSK9 and LDL cholesterol levels among patients at high cardiovascular risk who had elevated LDL cholesterol levels.

AB - BACKGROUND In a previous study, a single injection of inclisiran, a chemically synthesized small interfering RNA designed to target PCSK9 messenger RNA, was found to produce sustained reductions in low-density lipoprotein (LDL) cholesterol levels over the course of 84 days in healthy volunteers. METHODS We conducted a phase 2, multicenter, double-blind, placebo-controlled, multipleascending- dose trial of inclisiran administered as a subcutaneous injection in patients at high risk for cardiovascular disease who had elevated LDL cholesterol levels. Patients were randomly assigned to receive a single dose of placebo or 200, 300, or 500 mg of inclisiran or two doses (at days 1 and 90) of placebo or 100, 200, or 300 mg of inclisiran. The primary end point was the change from baseline in LDL cholesterol level at 180 days. Safety data were available through day 210, and data on LDL cholesterol and proprotein convertase subtilisin-kexin type 9 (PCSK9) levels were available through day 240. RESULTS A total of 501 patients underwent randomization. Patients who received inclisiran had dose-dependent reductions in PCSK9 and LDL cholesterol levels. At day 180, the least-squares mean reductions in LDL cholesterol levels were 27.9 to 41.9% after a single dose of inclisiran and 35.5 to 52.6% after two doses (P<0.001 for all comparisons vs. placebo). The two-dose 300-mg inclisiran regimen produced the greatest reduction in LDL cholesterol levels: 48% of the patients who received the regimen had an LDL cholesterol level below 50 mg per deciliter (1.3 mmol per liter) at day 180. At day 240, PCSK9 and LDL cholesterol levels remained significantly lower than at baseline in association with all inclisiran regimens. Serious adverse events occurred in 11% of the patients who received inclisiran and in 8% of the patients who received placebo. Injection-site reactions occurred in 5% of the patients who received injections of inclisiran. CONCLUSIONS In our trial, inclisiran was found to lower PCSK9 and LDL cholesterol levels among patients at high cardiovascular risk who had elevated LDL cholesterol levels.

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