Drug

Inclisiran

Inclisiran is a small interfering RNA that lowers LDL cholesterol by reducing PCSK9 production.

Sources: FDA label · 17 registered trials

Inclisiran at a glance

Mechanism: small interfering RNA (siRNA) directed to proprotein convertase subtilisin kexin type 9 (PCSK9) mRNA · FDA label (DailyMed)

FDA-approved indications

As an adjunct to diet and exercise to reduce low-density lipoprotein cholesterol (LDL-C) in adults with hypercholesterolemia.
As an adjunct to diet and exercise to reduce low-density lipoprotein cholesterol (LDL-C) in adults and pediatric patients aged 12 years and older with heterozygous familial hypercholesterolemia (HeFH).
As an adjunct to diet and exercise to reduce low-density lipoprotein cholesterol (LDL-C) in pediatric patients aged 12 years and older with homozygous familial hypercholesterolemia (HoFH).

Show all 5

As an adjunct to diet and exercise to reduce low-density lipoprotein cholesterol (LDL-C) in cardiovascular outcomes trials have demonstrated that reducing LDL-C lowers the risk for major adverse cardiovascular events (MACE) in adults at increased risk when treated with statins or monoclonal antibody proprotein convertase subtilisin kexin type 9 (PCSK9)…

Overview

Unverified · drafted by AI from the sources cited below

Definition

Inclisiran is a chemically synthesized small interfering RNA (siRNA) molecule and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor used in the management of hypercholesterolemia and dyslipidemia.1234 PCSK9 is a serine protease that binds to low-density lipoprotein (LDL) receptors and targets them for lysosomal degradation, which reduces receptor recycling and decreases the removal rate of circulating low-density lipoprotein cholesterol (LDL-C).2 Inclisiran lowers LDL-C levels by targeting the hepatic production of PCSK9, preventing its translation through the post-transcriptional degradation of PCSK9 mRNA.2

Treatment

In the management of dyslipidemia, a stepwise algorithm starting with oral agents and escalating to RNA-based therapies is used to address statin intolerance, adherence barriers, and residual risk.1 In a real-world cohort of 109 patients from the German Inclisiran Network followed for up to 3 years (median 33 months, interquartile range 27-39), where only ~30% received statins due to statin intolerance, the median (95% CI) LDL-C reduction from baseline to nadir was -46% (-60.8 to -33.8%).2 The median individual LDL-C reduction across the follow-up period was -28% (-33.8 to -24.2%), with high interindividual and intraindividual variability in LDL-C response.2 Additionally, in a prospective registry of 1112 patients treated with PCSK9-targeting pharmacotherapy—including alirocumab, evolocumab, or inclisiran—therapy produced sustained reductions in lipoprotein(a), with mean changes of -15.3%, -16.7%, and -19.0% at 3, 9, and 21 months, respectively (all p < 0.001).3 In preclinical models, 10-week treatment with inclisiran in ApoE −/− mice with induced vulnerable carotid plaques was utilized to evaluate macrophage phagocytosis and plaque vulnerability.

Open questions

Real-world evidence regarding the long-term effectiveness and treatment persistence of inclisiran remains limited.1 Furthermore, comparative real-world data evaluating lipoprotein(a) reduction across available PCSK9-targeting agents are scarce.2

Landmark trials

Primary results of 2 trials behind the evidence on inclisiran, as each trial’s own publication reports them.

ORION-10day 510 placebo-corrected % change
inclisiran vs placebo · 1,561 patients · N Engl J Med 2020
Primary outcome: the placebo-corrected percentage change in LDL cholesterol level from baseline to day 510
“by 52.3% (95% confidence interval [CI], 48.8 to 55.7) in the ORION-10 trial”
ORION-10time-adjusted % change after day 90 up to day 540
inclisiran vs placebo · 1,561 patients · N Engl J Med 2020
Primary outcome: the time-adjusted percentage change in LDL cholesterol level from baseline after day 90 and up to day 540
“time-adjusted reductions of 53.8% (95% CI, 51.3 to 56.2)”
ORION-11day 510 placebo-corrected % change
inclisiran vs placebo · 1,617 patients · N Engl J Med 2020
Primary outcome: the placebo-corrected percentage change in LDL cholesterol level from baseline to day 510
“by 49.9% (95% CI, 46.6 to 53.1) in the ORION-11 trial”
ORION-11time-adjusted % change after day 90 up to day 540
inclisiran vs placebo · 1,617 patients · N Engl J Med 2020
Primary outcome: the time-adjusted percentage change in LDL cholesterol level from baseline after day 90 and up to day 540
“and 49.2% (95% CI, 46.8 to 51.6)”

Results are quoted from each trial’s primary publication abstract (PubMed); the trial name links to the paper. Ratios below 1 favour the intervention.

Trials by indication

Registered trials with inclisiran in an arm, past phase 1 with at least 50 participants: the largest in each indication, newest first. Trials that give it only as the comparator are tagged; trials that give it in every arm are listed last.

