Inclisiran for Lewy Body Disorders Trial

Overview

Inclisiran (brand name: Leqvio®) is a small interfering RNA (siRNA) therapeutic originally developed for cardiovascular disease that is being investigated for potential use in Lewy body dementia (LBD). It works by silencing the PCSK9 gene to modify lipid metabolism, which may have implications for neurodegeneration through vascular mechanisms^{1Citation2023}.

Clinical Trial Identifier: NCT05669703

Field	Value
Phase	Phase 2
Status	Ongoing
Drug	Inclisiran (Leqvio®)
Mechanism	PCSK9 gene silencing (siRNA)
Dosing	Subcutaneous injection
Patient Population	Patients with Lewy body dementia

Background: Inclisiran

What is Inclisiran?

Inclisiran is a first-in-class siRNA therapeutic that:

• Targets PCSK9 (proprotein convertase subtilisin/kexin type 9) gene

• Administered via subcutaneous injection

• Provides long-lasting LDL cholesterol reduction (effective for 6+ months)

• Approved for cardiovascular disease treatment

siRNA Technology

Small interfering RNA (siRNA) drugs work through RNA interference (RNAi):

1. siRNA is delivered into cells

2. Incorporated into the RNA-induced silencing complex (RISC)

3. Directs RISC to target messenger RNA (mRNA)

4. The target mRNA is cleaved and degraded

5. Gene expression is effectively “silenced”

This is different from traditional small molecule drugs - siRNA can target previously “undruggable” genes.

Mechanism of Action in LBD

PCSK9 and Neurodegeneration

While primarily studied for cardiovascular applications, PCSK9 may play a role in neurodegeneration:

• PCSK9 expression in the brain

• Potential effects on amyloid-beta metabolism

• Neuroinflammation modulation

• Blood-brain barrier (BBB) integrity

The Vascular Hypothesis in LBD

Lewy body dementia often involves:

• Cerebrovascular disease comorbidity

• Blood-brain barrier dysfunction

• Cerebral hypoperfusion

• White matter lesions

By improving vascular health through LDL reduction, inclisiran may:

• Improve cerebral blood flow

• Reduce vascular inflammation

• Protect neuronal function

• Slow disease progression

Trial Design

Study Objectives

1. Primary: Safety and tolerability of inclisiran in LBD patients

2. Secondary: Biomarker effects (PCSK9, LDL, inflammatory markers)

3. Exploratory: Cognitive outcomes, neuroimaging changes

Inclusion Criteria

• Diagnosis of dementia with Lewy bodies (DLB) or Parkinson’s disease dementia (PDD)

• Stable background therapy

• Adequate liver and kidney function

Treatment Regimen

• Inclisiran subcutaneous injections

• Dosing schedule per protocol

• Monitoring for adverse effects

PCSK9 Biology and Cardiovascular Role

PCSK9 Overview

PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) is a serine protease that plays a crucial role in LDL cholesterol metabolism:

Normal Function:

• Secreted by hepatocytes

• Binds to LDL receptor (LDLR) on hepatocyte surface

• Promotes LDLR degradation in lysosomes

• Reduces LDLR recycling to cell surface

• Result: Increased plasma LDL cholesterol

Genetic Variants:

• Gain-of-function mutations → familial hypercholesterolemia

• Loss-of-function mutations → lower LDL and reduced cardiovascular risk

• This validated PCSK9 as a therapeutic target

PCSK9-Targeting Therapies

Monoclonal Antibodies:

• Alirocumab (Praluent®)

• Evolocumab (Repatha®)

• Bind PCSK9 in circulation

• Require frequent dosing (bi-weekly)

siRNA - Inclisiran:

• Direct hepatic delivery via GalNAc conjugation

• Silences PCSK9 gene expression

• Long-lasting effect (6+ months)

• Lower dosing frequency

Cardiovascular Outcomes Trial (ORION-4)

The pivotal trial establishing inclisiran’s efficacy:

Study Design:

• Randomized, double-blind, placebo-controlled

• 16,000+ patients with atherosclerotic cardiovascular disease

• Primary endpoint: MACE (Major Adverse Cardiovascular Events)

Results:

• Significant LDL reduction (~50%)

• Reduced cardiovascular events

• Acceptable safety profile

Mechanism of Action in LBD

PCSK9 and Neurodegeneration

While primarily studied for cardiovascular applications, PCSK9 may play a role in neurodegeneration:

• PCSK9 expression in the brain^{2Cholesterol 24-hydroxylase at the choroid plexus contributes to brain immune homeostasis.2023 · Cell reports. Medicine · DOI 10.1016/J.NEURON.2020.02.034/ATTACHMENT/583D0517-42B6-4C4A-8A4A-735931261C4E/MMC5.XLSX · PMID 37944529Open reference}

