EX039 is a novel oral therapeutic candidate being developed by Excelsior Biopharma Inc. for the treatment of mild Alzheimer's disease. The drug is currently in Phase 2 clinical evaluation as an add-on therapy to acetylcholinesterase inhibitors.
Alzheimer's disease represents the most common cause of dementia worldwide, affecting an estimated 55 million people globally. The disease is characterized by progressive cognitive decline, memory loss, and functional impairment. Current approved treatments provide symptomatic benefits but do not modify the underlying disease process. EX039 represents an innovative approach targeting cholinergic augmentation beyond standard acetylcholinesterase inhibitor therapy.
| Attribute |
Details |
| NCT Number |
NCT05413655 |
| Protocol ID |
EX-039-10701 |
| Sponsor |
Excelsior Biopharma Inc. |
| Collaborator |
Formosa Biomedical Technology Corp. |
| Status |
Recruiting |
| Start Date |
August 8, 2022 |
| Estimated Completion |
February 2027 |
¶ Phase 2, Randomized, Double-Blind, Placebo-Controlled
The trial employs a quadruple-blind design with the following characteristics:
- Allocation: Randomized
- Intervention Model: Parallel
- Primary Purpose: Treatment
- Masking: Participant, Care Provider, Investigator, Outcomes Assessor
¶ Arms and Dosage
| Arm |
Type |
Dosage |
| EX039 High Dose |
Experimental |
1000 mg/day |
| EX039 Low Dose |
Experimental |
750 mg/day |
| Placebo |
Placebo Comparator |
Daily |
- Enrollment: 120 subjects (estimated)
- Age: 50-80 years
- Diagnosis: Probable mild AD (NINCDS-ADRDA criteria)
- MMSE: 10-26 (within 3 months)
- CDR Score: 1.0
-
ADAS-cog Change — Alzheimer's Disease Assessment Scale-cognitive subscale
- Score range: 0-70
- Higher scores indicate greater cognitive impairment (≥18)
-
CDR-SB Change — Clinical Dementia Rating-Sum of Boxes
- Score range: 0-18
- Higher scores indicate more worsening
-
CIBIC-Plus: Clinician's Interview-Based Impression of Change Plus Caregiver Input
- Assessed at Weeks 4, 12, 20, and 28
-
Responder Rate: Percentage of subjects with ≥4-point ADAS-cog improvement without CDR-SB or CIBIC-Plus deterioration at Week 28
- Treatment-Emergent Adverse Events (TEAEs) — Week 30
- Safety and Tolerability Assessment
- Age 50-80 years
- Probable mild AD diagnosis per NINCDS-ADRDA 2011 criteria
- MMSE score 10-26 (within 3 months)
- CDR score of 1.0
- Stable on acetylcholinesterase inhibitor therapy
- Physically healthy with normal laboratory values
- Adequate birth control for subjects of childbearing potential
- Other causes of dementia
- Substantial cerebrovascular disease
- Cancer history (except basal cell carcinoma) within 5 years
- Uncontrolled cardiovascular, gastrointestinal, or endocrine conditions
- Symptomatic neurological disease (other than AD)
- Significant psychiatric disorders
- Suicidal behavior within 2 years
- Hachinski Ischemic Score >4
| Facility |
Location |
Status |
| National Taiwan University Hospital |
Taipei, Taiwan |
Recruiting |
- Dr. Ching-Kuan Liu — Kaohsiung Medical University
The specific mechanism of action of EX039 has not been publicly disclosed. The trial evaluates the drug as an add-on to acetylcholinesterase inhibitors, suggesting a complementary mechanism to existing symptomatic treatments for Alzheimer's disease.
Acetylcholinesterase inhibitors (AChEIs) represent the cornerstone of symptomatic treatment for Alzheimer's disease. These medications work by inhibiting the enzyme acetylcholinesterase, which breaks down acetylcholine in the synaptic cleft. In Alzheimer's disease, there is significant degeneration of cholinergic neurons in the basal forebrain, leading to reduced acetylcholine levels that contribute to cognitive impairment.
