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JAMA Cardiol. 2019 Sep 25. doi: 10.1001/jamacardio.2019.3502. [Epub ahead of print]

Effect of 1 or 2 Doses of Inclisiran on Low-Density Lipoprotein Cholesterol Levels: One-Year Follow-up of the ORION-1 Randomized Clinical Trial.

Author information

1
Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, Imperial College London, Charing Cross Hospital, London, England.
2
The Medicines Company, Parsippany, New Jersey.
3
Cardiovascular Medicine, Saga University, Nabeshima, Saga, Japan.
4
University of Toronto, Toronto, Ontario, Canada.
5
Charité-Universitats medizin Berlin, Berlin, Germany.
6
Department of Cardiology, Mayo Clinic, Rochester, Minnesota.
7
University of Amsterdam, Amsterdam, the Netherlands.

Abstract

Importance:

Sustained reductions in low-density lipoprotein cholesterol (LDL-C) with lipid-lowering therapies that require frequent dosing are reliant on patient adherence, and poor adherence is associated with worse clinical outcomes.

Objective:

To determine whether inclisiran, a small interfering RNA, reduces mean LDL-C exposure with an infrequent dosing regimen.

Design, Setting, and Participants:

Prespecified analysis of a randomized, double-blind, placebo-controlled multicenter phase 2 clinical trial. Participants were followed up monthly for LDL-C levels and proprotein convertase subtilisin-kexin type 9 (PCSK9) measurements as well as safety until their LDL-C levels had returned to within 20% of their change from baseline (maximum 360 days). The study included patients with elevated LDL-C despite maximally tolerated statin therapy. Data were analyzed between January 11, 2016, and June 7, 2017.

Interventions:

One dose (200, 300, or 500 mg on day 1) or 2 doses (100, 200, or 300 mg on days 1 and 90) of inclisiran sodium or placebo.

Main Outcomes and Measures:

Duration of time to return to within 20% of change from baseline for LDL-C levels and time-averaged LDL-C reductions over 1 year.

Results:

At baseline, among the 501 participants, 65% were men (n = 326 of 501), mean age was 63 years, 6% had familial hypercholesterolemia (n = 28 of 501), and 69% had established ASCVD (n = 347 of 501). Baseline LDL-C was 128 mg/dL among 501 randomized participants. The percentage of participants who were followed up to day 360 because their LDL-C levels had not returned to within 20% of their change from baseline ranged from 48.3% to 65.0% for those receiving a single dose and between 55.9% and 83.1% of those receiving 2 doses, with similar effects observed for PCSK9. Time-averaged reduction in LDL-C levels over 1 year after a single dose ranged from 29.5% to 38.7% (P < .001 between groups) and from 29.9% to 46.4% (P < .001 between groups) for those who received 2 doses. The 2-dose 300-mg regimen produced the highest proportion of responders at day 360 and the greatest mean reduction in LDL-C over 1 year. Incidence of adverse events was similar through to 1 year.

Conclusions and Relevance:

Treatment with inclisiran resulted in durable reductions in LDL-C over 1 year. Inclisiran may offer a novel approach to LDL-C reduction with the convenience of infrequent dosing.

Trial Registration:

ClinicalTrials.gov identifier: NCT02597127.

PMID:
31553410
PMCID:
PMC6763983
[Available on 2020-09-25]
DOI:
10.1001/jamacardio.2019.3502

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