New England Journal of Medicine APRIL 09, 2020

Two Phase 3 Trials of Inclisiran in Patients with Elevated LDL Cholesterol

Kausik K. Ray, R. Scott Wright, et al.

Bottom Line

In the ORION-11 trial, inclisiran, a small interfering RNA targeting PCSK9, demonstrated a sustained, placebo-corrected 50% reduction in LDL cholesterol levels over 18 months in patients with ASCVD or high cardiovascular risk despite maximal statin therapy.

Key Findings

1. Inclisiran treatment resulted in a mean percentage change in LDL cholesterol of -49% at day 510 compared with +4% in the placebo group (P < 0.0001).

2. The time-averaged reduction in LDL cholesterol from day 90 to day 540 was 50% for the inclisiran group versus the placebo group.

3. Adverse events were generally balanced between groups, with 83% of inclisiran-treated patients versus 82% of placebo-treated patients reporting any treatment-emergent adverse event.

4. Injection-site adverse reactions were more frequent with inclisiran (4.7%) than with placebo (0.5%), though these were predominantly mild and transient.

Study Design

Design

RCT

Double-Blind

Sample

1,617

Patients

Duration

18 mo

Median

Setting

Multicenter, International

Population Adults with established atherosclerotic cardiovascular disease (ASCVD) or ASCVD risk-equivalents with elevated LDL cholesterol despite maximum tolerated doses of statins.

Intervention Subcutaneous injection of 300 mg of inclisiran administered on days 1, 90, 270, and 450.

Comparator Subcutaneous injection of placebo administered on days 1, 90, 270, and 450.

Outcome Percentage change in LDL cholesterol from baseline to day 510 and the time-adjusted percentage change in LDL cholesterol from baseline after day 90 and up to day 540.

Study Limitations

• The trial was not powered to detect differences in hard clinical cardiovascular outcomes, only lipid-lowering efficacy.

• The duration of follow-up (18 months) is relatively short to establish long-term safety and cardiovascular risk reduction compared to established monoclonal antibody PCSK9 inhibitors.

• The study population, while diverse in risk, may not fully capture the long-term rare adverse effect profile of a novel siRNA mechanism.

Clinical Significance

Inclisiran offers a novel, twice-yearly subcutaneous dosing regimen that provides sustained, significant LDL-C lowering in patients already on maximal statin therapy. This may enhance long-term adherence compared to current daily oral or bi-weekly injectable therapies, potentially improving outcomes for patients with atherosclerotic cardiovascular disease who are unable to reach cholesterol targets.

Historical Context

Following the success of monoclonal antibody PCSK9 inhibitors (evolocumab and alirocumab), which demonstrated substantial LDL lowering and clinical benefit, inclisiran emerged as a first-in-class small interfering RNA therapy. By inhibiting the synthesis of PCSK9 in the liver rather than inhibiting the protein in the blood, it introduced the possibility of less frequent, durable dosing, representing a paradigm shift in the management of hypercholesterolemia.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

How does the mechanism of action of inclisiran differ from that of monoclonal antibodies like evolocumab in targeting the PCSK9 protein?

Key Response

Inclisiran is a small interfering RNA (siRNA) that works intracellularly by binding to the RNA-induced silencing complex (RISC) to promote the catalytic breakdown of PCSK9 messenger RNA, preventing the synthesis of the protein itself. In contrast, monoclonal antibodies (mAbs) like evolocumab bind to and neutralize PCSK9 protein that has already been secreted into the systemic circulation. This allows inclisiran to have a significantly longer duration of action, as it stops the production 'at the source' rather than clearing the product.

Resident

In a patient with ASCVD who remains above their LDL-C goal despite maximally tolerated statin and ezetimibe, what are the primary clinical advantages of choosing inclisiran over a PCSK9 monoclonal antibody?

Key Response

The primary clinical advantage is the dosing frequency and the impact on adherence. Inclisiran is administered as a subcutaneous injection initially, at 3 months, and then every 6 months thereafter by a healthcare professional. This 'vaccine-like' schedule eliminates the daily or bi-weekly adherence burden associated with statins or PCSK9 mAbs, which is particularly beneficial for patients with poor medication compliance or those who prefer not to self-inject.

Fellow

The ORION-11 trial demonstrated a 50% reduction in LDL-C, but how should a clinician interpret the 'exploratory' cardiovascular endpoint results in the context of the lack of a dedicated outcomes trial at the time of publication?