The main AChEIs approved for AD treatment include:
- Donepezil (Aricept)
- Rivastigmine (Exelon)
- Galantamine (Razadyne)
- Tacrine (withdrawn due to hepatotoxicity)
These agents provide symptomatic benefits by increasing acetylcholine availability at synapses, but they do not modify the underlying disease process. The rationale for add-on therapies like EX039 is to potentially enhance or extend the benefits of cholinergic augmentation.
Memory and cognitive function depend on proper synaptic signaling. In AD, synaptic loss correlates strongly with cognitive decline and is considered one of the earliest pathological features. The cholinergic system plays a critical role in modulating synaptic plasticity, attention, and memory formation.
Key aspects of cholinergic signaling in the brain include:
- Presynaptic regulation: Acetylcholine release modulates neurotransmitter release from other neurons
- Postsynaptic signaling: Muscarinic and nicotinic receptors transduce cholinergic signals
- Network modulation: Cholinergic neurons from the basal forebrain project widely to cortical and hippocampal regions, regulating cortical arousal and attention
Given that EX039 is being tested as an add-on to AChEIs, several mechanistic possibilities are being explored:
- Enhanced cholinergic transmission: The drug may further increase synaptic acetylcholine levels through additional mechanisms beyond AChE inhibition
- Neuroprotective effects: May protect cholinergic neurons from degeneration
- Modulation of amyloid processing: Could influence APP processing pathways
- Anti-inflammatory effects: May reduce neuroinflammation that contributes to cholinergic neuron loss
The ADAS-Cog is the most widely used cognitive measure in AD clinical trials. It assesses:
- Word recall: Immediate and delayed recall of word lists
- Naming: Ability to name objects and fingers
- Construction: Visual-spatial ability (copying figures)
- Ideational praxis: Following commands
- Orientation: Time, place, and person orientation
- Word recognition: Remembering word lists
- Understanding: Following spoken commands
Scores range from 0 (no impairment) to 70 (severe impairment). A 4-point change is typically considered clinically meaningful.
The CDR-SB provides a global measure of dementia severity:
- Memory: Primary domain
- Orientation: Awareness of time, place, person
- Judgment: Problem-solving ability
- Community affairs: Social functioning
- Home and hobbies: Domestic skills
- Personal care: Self-care abilities
Each domain is rated 0-3, and the sum provides a continuous measure of disease severity.
The quadruple-blind design (participant, care provider, investigator, outcomes assessor) minimizes bias in both treatment administration and outcome assessment. This is particularly important in:
- Objective measures: ADAS-Cog requires standardized administration
- Subjective assessments: CIBIC-Plus relies on clinician judgment
- Placebo effects: Cognitive symptoms can be influenced by participant expectations
The inclusion criteria target patients with mild AD (CDR=1.0, MMSE 10-26) because:
- Patients at this stage can reliably report symptoms and complete assessments
- Disease progression is still measurable over the trial timeframe
- Regulatory agencies have established clear efficacy endpoints for this population
In mild AD, neuroimaging typically reveals:
- Hippocampal atrophy: Early marker of neurodegeneration
- Entorhinal cortex involvement: Often affected before hippocampus
- Cortical thinning: Especially in temporoparietal regions
- White matter changes: Disrupted connectivity
Cerebrospinal fluid and blood biomarkers in mild AD:
- Amyloid-beta 42: Reduced levels (reflecting plaque deposition)
- Total tau: Elevated (indicating neuronal injury)
- Phosphorylated tau: Elevated (specific for AD pathology)
- Neurofilament light chain: Marker of neurodegeneration
Patients with mild AD typically present with:
- Memory difficulties: Especially for recent events
- Word-finding problems: Anomia in conversation
- Difficulty with complex tasks: Managing finances, medication
- Mood changes: Often depression or anxiety
- Reduced motivation: Apathy is common
¶ Competitive Landscape
Several approaches are being explored to enhance cholinergic signaling:
| Drug |
Mechanism |
Phase |
Company |
| EX039 |
Add-on to AChEIs |
Phase 2 |
Excelsior Biopharma |
| ABT-288 |
M1 muscarinic agonist |
Phase 1 |
AbbVie |
| PRX-3140 |
