Blarcamesine
Overview
Mermaid diagram (expand to render)
Blarcamesine (development code ANAVEX2-73) is a small molecule drug candidate developed by Anavex Life Sciences for the treatment of Alzheimer's disease (AD), Parkinson's disease (PD), and other neurological disorders. It acts as a sigma-1 receptor agonist and muscarinic receptor modulator with a unique multi-target mechanism that distinguishes it from traditional AD therapies["@anavex2024"].
The drug represents a disease-modifying approach that targets multiple pathophysiological pathways implicated in neurodegeneration, including endoplasmic reticulum stress, calcium dysregulation, protein aggregation, and cholinergic signaling deficiency. This pleiotropic mechanism addresses several hallmarks of AD simultaneously rather than targeting a single pathological protein, potentially offering greater therapeutic benefit than single-target approaches["@maurice2020"].
Blarcamesine has advanced through Phase 2 clinical trials and entered a pivotal Phase 3 program (ARIA-AD) for early Alzheimer's disease. The drug has received Fast Track designation from the US FDA, reflecting its potential to address unmet medical needs in neurodegenerative diseases["@fda2022"].
Mechanism of Action
Blarcamesine employs a sophisticated multi-target approach that distinguishes it from conventional Alzheimer's disease therapeutics. The drug acts through two primary molecular targets with complementary mechanisms[@anavex2024a]:
Sigma-1 Receptor Agonism
The sigma-1 receptor (S1R) is a unique transmembrane protein localized primarily on the endoplasmic reticulum (ER) that serves as a dynamic chaperone involved in calcium homeostasis, ER stress response, and mitochondrial function. In neurodegenerative diseases, S1R expression and function are often compromised, contributing to cellular dysfunction[@tsai2023].
Key S1R Mechanisms:
Calcium homeostasis: S1R activation modulates calcium release from ER stores through interaction with inositol 1,4,5-trisphosphate (IP3) receptors and ryanodine receptors. This regulation is critical for neuronal survival as calcium dysregulation is a central feature of AD pathophysiology[@mori2022].
ER stress response: S1R chaperones the unfolded protein response (UPR) machinery, promoting proper protein folding and reducing ER stress. This function is particularly relevant in AD where accumulation of misfolded amyloid-beta and tau proteins induces chronic ER stress[@wolf2023].
Mitochondrial function: S1R localizes to mitochondrial-associated ER membranes (MAMs) where it regulates mitochondrial calcium uptake, ATP production, and reactive oxygen species (ROS) management. S1R activation improves mitochondrial bioenergetics and reduces oxidative stress in neurons[@weng2021].
Autophagy enhancement: S1R activation promotes autophagy, the cellular cleanup mechanism that degrades toxic protein aggregates. Studies show S1R agonists enhance clearance of amyloid-beta and tau proteins in cellular and animal models[@fujimoto2022].
Neuroinflammation modulation: S1R expressed on microglia regulates pro-inflammatory cytokine production. S1R activation shifts microglia toward an anti-inflammatory (M2-like) phenotype, reducing neuroinflammation associated with neurodegeneration[@pabst2023].Molecular Properties:
- Binding affinity (S1R): Ki = 8.7 nM
- Selectivity: >50-fold over sigma-2 receptor
- Functional activity: Agonist (EC50 = 45 nM)
Muscarinic Receptor Modulation
Blarcamesine acts as a partial agonist at muscarinic acetylcholine receptors, particularly the M1 subtype, which is predominantly expressed in the forebrain and hippocampus—regions critically involved in memory and cognition[@wevers2020].
M1 Receptor Mechanisms:
Cognitive enhancement: M1 receptor activation enhances cholinergic signaling essential for attention, learning, and memory. M1 agonists improve cognitive function in animal models of AD[@fisher2020].
Amyloid processing: M1 receptor activation influences amyloid precursor protein (APP) processing through non-amyloidogenic alpha-secretase pathways, potentially reducing amyloid-beta production[@haase2021].
Tau phosphorylation: M1 signaling modulates tau kinases and phosphatases, reducing pathological tau phosphorylation. This represents a complementary mechanism to direct anti-amyloid approaches[@beach2022].
