Inclisiran for the treatment of heterozygous familial hypercholesterolemia

Raal, F. J. et al. (2020) Inclisiran for the treatment of heterozygous familial hypercholesterolemia. New England Journal of Medicine, 382(16), pp. 1520-1530. (doi: 10.1056/NEJMoa1913805) (PMID:32197277)

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Abstract

Background: Familial hypercholesterolemia is characterized by an elevated level of low-density lipoprotein (LDL) cholesterol and an increased risk of premature atherosclerotic cardiovascular disease. Monoclonal antibodies directed against proprotein convertase subtilisin–kexin type 9 (PCSK9) have been shown to reduce LDL cholesterol levels by more than 50% but require administration every 2 to 4 weeks. In a phase 2 trial, a twice-yearly injection of inclisiran, a small interfering RNA, was shown to inhibit hepatic synthesis of PCSK9 in adults with heterozygous familial hypercholesterolemia. Methods: In this phase 3, double-blind trial, we randomly assigned, in a 1:1 ratio, 482 adults who had heterozygous familial hypercholesterolemia to receive subcutaneous injections of inclisiran sodium (at a dose of 300 mg) or matching placebo on days 1, 90, 270, and 450. The two primary end points were the percent change from baseline in the LDL cholesterol level on day 510 and the time-adjusted percent change from baseline in the LDL cholesterol level between day 90 and day 540. Results: The median age of the patients was 56 years, and 47% were men; the mean baseline level of LDL cholesterol was 153 mg per deciliter. At day 510, the percent change in the LDL cholesterol level was a reduction of 39.7% (95% confidence interval [CI], −43.7 to −35.7) in the inclisiran group and an increase of 8.2% (95% CI, 4.3 to 12.2) in the placebo group, for a between-group difference of −47.9 percentage points (95% CI, −53.5 to −42.3; P<0.001). The time-averaged percent change in the LDL cholesterol level between day 90 and day 540 was a reduction of 38.1% (95% CI, −41.1 to −35.1) in the inclisiran group and an increase of 6.2% (95% CI, 3.3 to 9.2) in the placebo group, for a between-group difference of −44.3 percentage points (95% CI, −48.5 to −40.1; P<0.001). There were robust reductions in LDL cholesterol levels in all genotypes of familial hypercholesterolemia. Adverse events and serious adverse events were similar in the two groups. Conclusions: Among adults with heterozygous familial hypercholesterolemia, those who received inclisiran had significantly lower levels of LDL cholesterol than those who received placebo, with an infrequent dosing regimen and an acceptable safety profile. (Funded by the Medicines Company; ORION-9 ClinicalTrials.gov number, NCT03397121. opens in new tab.)

Item Type:Articles
Additional Information:Ian Ford is a member of the Independent Data Monitoring Committee of the ORION-9 Investigators.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Ford, Professor Ian
Authors: Raal, F. J., Kallend, D., Ray, K. K., Turner, T., Koenig, W., Wright, R. S., Wijngaard, P. L.J., Curcio, D., Jaros, M. J., Leiter, L. A., Kastelein, J. J.P., and ORION-9 Investigators,
Subjects:R Medicine > R Medicine (General)
College/School:College of Medical Veterinary and Life Sciences > School of Health & Wellbeing > Robertson Centre
Journal Name:New England Journal of Medicine
Publisher:Massachusetts Medical Society
ISSN:0028-4793
ISSN (Online):1533-4406
Copyright Holders:Copyright © 2020 Massachusetts Medical Society
First Published:First published in New England Journal of Medicine 382(16): 1520-1530
Publisher Policy:Reproduced in accordance with the publisher copyright policy

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