Key Response

While ORION-11 showed a lower incidence of cardiovascular events in the inclisiran group compared to placebo, the trial was not powered for MACE (Major Adverse Cardiovascular Events). Fellows must distinguish between efficacy based on a surrogate marker (LDL-C) and proven clinical benefit (reduction in MI or stroke). Evidence integration requires acknowledging that while the 'LDL hypothesis' suggests benefit, definitive recommendations usually await dedicated outcome trials like ORION-4 to confirm that the specific mechanism of siRNA-mediated PCSK9 inhibition translates to the same risk reduction seen with statins and mAbs.

Attending

Given the results of ORION-11, how does the introduction of long-acting siRNA therapy shift the population health management strategy for high-risk ASCVD patients in a value-based care model?

Key Response

It shifts the focus from 'patient-dependent' daily adherence to a 'system-dependent' administration model. In a value-based care setting, using a twice-yearly clinician-administered drug allows for guaranteed LDL-C suppression, potentially reducing the long-term costs associated with ASCVD complications and hospitalizations caused by statin non-adherence, which is estimated to be as high as 50% after one year in real-world settings.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

Considering the chemical structure of inclisiran, what is the significance of the GalNAc (N-acetylgalactosamine) conjugation, and how does it influence the drug's pharmacokinetics and safety profile?

Key Response

GalNAc conjugation targets the asialoglycoprotein receptors (ASGPR) which are highly expressed specifically on hepatocytes. This allows for targeted delivery to the liver, facilitating rapid uptake and minimizing systemic exposure to other tissues. This liver-specificity is why very low doses are effective and why the drug has a minimal 'off-target' safety profile, despite the long-lasting intracellular presence of the RISC complex.

Journal Editor

In ORION-11, injection-site reactions were significantly higher in the inclisiran group (5% vs 0.7%). As a reviewer, how would you evaluate the potential impact of this finding on the 'double-blind' integrity of the study?

Key Response

A seasoned reviewer would flag the risk of 'unblinding' because localized reactions (pain, erythema, rash) can lead patients and investigators to correctly guess their treatment assignment. If unblinded, subjective reporting of other side effects or even the 'standard of care' background therapy could be biased. Editors look for whether the trial used an independent, blinded endpoint adjudication committee and whether the primary endpoint (a laboratory value) is sufficiently objective to withstand potential unblinding.

Guideline Committee

Should inclisiran be given the same Class I recommendation as PCSK9 monoclonal antibodies in the current AHA/ACC or ESC guidelines for patients with ASCVD who are not at goal?

Key Response

Currently, AHA/ACC guidelines (2018/2022) give a Class I or IIa recommendation to PCSK9 mAbs because of large-scale outcome trials (FOURIER/ODYSSEY). While ORION-11 provides high-level evidence (Level A) for LDL-C reduction, the lack of a completed, dedicated CV outcome trial at the time of initial review often results in a 'Class IIb' recommendation or a specific notation that it is an alternative to mAbs. The committee must weigh the strength of the surrogate endpoint against the established outcome evidence of existing therapies.

Clinical Landscape

Noteworthy Related Trials

2015

IMPROVE-IT Trial

n = 18,144 · NEJM

Tested

Ezetimibe added to simvastatin

Population

Patients with recent acute coronary syndrome

Comparator

Simvastatin monotherapy

Endpoint

Composite of cardiovascular death, major coronary event, or nonfatal stroke

Key result: The addition of ezetimibe to statin therapy resulted in incremental lowering of LDL cholesterol and improved cardiovascular outcomes.

2017

FOURIER Trial

n = 27,564 · NEJM

Tested

Evolocumab

Population

Patients with stable atherosclerotic cardiovascular disease

Comparator

Placebo

Endpoint

Composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization

Key result: Evolocumab significantly reduced the risk of cardiovascular events compared to placebo in patients already receiving statin therapy.

2018

ODYSSEY OUTCOMES Trial

n = 18,924 · NEJM

Tested

Alirocumab

Population

Patients with a recent acute coronary syndrome

Comparator

Placebo

Endpoint

Composite of death from coronary heart disease, nonfatal myocardial infarction, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization

Key result: Alirocumab reduced the occurrence of major adverse cardiovascular events and was associated with a lower risk of all-cause mortality.

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