M1/M4 agonist |
Preclinical |
Procter & Gamble |
EX039 appears to be a symptomatic enhancer rather than a disease-modifying therapy. This distinction is important:
Symptomatic treatments:
- Improve symptoms without affecting disease progression
- May be combined with disease-modifying agents
Disease-modifying treatments:
- Target underlying pathological processes
- Slow or halt disease progression
- Examples: anti-amyloid antibodies, anti-tau therapies
Understanding the safety profile of the background therapy is important:
- Gastrointestinal: Nausea, vomiting, diarrhea (most common)
- Cardiovascular: Bradycardia, syncope
- Neurological: Dizziness, headache
- Weight loss: Due to appetite suppression
The trial includes comprehensive safety monitoring:
- Physical and neurological examinations
- Vital signs and ECGs
- Laboratory panels (hematology, chemistry)
- Adverse event collection throughout the study
With 120 participants and multiple arms:
- Power calculations: Based on detecting a 4-point ADAS-Cog difference
- Multiple comparisons: Statistical corrections for multiple dose arms
- Dropout adjustment: Typically 15-20% attrition anticipated
The primary analysis will use:
- Mixed-effects models: For repeated measures
- Intention-to-treat: All randomized participants
- Multiple imputation: For missing data
If successful, this trial could lead to:
- Regulatory submission: Based on Week 28 primary endpoints
- Combination therapy label: First add-on to AChEIs
- Long-term extension studies: Open-label follow-up
- Biomarker studies: Patient stratification based on response
While the specific pharmacokinetic profile of EX039 has not been publicly disclosed, the drug's development as an oral add-on therapy provides insights into its expected properties:
Absorption and Distribution:
- Oral bioavailability optimized for CNS penetration
- Blood-brain barrier permeability critical for central cholinergic effects
- Steady-state concentrations likely achieved within 1-2 weeks of dosing
Metabolism and Elimination:
- Hepatic metabolism expected (CYP450 system involvement)
- Renal excretion of metabolites likely primary elimination route
- Drug-drug interaction potential with CYP inhibitors/inducers
Dosing Considerations:
- The 750-1000 mg/day dosing range suggests either moderate potency or need for high receptor occupancy
- Twice-daily dosing likely to maintain therapeutic plasma levels
- Food effect studies may inform administration recommendations
As an add-on therapy, understanding potential drug interactions is critical:
With Acetylcholinesterase Inhibitors:
- Additive cholinergic effects possible (increased ACh levels + direct receptor activation)
- Monitoring for enhanced cholinergic side effects (nausea, diarrhea, bradycardia)
- Potential for synergistic cognitive benefits
Other Interactions:
- Anticholinergic medications may reduce efficacy
- CYP3A4 inhibitors may increase EX039 exposure
- Alcohol may enhance CNS depressant effects
The add-on mechanism suggests multiple potential pharmacodynamic effects:
- Enhanced Cholinergic Transmission: Direct receptor agonism may amplify AChEI effects
- Neuroprotective Signaling: Potential anti-apoptotic and anti-inflammatory effects
- Synaptic Plasticity Enhancement: Supporting memory consolidation
- Disease Modification: Unclear whether EX039 modifies underlying pathology
EX039 development occurs within the modern AD biomarker framework:
Amyloid Biomarkers:
- CSF Aβ42/Aβ40 ratio (reduced in AD)
- Amyloid PET (florbetapir, florbetaben)
- Both used for patient enrichment in modern trials
Neurodegeneration Biomarkers:
- CSF total tau (elevated in AD)
- CSF phosphorylated tau (p-tau181, p-tau217)
- Neurofilament light chain (NfL) - marker of neuronal injury
Neuroimaging:
- MRI volumetry (hippocampal atrophy)
- FDG-PET (hypometabolism in temporoparietal cortex)
- Tau PET (optional for patient stratification)
The EX039 Phase 2 trial may incorporate biomarker assessments:
- Patient Enrichment: Confirming AD pathology via CSF or PET
- Mechanistic Biomarkers: Measuring target engagement
- Prognostic Biomarkers: Identifying patients likely to respond
- Safety Biomarkers: Monitoring for adverse effects
For more detailed biomarker information, see:
¶ Competitive Landscape
EX039 represents a niche in AD therapeutics — add-on to standard of care:
| Drug |
Company |
Mechanism |
Status |
| EX039 |
Excelsior Biopharma |
Add-on AChEI |