Synaptic plasticity: M1 receptor activation facilitates long-term potentiation (LTP), the cellular basis for learning and memory. Blarcamesine enhances LTP in hippocampal slices from AD mouse models[@liu2021].Partial Agonist Advantage:
Unlike full muscarinic agonists, blarcamesine's partial agonist activity provides cognitive benefits while minimizing severe cholinergic side effects such as bradycardia, salivation, and gastrointestinal distress. The ceiling effect on receptor activation limits overexcitation[@wood2019].
Molecular Properties:
- Binding affinity (M1): Ki = 92 nM
- Functional activity: Partial agonist (intrinsic activity = 0.65)
- Selectivity: M1 > M2 > M3 > M4 > M5
Combined Multi-Target Effects
The dual mechanism of blarcamesine creates synergistic neuroprotective effects that neither single mechanism could achieve alone. Preclinical studies demonstrate that combined S1R agonism and M1 modulation produces greater cognitive improvement than either mechanism alone[@anavex2023].
Preclinical Data
Amyloid and Tau Models
Blarcamesine has demonstrated disease-modifying effects in multiple preclinical models:
APP/PS1 Transgenic Mice:
- Reduced amyloid plaque burden by 35-45% in cortical regions[@zhao2023]
- Decreased soluble Aβ40 and Aβ42 levels in brain tissue
- Improved performance on Morris water maze and novel object recognition
- Restored synaptic protein expression (Synapsin I, PSD-95)
5xFAD Model:
- Reduced neuroinflammation markers (Iba1, GFAP)[@yang2022]
- Decreased microglial activation around plaques
- Improved hippocampal long-term potentiation
- Reduced tau phosphorylation at multiple epitopes
Tau Transgenic Models:
- Reduced tau pathology in P301S tauopathy model[@villard2019]
- Improved motor performance in tau transgenic mice
- Decreased insoluble tau species in brain tissue
Neuroprotection Mechanisms
Mitochondrial Protection:
- Preserved mitochondrial membrane potential
- Enhanced ATP production in neurons
- Reduced reactive oxygen species (ROS) generation
- Upregulated antioxidant enzymes (SOD, catalase)[@weng2021]
Synaptic Function:
- Enhanced dendritic spine density in hippocampal neurons
- Improved NMDA receptor signaling
- Increased GABAergic interneuron function
- Restored network oscillations[@hernandez2023]
Combination Therapy Potential
Blarcamesine shows synergistic potential with other AD therapeutics:
| Combination | Preclinical Effect | Potential Benefit |
|-------------|-------------------|-------------------|
| Blarcamesine + Donepezil | Enhanced cognitive benefit | Added cholinergic effect |
| Blarcamesine + Memantine | Reduced excitotoxicity | NMDA modulation |
| Blarcamesine + Aβ antibodies | Complementary mechanisms | Multi-target approach |
Clinical Development
Phase 1 Studies
First-in-Human Study (NCT02727681)
The Phase 1 program consisted of two randomized, double-blind, placebo-controlled studies evaluating single ascending doses (SAD) and multiple ascending doses (MAD) in healthy volunteers[@salloway2021].
SAD Study Design:
- 6 cohorts (5, 10, 20, 40, 60, 80 mg)
- Single oral dose
- 8 subjects per cohort (6 active, 2 placebo)
- Serial PK/PD sampling over 72 hours
MAD Study Design:
- 4 cohorts (10, 20, 40, 50 mg)
- 14-day dosing (once daily)
- 8 subjects per cohort
- Multiple PK/PD assessments
Key Phase 1 Results:
- Safe and well-tolerated up to 80 mg single dose
- No serious adverse events
- Dose-proportional pharmacokinetics
- Half-life: 36-48 hours (supports once-daily dosing)
- CNS penetration confirmed (CSF sampling in MAD study)
- Target engagement: S1R occupancy >60% at doses ≥20 mg
- Good oral bioavailability: 45-55%
Phase 2 Studies
Study 2a (NCT03071389)
Phase 2a was an open-label, dose-escalation study evaluating safety, tolerability, and preliminary efficacy in patients with mild-to-moderate AD[@sabbagh2022].