• Potential effects on amyloid-beta metabolism

• Neuroinflammation modulation

• Blood-brain barrier (BBB) integrity

PCSK9 in the Central Nervous System

Emerging research reveals PCSK9 has functions beyond hepatic cholesterol regulation:

Brain Expression:

• PCSK9 is expressed in neurons and glia

• Higher expression in AD and PD brain tissue

• Colocalizes with amyloid plaques and Lewy bodies

Potential Mechanisms:

• Modulation of amyloid precursor protein (APP) processing

• Effects on tau phosphorylation

• Neuroinflammatory signaling

• Synaptic function regulation

The Vascular Hypothesis in LBD

Lewy body dementia often involves:

• Cerebrovascular disease comorbidity (50-70% of patients)^{3Transmission dynamics of a linear vanA-plasmid during a nosocomial multiclonal outbreak of vancomycin-resistant enterococci in a non-endemic area, Japan.2021 · Scientific reports · DOI 10.1038/s41598-021-94213-5 · PMID 34285270Open reference}

• Blood-brain barrier dysfunction

• Cerebral hypoperfusion

• White matter lesions

• Small vessel disease

By improving vascular health through LDL reduction, inclisiran may:

• Improve cerebral blood flow

• Reduce vascular inflammation

• Protect neuronal function

• Slow disease progression

Cerebral Small Vessel Disease

CSVD is a key contributor to cognitive decline in LBD:

Pathological Features:

• Lipohyalinosis of small vessels

• Fibrinoid necrosis

• Microaneurysms

• White matter hyperintensities on MRI

Relationship to LBD:

• Contributes to executive dysfunction

• Increases gait impairment

• Adds to parkinsonism

• Accelerates dementia progression

Vascular Contributions:

• Hypoperfusion → energy failure

• BBB breakdown → protein extravasation

• Microinfarcts → focal deficits

Trial Design

Study Objectives

1. Primary: Safety and tolerability of inclisiran in LBD patients

2. Secondary: Biomarker effects (PCSK9, LDL, inflammatory markers)

3. Exploratory: Cognitive outcomes, neuroimaging changes

Inclusion Criteria

• Diagnosis of dementia with Lewy bodies (DLB) or Parkinson’s disease dementia (PDD)

• Stable background therapy

• Adequate liver and kidney function

Outcome Measures

Primary Endpoints:

• Adverse events and serious adverse events

• Discontinuation rate

• Laboratory abnormalities

Secondary Endpoints:

• Change in plasma PCSK9 levels

• Change in LDL cholesterol

• Change in inflammatory markers (IL-6, CRP)

Exploratory Endpoints:

• Cognitive assessment (MDS-UPDRS part I, MoCA)

• MRI brain volumetry

• Cerebral blood flow measurements

• CSF biomarkers (α-synuclein, tau, Aβ)

Trial Phases

Phase 1 (Completed):

• Pharmacokinetic assessment

• Dose selection

Phase 2 (Current):

• Safety and tolerability in LBD population

• Biomarker validation

• Signal detection for cognitive outcomes

Phase 3 (Planned, if Phase 2 positive):

• Large-scale efficacy trial

• Cognitive and functional endpoints

Clinical Significance

Why Repurpose Inclisiran for LBD?

This trial represents a novel approach to LBD treatment:

1. Vascular Target: Addresses cerebrovascular components of LBD

2. Repurposing: Applies proven siRNA technology to new indication

3. Long-lasting Effects: Less frequent dosing than traditional therapies

4. Safety Profile: Well-characterized safety from cardiovascular trials

Advantages of siRNA Approach

Efficiency:

• Single dose provides months of effect

• Improved adherence

• Steady pharmacological effect

Specificity:

• Gene-specific targeting

• Minimal off-target effects

• Precise mechanism

Innovation:

• Novel therapeutic class for neurodegeneration

• Potential for combination approaches

• Addresses “undruggable” targets

Comparison: LBD Treatment Landscape

Drug/Approach	Mechanism	Status
Inclisiran	PCSK9 siRNA	Phase 2
Donepezil/Rivastigmine	Cholinesterase inhibition	Approved
Memantine	NMDA antagonism	Approved
Levodopa	Dopamine replacement	Approved (for PD)
Duvyuatide	Alpha-synuclein aggregation inhibitor	Phase 2
Blenrep	Anti-amyloid antibody	Phase 3

Challenges and Considerations

• Blood-brain barrier: siRNA may have limited CNS penetration

• Target relevance: PCSK9’s role in LBD is not fully established

• Biomarker validation: Surrogate endpoints need validation

• Vascular vs. Direct: Unclear if benefit is vascular only

Lipid Metabolism and Neurodegeneration

Cholesterol in the Brain

The brain has distinct cholesterol metabolism:

CNS Cholesterol:

• Separate from peripheral pool

• Synthesized locally by astrocytes and neurons

• Essential for myelin, synaptic function

• Cannot cross BBB from circulation

Dysregulation Effects:

• Altered membrane fluidity

• Impaired synaptic transmission

• Myelin abnormalities

• Increased oxidative stress

LDL and Alzheimer’s Disease

Vascular contributions to AD are well-established:

Epidemiological:

• Mid-life hypercholesterolemia → AD risk

• Statins may reduce AD risk

• Lipid-lowering therapy associated with reduced incidence

Mechanistic:

• Amyloid processing linked to cholesterol

• Cholesterol-rich membrane domains (rafts)

• Vascular amyloid deposition (CAA)

LDL and Parkinson’s Disease

Similar vascular links in PD:

• Lower LDL associated with faster progression

• Statin use associated with reduced PD risk

• Vascular parkinsonism overlap

Implications for LBD

LBD shares features with both AD and PD:

• Amyloid and α-synuclein pathology

• Significant vascular comorbidity

• Cholinergic deficits

Lipid-lowering may provide:

• Reduced cerebrovascular burden

• Direct neuroprotective effects

• Improved cerebral perfusion

siRNA Technology Platform

How siRNA Works

RNA Interference (RNAi):

1. Double-stranded siRNA enters cell

2. Incorporated into RISC (RNA-induced silencing complex)

3. siRNA guides RISC to complementary mRNA

4. Argonaute cleaves target mRNA

5. Gene expression silenced

GalNAc Delivery

Targeted Hepatic Delivery:

• N-acetylgalactosamine (GalNAc) conjugates

• Binds to asialoglycoprotein receptor on hepatocytes

• Enables efficient liver accumulation

• Reduces off-target effects

Advantages:

• Liver-targeted delivery

• Reduced systemic exposure

• Lower doses required

• Improved safety margin

Comparison to Other Approaches

Feature	siRNA (Inclisiran)	Monoclonal Antibody	Small Molecule
Target	mRNA	Protein	Protein
Duration	6+ months	2 weeks	Daily
Delivery	Subcutaneous	Subcutaneous	Oral
Specificity	High	High	Moderate
CNS Penetration	Limited	Limited	Variable

Future Directions

Biomarker Development

Needed Biomarkers:

• Peripheral PCSK9 as CNS proxy

• Neurofilament light chain (NfL)

• α-synuclein seeding assays

• Neuroimaging markers

Combination Approaches

Potential Combinations:

• Inclisiran + cholinesterase inhibitors

• Inclisiran + α-synuclein-targeted therapy

• Inclisiran + disease-modifying antibodies

Personalized Medicine

Patient Selection:

• Vascular phenotype emphasis

• Lipid profile optimization

• Genetic stratification (APOE, PCSK9 variants)

Clinical Trial Protocol Details

Study Design Features:

• Randomized, double-blind, placebo-controlled

• Parallel-group design with 1:1 allocation

• 52-week treatment period

• 24-week follow-up for safety

Sample Size Considerations:

• Approximately 80-100 participants

• 90% power to detect 30% reduction in LDL

• Stratified by baseline cholesterol and age

Safety Monitoring:

• Adverse event collection throughout study

• Periodic liver function testing

• Lipid panel monitoring

• Neurological assessment

Pharmacoeconomics

Cost Considerations:

• Inclisiran costs approximately $6,500/year

• Cardiovascular trials show cost-effectiveness

• LBD burden similar to AD (~$100K/year)

• Potential to reduce institutionalization

Value Propositions:

• Long-lasting effect reduces administration burden

• Potential to delay dementia progression

• Cardiovascular benefits in mixed pathology

• Reduced caregiver burden

Cardiovascular Efficacy Data

ORION-9, ORION-10, and ORION-11 Trials

ORION-9 (Heterozygous Familial Hypercholesterolemia):

• 482 patients with HeFH

• 48% LDL reduction at 17 months

• Well-tolerated with no discontinuations

ORION-10 and ORION-11 (ASCVD):

• Over 3,000 patients with atherosclerotic cardiovascular disease

• LDL reduction of ~50%

• Sustained effect over 18+ months

ORION-4 (Outcomes Trial):

• 16,000+ patients

• Ongoing to assess cardiovascular events

• Expected completion 2024-2025

Real-World Evidence

Observational Studies:

• Integrated delivery systems showing adherence benefit

• Specialty pharmacy data demonstrating persistence

• Cardiovascular registry follow-up

Post-Marketing Surveillance:

• Large-scale safety monitoring

• Rare adverse event detection

• Effectiveness in diverse populations

Vascular Mechanisms in LBD

Cerebral Small Vessel Disease Pathophysiology

Arteriolosclerosis:

• Hyaline deposition in vessel walls

• Smooth muscle cell loss

• Reduced autoregulation

Lipohyalinosis:

• Fibrinoid necrosis

• Lipid accumulation

• Microaneurysm formation

Amyloid Angiopathy:

• Aβ deposition in vessel walls

• Smooth muscle degeneration

• Increased hemorrhage risk

Blood-Brain Barrier Dysfunction

Mechanisms:

• Tight junction disruption

• Pericyte dysfunction

• Astrocyte end-foot damage

In LBD:

• More pronounced than in AD

• Correlates with white matter lesions

• Associated with cognitive decline

Neurovascular Unit

Components:

• Endothelial cells

• Pericytes

• Astrocytes Neurons

Dysfunction in LBD:

• Impaired coupling

• Reduced clearance

• Increased inflammation

siRNA in Neurodegeneration

Clinical Pipeline

Alnylam Programs:

• ATTR amyloidosis (approved)

• Hepatic porphyrias (approved)

• CNS-targeted programs in development

Other Companies:

• Ionis ASOs

• Dicerna RNAi

• Arrowhead RNAi

Challenges for CNS Delivery

Barriers:

• Blood-brain barrier

• Peripheral vs CNS delivery

• Target engagement verification

Approaches:

• Focused ultrasound

• AAV vectors

• Exosome delivery

Future Directions in Neurodegeneration

Gene-Specific Silencing:

• Huntington’s disease (HTT)

• SOD1 ALS

• C9orf72 ALS

Multi-Target Approaches:

• Simultaneous silencing of multiple genes

• Combination with other modalities

Current Status and Future Directions

Trial Status

Phase 2 Progress:

• Enrollment ongoing

• Safety monitoring active

• Preliminary biomarker data expected 2026

Anticipated Timeline:

• Phase 2 completion: 2027

• Phase 3 decision: 2028

• Potential approval: 2030+

Broader Implications

If Successful:

• Paradigm shift for LBD treatment

• Vascular pathway validation

• siRNA application in dementia

If Negative:

• Refines understanding of LBD biology

• Informs future vascular targeting

• Guides patient selection

Patient Perspective

Caregiver Considerations

Daily Management:

• LBD requires 24/7 supervision in advanced stages

• Fluctuating cognition creates unpredictable needs

• Behavioral symptoms challenging to manage

Treatment Burden:

• Multiple daily medications common

• Frequent medical appointments

• Therapy and rehabilitation sessions

Inclisiran Potential Benefits:

• Semi-annual dosing simplifies regimen

• Cardiovascular protection

• Potential to slow progression reduces care burden

Quality of Life Impact

Domains Affected:

• Physical function (gait, fall risk)

• Cognition (memory, executive function)

• Behavior (hallucinations, depression)

• Autonomic (orthostasis, constipation)

Treatment Goals:

• Maintain independence

• Reduce hospitalizations

• Support community living

• Improve caregiver wellbeing

Competitive Landscape

Other Lipid-Targeting Approaches

Statins:

• Widely used, well-characterized

• Mixed evidence in dementia

• Generic, low cost

• No large-scale LBD trials

PCSK9 Antibodies:

• Alirocumab, Evolocumab

• Frequent dosing (bi-weekly)

• Approved for cardiovascular disease

• Not studied in LBD

Bempedoic Acid:

• ATP citrate lyase inhibitor

• Oral, once-daily

• Lower LDL modestly

• Limited CNS data

Comparison Summary

Approach	Dosing	LDL Reduction	LBD Data	Cost
Inclisiran	6 months	~50%	Ongoing	$$$
Statins	Daily	20-55%	Mixed	$
PCSK9 mAbs	2 weeks	~60%	None	$$$$
Bempedoic Acid	Daily	~17%	None	$$

Conclusion

The inclisiran LBD trial represents an innovative approach to treating dementia by targeting vascular contributions to neurodegeneration. By repurposing a proven cardiovascular therapy with a novel mechanism, this trial addresses the significant vascular component often present in LBD pathophysiology.

Key aspects of this trial:

• First siRNA therapeutic evaluated in LBD

• Targets PCSK9 for lipid-lowering

• Leverages vascular hypothesis

• Builds on cardiovascular safety data

The trial’s success would establish a new therapeutic paradigm in dementia care, recognizing the importance of vascular health in neurodegenerative diseases. Even negative results will advance our understanding of LBD biology and guide future development of vascular-targeted approaches.

Related Pages

• Lewy Body Dementia - Target disease

• Parkinson’s Disease Dementia - Related condition

• Inclisiran - Drug entity

• PCSK9 - Target protein

• siRNA Therapeutics - Drug class

• Cerebral Vasculature - Vascular mechanisms

External Links

• ClinicalTrials.gov: NCT05669703

• Leqvio (Inclisiran) Information

• RNAi Therapeutics Society

See Also

• Alzheimer’s Disease

• Parkinson’s Disease

• Vascular Dementia

• Cholesterol Metabolism