Phase 2 |
| ABT-288 |
AbbVie |
M1 agonist |
Phase 1 |
| PRX-3140 |
Procter & Gamble |
M1/M4 agonist |
Preclinical |
| HT-0712 |
Heptares |
M1 positive allosteric modulator |
Phase 1 |
The AD therapeutic landscape is rapidly evolving:
Disease-Modifying Therapies (Approved):
Symptomatic Therapies (Approved):
- Donepezil, Rivastigmine, Galantamine — AChEIs
- Memantine — NMDA antagonist
Agents in Development:
- Anti-tau antibodies (E2814, Bepranemab)
- BACE inhibitors (various)
- Neuroprotective agents (various)
EX039's positioning depends on several factors:
- Efficacy vs. AChEIs alone: Must demonstrate added benefit
- Safety profile: Comparable or better than existing options
- Convenience: Oral dosing with stable background therapy
- Cost: Competitive pricing with existing treatments
The trial's Taiwan focus represents an important trend in global drug development:
Advantages of Taiwan:
- Experienced clinical trial infrastructure
- Strong medical research capabilities
- Established regulatory framework (TFDA)
- Cost-effective operations compared to US/EU
Principal Investigator:
- Dr. Ching-Kuan Liu at Kaohsiung Medical University
- Established AD research program in Taiwan
If successful, subsequent trials would likely expand geographically:
- Phase 3: Multi-regional trials including US, Europe, Japan
- Regulatory submissions: FDA, EMA, PMDA
- Manufacturing scale-up: Ensuring commercial supply
The trial operates under Taiwanese regulatory oversight:
Regulatory Body: Taiwan Food and Drug Administration (TFDA)
Clinical Trial Application: Approved under Taiwan's clinical trial framework
International Standards: ICH-GCP compliance expected
Successful Phase 2 results would support:
- Phase 3 protocol development with regulatory agency input
- Pediatric investigation plan (though AD is adult indication)
- Accelerated approval pathways if biomarker endpoints included
- Orphan drug considerations for rare AD subtypes
If approved, standard post-marketing obligations would include:
- Pharmacovigilance monitoring
- Safety updates to regulatory agencies
- Potential confirmatory trials
- Quality control for manufacturing
For patients and caregivers, EX039 represents:
Convenience Factors:
- Oral administration (no injections or infusions)
- Once or twice daily dosing
- Compatible with existing AChEI regimen
- No special monitoring equipment required
Quality of Life Considerations:
- Potential cognitive stabilization or improvement
- Maintain independence longer
- Reduced caregiver burden
- Delayed institutionalization
If approved, access depends on:
- Reimbursement: Taiwan NHI coverage decisions
- Pricing: Cost-effectiveness vs. alternatives
- Distribution: Manufacturing capacity and supply chain
- Competition: Entry of other add-on therapies
¶ Research Gaps and Future Directions
This trial addresses several unmet needs:
- Add-on options: Patients with inadequate response to AChEIs alone
- Novel mechanisms: Beyond AChE inhibition
- Disease modification: Potential to slow progression
- Combination approaches: Optimizing multi-target therapy
Regardless of trial outcome, valuable insights will emerge:
- Mechanism validation: Does add-on cholinergic augmentation work?
- Biomarker correlation: Which patients respond best?
- Long-term effects: Safety and efficacy beyond 28 weeks
- Combination optimization: Ideal AChEI + EX039 regimen
Regardless of regulatory outcome, this trial contributes to:
- AD pathophysiology understanding: Cholinergic system biology
- Clinical trial methodology: Add-on trial design
- Biomarker development: Patient selection and monitoring
- Global drug development: Taiwan as clinical trial hub
- Overall Status: Recruiting
- Last Verified: February 2025
- Last Updated: February 26, 2025
- Primary Completion (Estimated): December 2026
- Study Completion (Estimated): February 2027
This trial represents an active Phase 2 program in Alzheimer's disease drug development, sponsored by a Taiwanese biotechnology company. The trial's focus on mild AD patients and use of standard cognitive endpoints (ADAS-cog, CDR-SB) aligns with current industry standards for AD therapeutic development.
The add-on approach is particularly interesting from a mechanistic perspective, as it suggests a complementary strategy to existing cholinergic treatments. Understanding how EX039 might enhance AChEI efficacy could provide insights into optimal combination therapies for Alzheimer's disease.