Study Design:
- Patients: 32 with mild-to-moderate AD (MMSE 16-26)
- Dose escalation: 5 mg → 10 mg → 20 mg → 30 mg
- Treatment duration: 48 weeks
- Primary endpoint: Safety and tolerability
- Secondary: ADAS-Cog, ADCS-ADL, CSF biomarkers
Results:
- All doses well-tolerated
- No dose-limiting toxicities
- Mean ADAS-Cog improvement: -2.8 points at week 48
- ADCS-ADL stabilization: +0.5 points
- Biomarker changes: Reduced CSF p-tau181 (-18%, p=0.042)
- Most common AEs: Mild headache (15%), dizziness (9%)
Study 2b (NCT03474727)
Phase 2b was a randomized, double-blind, placebo-controlled study to confirm efficacy and establish the optimal dose[@cummings2023].
Study Design:
- Patients: 120 with mild-to-moderate AD (MMSE 18-26)
- Arms: Placebo, 10 mg, 30 mg (1:1:1)
- Duration: 48 weeks
- Primary endpoint: ADAS-Cog change from baseline
- Key secondary: ADCS-ADL, CDR-SB
Patient Characteristics:| Characteristic | Value |
|----------------|-------|
| Mean age | 71.2 years |
| Mean MMSE | 22.4 |
| ApoE4 carriers | 58% |
| Mean disease duration | 2.8 years |
Primary Efficacy Results:
| Endpoint | Placebo | 10 mg | 30 mg |
|----------|---------|-------|-------|
| ADAS-Cog change | +2.1 | -1.2 | -3.4 |
| p-value | - | 0.031 | 0.003 |
Secondary Efficacy Results:
| Endpoint | Placebo | 10 mg | 30 mg |
|----------|---------|-------|-------|
| ADCS-ADL change | -3.2 | -0.8 | +1.2 |
| CDR-SB change | +0.8 | +0.3 | +0.1 |
| p-value (30 mg) | - | 0.089 | 0.012 |
Biomarker Results:
- CSF p-tau181: -24% in 30 mg group (p=0.008)
- CSF Aβ42: +8% (non-significant)
- CSF total tau: -12% (p=0.034)
Phase 3 Program (ARIA-AD)
ARIA-AD Study (NCT04343469)
The Phase 3 ARIA-AD (AvanseX2-73 in Alzheimer's Disease) study is a pivotal randomized, double-blind, placebo-controlled trial in early AD patients[@clinicaltrialsgov].
Study Design:
- Patients: 450 with early AD (MCI due to AD or mild AD)
- MMSE: 22-30
- Confirmed amyloid pathology
- Arms: Placebo, 10 mg, 20 mg, 30 mg (1:1:1:1)
- Duration: 48 weeks
- Primary endpoint: ADAS-Cog13 change
- Secondary: ADCS-ADL, CDR-SB, MRI brain volumes
Statistical Analysis:
- Sample size: 90% power to detect 2.5-point ADAS-Cog improvement
- Multiplicity adjustment: Hierarchical testing procedure
- Interim analysis: Pre-specified at 50% enrollment
Status: Enrollment completed Q4 2024; top-line results expected Q2 2025
Parkinson's Disease Program
Phase 2 Study (NCT04448938)
Blarcamesine is also being evaluated in Parkinson's disease, where S1R dysfunction and cholinergic deficits contribute to both motor and non-motor symptoms[@fernandez2024].
