Pooled Patient-Level Analysis of Inclisiran Trials in Patients With Familial Hypercholesterolemia or Atherosclerosis.

Abstract

BACKGROUND:

Inclisiran is a double-stranded small interfering RNA that suppresses proprotein convertase subtilisin-kexin type 9 (PCSK9) translation in the liver, leading to sustained reductions in low-density lipoprotein cholesterol (LDL-C) and other atherogenic lipoproteins with twice-yearly dosing.

OBJECTIVES:

The purpose of this study was to conduct a patient-level pooled analysis from 3 phase 3 studies of inclisiran.

METHODS:

Participants with heterozygous familial hypercholesterolemia (ORION-9 [Trial to Evaluate the Effect of Inclisiran Treatment on Low Density Lipoprotein Cholesterol (LDL-C) in Subjects With Heterozygous Familial Hypercholesterolemia (HeFH)]), atherosclerotic cardiovascular disease (ASCVD) (ORION-10 [Inclisiran for Participants With Atherosclerotic Cardiovascular Disease and Elevated Low-density Lipoprotein Cholesterol]), or ASCVD and ASCVD risk equivalents (ORION-11 [Inclisiran for Subjects With ASCVD or ASCVD-Risk Equivalents and Elevated Low-density Lipoprotein Cholesterol]) taking maximally tolerated statin therapy, with or without other LDL-C-lowering agents, were randomly assigned in a 1:1 ratio to receive either inclisiran or placebo, administered by subcutaneous injection on day 1, day 90, and every 6 months thereafter for 540 days. The coprimary endpoints were the placebo-corrected percentage change in LDL-C level from baseline to day 510 and the time-adjusted percentage change in LDL-C level from baseline after day 90 to day 540. Levels of other atherogenic lipoproteins and treatment-emergent adverse events were also assessed.

RESULTS:

A total of 3,660 participants (n = 482, n = 1,561, and n = 1,617 from ORION-9, -10, and -11, respectively) underwent randomization. The placebo-corrected change in LDL-C with inclisiran at day 510 was -50.7% (95% confidence interval: -52.9% to -48.4%; p < 0.0001). The corresponding time-adjusted change in LDL-C was -50.5% (95% confidence interval: -52.1% to -48.9%; p < 0.0001). Safety was similar in both groups. Treatment-emergent adverse events at the injection site were more frequent with inclisiran than placebo (5.0% vs. 0.7%), but were predominantly mild, and none were severe or persistent. Liver and kidney function tests, creatine kinase values, and platelet counts did not differ between groups.

CONCLUSIONS:

These pooled safety and efficacy data show that inclisiran, given twice yearly in addition to maximally tolerated statin therapy with or without other LDL-C lowering agents, is an effective, safe, and well-tolerated treatment to lower LDL-C in adults with heterozygous familial hypercholesterolemia, ASCVD, or ASCVD risk equivalents.

• Authors: R Scott Wright, Kausik K Ray, Frederick J Raal, David G Kallend, Mark Jaros, Wolfgang Koenig, Lawrence A Leiter, Ulf Landmesser, Gregory G Schwartz, Andrew Friedman, Peter L J Wijngaard, Lorena Garcia Conde, John J P Kastelein, ORION Phase III Investigators
• Journal: Journal of the American College of Cardiology (J Am Coll Cardiol) Vol. 77 Issue 9 Pg. 1182-1193 (03 09 2021) ISSN: 1558-3597 [Electronic] United States
• PMID: 33663735 (Publication Type: Journal Article, Meta-Analysis, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 American College of Cardiology Foundation. All rights reserved.

Chemical References

• ALN-PCS
• Cholesterol, LDL
• RNA, Small Interfering

Topics

• Aged
• Atherosclerosis (blood, diagnosis, drug therapy)
• Cholesterol, LDL (antagonists & inhibitors, blood)
• Clinical Trials, Phase III as Topic (methods)
• Female
• Humans
• Hyperlipoproteinemia Type II (blood, diagnosis, drug therapy)
• Male
• Middle Aged
• RNA, Small Interfering (pharmacology, therapeutic use)