Cardiovascular prevention4 of 6

A Randomized, Double-blind, Placebo-controlled Multicenter Study to Evaluate the Effect of Inclisiran on Preventing Major Adverse Cardiovascular Events in High-risk Primary Prevention Patients (VICTORION-1 PREVENT)
NCT05739383 · Phase 3 · Active not recruiting · 14,012 participants · started 2023
A Randomized, Double-blind, Placebo-controlled, Multicenter Trial, Assessing the Impact of Inclisiran on Major Adverse Cardiovascular Events in Participants With Established Cardiovascular Disease (VICTORION-2 PREVENT)
NCT05030428 · Phase 3 · Active not recruiting · 17,004 participants · started 2021
HPS-4/TIMI 65/ORION-4: A Double-blind Randomized Placebo-controlled Trial Assessing the Effects of Inclisiran on Clinical Outcomes Among People With Atherosclerotic Cardiovascular Disease
NCT03705234 · Phase 3 · Active not recruiting · 16,124 participants · started 2018
ORION-11
Inclisiran for Subjects With ASCVD or ASCVD-Risk Equivalents and Elevated Low-density Lipoprotein Cholesterol
NCT03400800 · Phase 3 · Completed · 1,617 participants · started 2017

Lipid management

A Multicenter, Randomized, Double-blind, Factorial Design Phase 2 Study to Evaluate the Pharmacodynamics, Safety and Tolerability of HDY015 Administered as a Free Combination of QCZ484 and Inclisiran Compared to QCZ484, Inclisiran, and Placebo in Participants With Hypertension and Concomitant Hypercholesterolemia
NCT07610278 · Phase 2 · Recruiting · 120 participants · started 2026
PCSK9-DUO Trial: Dual PCSK9 Inhibition With Inclisiran and Alirocumab in Patients With High Cardiovascular Risk in Secondary Prevention
NCT07581808 · Phase 4 · Not yet recruiting · 60 participants · started 2026
VICTORION-CHALLENGE
A Randomized, Multicenter, Open-label Trial Comparing the Effectiveness of Inclisiran to Bempedoic Acid on LDL Cholesterol (LDL-C) Lowering in Participants With Atherosclerotic Cardiovascular Disease (VICTORION-CHALLENGE)
NCT06431763 · Phase 4 · Completed · 402 participants · started 2024

Coronary artery disease

V-INTERVENTION
Evaluation of Inclisiran Versus Placebo for the Prevention of Major Adverse Cardiovascular and Limb Events in Patients Undergoing Percutaneous Coronary Intervention or Peripheral Endovascular Intervention (V-INTERVENTION)
NCT06909565 · Phase 4 · Recruiting · 6,000 participants · started 2025
Effectiveness of Inclisiran for Patients With Coronary Heart Disease in China: a Multicenter, Standard of Care-Controlled Pragmatic Randomized Trial
NCT06941792 · Phase 4 · Active not recruiting · 1,590 participants · started 2025
VICTORION-PLAQUE
A Multi-center, Randomized, Double-blind, Placebo-controlled, Parallel-group Phase IIIb Study Evaluating the Effect of Inclisiran on Atherosclerotic Plaque Progression Assessed by Coronary Computed Tomography Angiography (CCTA) in Participants With a Diagnosis of Non-obstructive Coronary Artery Disease Without Previous Cardiovascular Events (VICTORION-PLAQUE)
NCT05360446 · Phase 3 · Active not recruiting · 610 participants · started 2022

Acute coronary syndrome

A Randomized, Double-blind, Placebo-controlled Study to Evaluate Efficacy and Safety of Early in Hospital Initiation of Inclisiran Treatment in Patients With Acute Coronary Syndromes: Victorion - RIDES
NCT07102628 · Phase 3 · Recruiting · 300 participants · started 2025

Other trials

A Multi-Center, Randomized, Open-label, Parallel, Controlled Phase Ⅳ Clinical Trial to Evaluate the Effect of Inclisiran on Coronary Atherosclerotic Plaque in Patients With Acute Myocardial Infarction and Elevated Low-density Lipoprotein Cholesterol
NCT06372925 · Phase 4 · Active not recruiting · 318 participants · started 2024

Source: ClinicalTrials.gov registry records.

How this page is built

A clinical question appears here only when its condition matches this topic, an outcome and a comparator were extracted from the studies, at least two studies and a patient count are on file, and the certainty is low or higher.

Supports benefit, no benefit shown, and mixed describe the direction of the measured effect. No benefit shown means the evidence does not support a benefit. It is not a finding of harm. Too little evidence means the question did not clear that bar.

Study count, RCT count, and patient count are separate. The patient total adds only studies that are linked into a study family and whose sample size is not flagged as implausible. A reversal is listed only when at least one randomized trial sits on each side of the change.

The overview is drafted from the guideline recommendations, trials, papers, and questions on this page, and every sentence has to cite one of them. It stays unverified until an NPI-verified clinician or a Synapse admin approves it. Approving records that person's name.