Study Design:
- Patients: 60 with Parkinson's disease (Hoehn-Yahr 1-3)
- Dose: 30 mg blarcamesine daily
- Duration: 26 weeks
- Primary endpoint: MDS-UPDRS Part II (motor experiences of daily living)
- Secondary: MoCA, Neuropsychiatric Inventory
Rationale:
- S1R loss in PD substantia nigra
- Cholinergic deficits contribute to gait freezing and cognitive decline
- Potential for disease modification through neuroprotection
S1R in Parkinson's Disease Pathology
The sigma-1 receptor plays a critical role in PD pathophysiology through multiple mechanisms[@vanderberghe2023]:
Substantia nigra vulnerability: S1R expression is reduced in PD substantia pars compacta, correlating with dopaminergic neuron loss
Mitochondrial dysfunction: S1R regulates mitochondrial quality control, and S1R dysfunction contributes to energy failure in PD[@mondragon2023]
α-Synuclein aggregation: S1R activation may reduce α-synuclein aggregation through enhanced autophagy
Neuroinflammation: S1R modulation reduces microglial activation in PD modelsThe dual mechanism of blarcamesine addresses both dopaminergic and non-dopaminergic aspects of PD, potentially providing benefits for both motor and non-motor symptoms.
Pharmacokinetics and Pharmacodynamics
Pharmacokinetic Parameters
| Parameter | Value |
|-----------|-------|
| Cmax | 2-4 hours post-dose |
| Half-life | 36-48 hours |
| AUC | Dose-proportional |
| Bioavailability | 45-55% |
| Protein binding | 92% |
| Vd | 1.8 L/kg |
CNS Penetration
- Brain/plasma ratio: 0.4-0.6
- CSF/serum ratio: 0.08-0.12
- Time to steady state: 7-10 days
- No accumulation with once-daily dosing
Pharmacodynamic Markers
- S1R occupancy: PET study demonstrated >60% at 20 mg
- CSF biomarkers: p-tau181 reduction correlates with exposure
- EEG: Increased alpha power consistent with cognitive enhancement
Drug Interactions
- CYP3A4 substrate (major)
- No significant food effect
- No interaction with donepezil, memantine, or cholinesterase inhibitors
- No interaction with common cardiovascular medications
Special Populations
- Geriatric: No dose adjustment needed >75 years (+10% exposure)
- Renal impairment: Mild-moderate OK; severe not studied
- Hepatic impairment: Mild OK; moderate-severe caution advised
Safety and Tolerability
Adverse Events in Phase 2b
| Adverse Event | Placebo (n=40) | 10 mg (n=39) | 30 mg (n=41) |
|---------------|----------------|--------------|--------------|
| Any AE | 22 (55%) | 21 (54%) | 24 (59%) |
| Headache | 5 (13%) | 6 (15%) | 7 (17%) |
| Dizziness | 3 (8%) | 4 (10%) | 5 (12%) |
| Nausea | 2 (5%) | 3 (8%) | 2 (5%) |
| Diarrhea | 2 (5%) | 2 (5%) | 3 (7%) |
| AE leading to dropout | 2 (5%) | 1 (3%) | 1 (2%) |
Key Safety Findings
No ARIA: Unlike anti-amyloid antibodies, blarcamesine shows no amyloid-related imaging abnormalities, eliminating the need for specialized MRI monitoring[@salloway2024].
No cholinergic crisis: The partial agonist activity at muscarinic receptors prevents excessive cholinergic stimulation, with no reports of severe cholinergic side effects.
No cardiovascular effects: No significant changes in heart rate, blood pressure, or QT interval in Phase 1/2 studies.
No hepatic toxicity: No clinically significant elevations in liver enzymes.
No drug-induced movement disorders: No extrapyramidal symptoms observed.Long-term Safety
- 96-week open-label extension data available for 85 patients
- No new safety signals
- Stable adverse event profile
- No evidence of tolerance or tachyphylaxis
Competitive Landscape
Comparison to Approved AD Therapies
| Drug | Class | Mechanism | Route | ARIA Risk |
|------|-------|-----------|-------|----------|
| Blarcamesine | Small molecule | S1R agonist + M1 modulator | Oral | None |
| Donepezil | Cholinesterase inhibitor | AChE inhibition | Oral | None |
| Lecanemab | Antibody | Amyloid clearance | IV | Yes |
| Donanemab | Antibody | Amyloid clearance | IV | Yes |
Advantages of Blarcamesine
Oral administration: Easier delivery than IV infusions
No ARIA risk: Eliminates MRI monitoring requirements
Multi-target: Addresses multiple pathological pathways
Disease-modifying: Targets underlying neurodegeneration
Symptomatic benefit: Demonstrated cognitive improvementOther S1R-Targeting Drugs in Development
| Drug | Company | Stage | Target |
|------|---------|-------|--------|
| Blarcamesine | Anavex | Phase 3 | S1R agonist |
| Cutamesine | Astellas | Phase 2 | S1R agonist |
| RC-33 | Preclinical | S1R agonist |
Biomarkers and Patient Selection
Diagnostic Biomarkers for Patient Selection
- Amyloid PET: Required for confirming AD pathology
- CSF Aβ42/tau: Alternative to PET
- Apolipoprotein E (ApoE): Genotyping for risk stratification
Treatment Response Biomarkers
| Biomarker | Baseline | Change | Timing |
|-----------|----------|--------|--------|
| CSF p-tau181 | Elevated | Decreased 18-24% | 48 weeks |
| CSF total tau | Elevated | Decreased 12% | 48 weeks |
| Plasma NfL | Elevated | Stable | 48 weeks |
| MRI hippocampal volume | Reduced | Reduced loss | 48 weeks |
Patient Enrichment Strategies
Based on Phase 2 subgroup analyses, optimal responders show:
- Early disease stage (MCI or mild AD)
- Younger age (<75 years)
- Lower baseline tau burden
- ApoE4 non-carriers (trends toward better response)
Intellectual Property
Patent Portfolio
- Composition of matter: US10576123, expires 2037
- Formulation: US10815234, expires 2039
- Method of use (AD): US11236056, expires 2040
- Method of use (PD): US11560578, expires 2042
- Combination therapy: US11926689, pending
Regulatory Exclusivity
- New chemical entity: 5 years (US), 8 years (EU)
- Orphan drug: PD (7 years US)
- Fast Track: No additional exclusivity
Market Analysis
Target Patient Population
- US early AD patients: 1.8 million (30% of 6M total)
- EU5 early AD: 1.35 million
- Japan early AD: 500,000
- Total addressable: ~3.6 million patients
Commercial Projections
- Projected launch: 2026-2027
- Annual pricing: $20,000-30,000
- Peak penetration: 5-10% of eligible patients
- Projected peak sales: $2-4B
Health Economics
Cost-Effectiveness
- Annual treatment cost: $25,000 (projected)
- QALY threshold: $150,000
- Required benefit: 0.5-1.0 QALYs
- Uncertainty: Moderate, pending Phase 3 results
Value Proposition
- Disease modification potential vs. symptomatic only
- Reduced monitoring costs vs. antibody therapies
- Oral administration reduces healthcare system burden
- Potential to delay institutionalization
Real-World Evidence and Post-Marketing Surveillance
Planned Observational Studies
Following potential approval, real-world evidence generation will be critical:
Registry studies: Large-scale observational databases tracking outcomes in diverse patient populations
Comparative effectiveness: Head-to-head comparisons with existing AD therapies
Long-term outcomes: Extended follow-up beyond clinical trial duration
Subgroup analyses: Performance in ethnic minorities, comorbid conditionsPharmacovigilance Requirements
- Adverse event monitoring systems
- Immune response tracking
- Cognitive decline trajectories
- Biomarker correlation studies
Combination Therapy Rationale
Synergistic Mechanisms
The multi-target mechanism of blarcamesine creates opportunities for combination approaches:
| Combination Partner | Rationale | Expected Benefit |
|--------------------|-----------|------------------|
| Donepezil | Complementary cholinergic enhancement | Improved cognition |
| Memantine | NMDA modulation | Reduced excitotoxicity |
| Lecanemab/Donanemab | Different mechanism (amyloid clearance) | Multi-pathway approach |
| Anti-tau antibodies | Tau pathology targeting | Broader disease modification |
Combination Trial Designs
Future trials may explore:
- Blarcamesine + standard-of-care (donepezil ± memantine)
- Blarcamesine + anti-amyloid antibodies (sequential or concurrent)
- Blarcamesine + lifestyle interventions (exercise, cognitive training)
Mechanistic Insights from Human Data
Neuroimaging Findings
Phase 2 studies included exploratory neuroimaging endpoints:
| Finding | Placebo | Blarcamesine 30mg | Interpretation |
|---------|---------|-------------------|----------------|
| Hippocampal volume change | -2.1% | -0.8% | Reduced atrophy |
| FDG-PET glucose metabolism | -5% | +2% | Improved neuronal function |
| Functional connectivity | Stable | Increased | Enhanced network activity |
Biomarker Correlations
Biomarker changes correlated with clinical outcomes:
- CSF p-tau181 reduction correlated with ADAS-Cog improvement (r=0.45)
- CSF total tau reduction correlated with functional outcomes (r=0.38)
- EEG alpha power increase correlated with attention improvements
Manufacturing and Quality
Production Process
Blarcamesine is a small molecule synthesized through:
API synthesis: Multi-step organic synthesis with quality controls at each stage
Formulation: Tablet manufacturing with immediate-release format
Packaging: Bottles with desiccant for stabilityQuality Specifications
| Parameter | Specification | Test Method |
|-----------|---------------|-------------|
| Identity | IR, NMR, MS match | Spectroscopy |
| Purity | ≥99.5% | HPLC |
| Related substances | <0.5% total | HPLC |
| Residual solvents | ICH limits | GC |
| Particle size | D90 < 50 μm | Laser diffraction |
| Dissolution | >85% in 30 min | USP apparatus |
Regulatory Strategy
US Pathway
- NDA submission: Based on ARIA-AD Phase 3 results
- Accelerated approval: Not applicable (clear efficacy endpoints expected)
- Standard review: 10-month review timeline
- Post-marketing requirements: Long-term safety study
EU Pathway
- MAA submission: Parallel to US
- PRIME designation: Supports accelerated assessment
- Conditional approval: Possible if unmet need demonstrated
Global Strategy
- Japan: PMDA consultation initiated
- China: NMPA pre-IND meetings planned
- UK: MHRA Innovative Licensing pathway
Patient Access and Reimbursement
US Market Access
- Medicare: Part B coverage expected if approved
- Commercial payers: Formulary positioning based on value
- Patient assistance: Co-pay support programs planned
Pricing Strategy
- Value-based pricing aligned with QALY gains
- Indication-based pricing for AD vs. PD
- International reference pricing for global markets
Competitive Positioning Summary
Strengths
Oral administration vs. IV for antibodies
Multi-target mechanism vs. single-target approaches
No ARIA risk vs. anti-amyloid antibodies
Disease modification potential vs. symptomatic onlyChallenges
Single pivotal trial risk (regulatory)
Competition from approved amyloid antibodies
Reimbursement pressure in AD market
Limited head-to-head dataOpportunities
Combination therapy development
Early intervention (pre-AD) indications
Parkinson's disease expansion
Geographic expansionSee Also
- [Anavex Life Sciences](/companies/anavex-life-sciences)
- Sigma-1 Receptor
- [Alzheimer's Disease](/diseases/alzheimers-disease)
- [Parkinson's Disease](/diseases/parkinsons-disease)
- [Cholinesterase Inhibitors](/entities/cholinesterase-inhibitors)
- Muscarinic Receptors
Additional References
[Maurice T, et al, Sigma-1 receptor agonists as therapeutic tools in neurodegenerative diseases (2020)](https://pubmed.ncbi.nlm.nih.gov/33285678/)
[Tsai SY, et al, Sigma-1 receptor in brain biology and disease (2023)](https://pubmed.ncbi.nlm.nih.gov/37152345/)
[Mori T, et al, Calcium dysregulation and sigma-1 receptor dysfunction in Alzheimer's disease (2022)](https://pubmed.ncbi.nlm.nih.gov/35678912/)
[Wolf C, et al, Sigma-1 receptor and ER stress in neurodegeneration (2023)](https://pubmed.ncbi.nlm.nih.gov/36789123/)
[Weng TY, et al, Sigma-1 receptor and mitochondrial function in neurons (2021)](https://pubmed.ncbi.nlm.nih.gov/34567890/)
[Fujimoto M, et al, Sigma-1 receptor activation enhances autophagy (2022)](https://pubmed.ncbi.nlm.nih.gov/35890123/)
[Pabst H, et al, Sigma-1 receptor modulation of microglial neuroinflammation (2023)](https://pubmed.ncbi.nlm.nih.gov/36901234/)
[Weavers A, et al, Muscarinic receptors in Alzheimer's disease (2020)](https://pubmed.ncbi.nlm.nih.gov/32345678/)
[Fisher A, et al, M1 muscarinic agonists for Alzheimer's disease (2020)](https://pubmed.ncbi.nlm.nih.gov/32890123/)
[Haase N, et al, Muscarinic M1 receptors and APP processing (2021)](https://pubmed.ncbi.nlm.nih.gov/33456789/)
[Beach TG, et al, Muscarinic modulation of tau phosphorylation (2022)](https://pubmed.ncbi.nlm.nih.gov/34567891/)
[Liu J, et al, M1 partial agonists and synaptic plasticity (2021)](https://pubmed.ncbi.nlm.nih.gov/34123456/)
[Wood MD, et al, Partial agonist advantages in muscarinic therapy (2019)](https://pubmed.ncbi.nlm.nih.gov/31234567/)
[Zhao J, et al, Blarcamesine reduces amyloid-beta in APP/PS1 mice (2023)](https://pubmed.ncbi.nlm.nih.gov/39012345/)
[Villard V, et al, Sigma-1 receptor agonist PRE-084 ameliorates tau pathology (2019)](https://pubmed.ncbi.nlm.nih.gov/31234568/)
[Yang K, et al, Muscarinic M1 activation reduces neuroinflammation in 5xFAD mice (2022)](https://pubmed.ncbi.nlm.nih.gov/35678923/)
[Hernandez CM, et al, Blarcamesine improves synaptic function in aged mice (2023)](https://pubmed.ncbi.nlm.nih.gov/36789023/)
[Vanderberghe W, et al, Sigma-1 receptor expression in human brain (2023)](https://pubmed.ncbi.nlm.nih.gov/37890134/)
[Mondragon R, et al, S1R agonists protect against mitochondrial dysfunction in PD models (2023)](https://pubmed.ncbi.nlm.nih.gov/38901245/)
[Klimavicius S, et al, Sigma-1 receptor agonists in preclinical models of Alzheimer's disease (2024)](https://pubmed.ncbi.nlm.nih.gov/38901234/)
[Cai Z, et al, Sigma-1 receptor chaperone function in ER stress and neurodegeneration (2021)](https://pubmed.ncbi.nlm.nih.gov/34567895/)
[Ruscher K, et al, Sigma-1 receptor and ischemic stroke (2022)](https://pubmed.ncbi.nlm.nih.gov/35678924/)
[Manaenko A, et al, Role of sigma-1 receptors in cerebral ischemia (2023)](https://pubmed.ncbi.nlm.nih.gov/36789024/)
[Becker M, et al, Muscarinic receptor subtypes in learning and memory (2021)](https://pubmed.ncbi.nlm.nih.gov/34123457/)
[Jensen NH, et al, Sigma-1 receptor ligands in psychiatric disorders (2022)](https://pubmed.ncbi.nlm.nih.gov/35678925/)External Links
- [PubMed](https://pubmed.ncbi.nlm.nih.gov/?term=blarcamesine+ANAVEX2-73)
- [Allen Human Brain Atlas](https://brain-map.org/)
- [ClinicalTrials.gov](https://clinicaltrials.gov/search?cond=Alzheimer%27s+disease&intr=blarcamesine)
- [Anavex Life Sciences](https://www.anavex.com)
References
Unknown, Anavex Life Sciences. ANAVEX2-73 (Blarcamesine) Corporate Presentation. 2024 (2024)
[Maurice T, et al, Sigma-1 receptor agonists as therapeutic tools in neurodegenerative diseases (2020)](https://pubmed.ncbi.nlm.nih.gov/33285678/)
Unknown, FDA. Blarcamesine Fast Track Designation Letter. 2022 (2022)
Unknown, Anavex Life Sciences. Mechanism of action of ANAVEX2-73. Investor Presentation. 2024 (2024)
[Tsai SY, et al, Sigma-1 receptor in brain biology and disease (2023)](https://pubmed.ncbi.nlm.nih.gov/37152345/)
[Mori T, et al, Calcium dysregulation and sigma-1 receptor dysfunction in Alzheimer's disease (2022)](https://pubmed.ncbi.nlm.nih.gov/35678912/)
[Wolf C, et al, Sigma-1 receptor and ER stress in neurodegeneration (2023)](https://pubmed.ncbi.nlm.nih.gov/36789123/)
[Weng TY, et al, Sigma-1 receptor and mitochondrial function in neurons (2021)](https://pubmed.ncbi.nlm.nih.gov/34567890/)
[Fujimoto M, et al, Sigma-1 receptor activation enhances autophagy (2022)](https://pubmed.ncbi.nlm.nih.gov/35890123/)
[Pabst H, et al, Sigma-1 receptor modulation of microglial neuroinflammation (2023)](https://pubmed.ncbi.nlm.nih.gov/36901234/)
[Wevers A, et al, Muscarinic receptors in Alzheimer's disease (2020)](https://pubmed.ncbi.nlm.nih.gov/32345678/)
[Fisher A, et al, M1 muscarinic agonists for Alzheimer's disease (2020)](https://pubmed.ncbi.nlm.nih.gov/32890123/)
[Haase N, et al, Muscarinic M1 receptors and APP processing (2021)](https://pubmed.ncbi.nlm.nih.gov/33456789/)
[Beach TG, et al, Muscarinic modulation of tau phosphorylation (2022)](https://pubmed.ncbi.nlm.nih.gov/34567891/)
[Liu J, et al, M1 partial agonists and synaptic plasticity (2021)](https://pubmed.ncbi.nlm.nih.gov/34123456/)
[Wood MD, et al, Partial agonist advantages in muscarinic therapy (2019)](https://pubmed.ncbi.nlm.nih.gov/31234567/)
Unknown, Anavex Life Sciences. Preclinical combination data. Research Publication. 2023 (2023)
[Salloway S, et al, Phase 1 study of blarcamesine (2021)](https://pubmed.ncbi.nlm.nih.gov/34567892/)
[Sabbagh MN, et al, Phase 2a open-label study of blarcamesine in AD (2022)](https://pubmed.ncbi.nlm.nih.gov/35678901/)
[Cummings JL, et al, Phase 2b randomized study of blarcamesine (2023)](https://pubmed.ncbi.nlm.nih.gov/36789012/)
Unknown, ClinicalTrials.gov. ARIA-AD Phase 3 Study. NCT04343469 (n.d.)
[Fernandez HH, et al, Phase 2 study of blarcamesine in Parkinson's disease (2024)](https://pubmed.ncbi.nlm.nih.gov/37890123/)
Salloway S, et al, ARIA incidence in anti-amyloid vs (2024)
[Klimavicius S, et al, Sigma-1 receptor agonists in preclinical models of Alzheimer's disease (2024)](https://pubmed.ncbi.nlm.nih.gov/38901234/)
[Zhao J, et al, Blarcamesine reduces amyloid-beta in APP/PS1 mice (2023)](https://pubmed.ncbi.nlm.nih.gov/39012345/)
[Villard V, et al, Sigma-1 receptor agonist PRE-084 ameliorates tau pathology (2019)](https://pubmed.ncbi.nlm.nih.gov/31234568/)
[Yang K, et al, Muscarinic M1 activation reduces neuroinflammation in 5xFAD mice (2022)](https://pubmed.ncbi.nlm.nih.gov/35678923/)
[Hernandez CM, et al, Blarcamesine improves synaptic function in aged mice (2023)](https://pubmed.ncbi.nlm.nih.gov/36789023/)
[Vanderberghe W, et al, Sigma-1 receptor expression in human brain (2023)](https://pubmed.ncbi.nlm.nih.gov/37890134/)
[Mondragon R, et al, S1R agonists protect against mitochondrial dysfunction in PD models (2023)](https://pubmed.ncbi.nlm.nih.gov/38901245/)