EX039 Phase 2 (NCT05413655) — Oral Therapeutic for Alzheimer's Disease

EX039 Phase 2 Clinical Trial (NCT05413655)

Overview

EX039 Phase 2 Clinical Trial (NCT05413655)

Overview

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["@ache2023"].

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["@alzheimers2024"]. 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.

Trial Identification

| 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 |

Study Design

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 |

Patient Population

• 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

Primary Endpoints

Week 28 Endpoints

• Score range: 0-70
• Higher scores indicate greater cognitive impairment (≥18)

• Score range: 0-18
• Higher scores indicate more worsening

Secondary Endpoints

Efficacy Measures

• 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

Safety Measures

• Treatment-Emergent Adverse Events (TEAEs) — Week 30
• Safety and Tolerability Assessment

Eligibility Criteria

Inclusion Requirements

• 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

Key Exclusion Criteria

• 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

Study Locations

Active Recruitment Sites

| Facility | Location | Status |
|----------|----------|--------|
| National Taiwan University Hospital | Taipei, Taiwan | Recruiting |

Principal Investigator

• Dr. Ching-Kuan Liu — Kaohsiung Medical University

Contact

• Cliff Lin — cliff.lin@excelsiorgroup.com.tw — +886-972821234

Mechanism of Action

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.

Background on Acetylcholinesterase Inhibitors

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[@ache2023]. 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)

Synaptic Dysfunction in Alzheimer's Disease

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[@synapse2024]. The cholinergic system plays a critical role in modulating synaptic plasticity, attention, and memory formation.

Key aspects of cholinergic signaling in the brain include:

Potential Mechanisms for Add-On Therapy

Given that EX039 is being tested as an add-on to AChEIs, several mechanistic possibilities are being explored:

Clinical Endpoints Explained

ADAS-Cog (Alzheimer's Disease Assessment Scale-Cognitive Subscale)

The ADAS-Cog is the most widely used cognitive measure in AD clinical trials[@adas2023]. 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

CDR-SB (Clinical Dementia Rating-Sum of Boxes)

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

Trial Design Rationale

Why Quadruple-Blind?

The quadruple-blind design (participant, care provider, investigator, outcomes assessor) minimizes bias in both treatment administration and outcome assessment. This is particularly important in:

Patient Population Selection

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

Neurobiology of Mild Alzheimer's Disease

Structural Changes

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

Biochemical Markers

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

Clinical Presentation

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

Other AChEIs in Development

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 |

Disease-Modifying vs. Symptomatic

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

• Target underlying pathological processes
• Slow or halt disease progression
• Examples: anti-amyloid antibodies, anti-tau therapies

Safety Considerations

Common Adverse Events with AChEIs

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

EX039 Safety Monitoring

The trial includes comprehensive safety monitoring:

• Physical and neurological examinations
• Vital signs and ECGs
• Laboratory panels (hematology, chemistry)
• Adverse event collection throughout the study

Statistical Considerations

Sample Size Justification

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

Endpoint Analysis

The primary analysis will use:

• Mixed-effects models: For repeated measures
• Intention-to-treat: All randomized participants
• Multiple imputation: For missing data

Future Directions

If successful, this trial could lead to:

Pharmacological Properties

Pharmacokinetics (Based on Preclinical Data)

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

• Hepatic metabolism expected (CYP450 system involvement)
• Renal excretion of metabolites likely primary elimination route
• Drug-drug interaction potential with CYP inhibitors/inducers

• 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

Potential Drug Interactions

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

• Anticholinergic medications may reduce efficacy
• CYP3A4 inhibitors may increase EX039 exposure
• Alcohol may enhance CNS depressant effects

Pharmacodynamic Considerations

The add-on mechanism suggests multiple potential pharmacodynamic effects:

Biomarker Context

Alzheimer's Disease Biomarker Framework

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

• CSF total tau (elevated in AD)
• CSF phosphorylated tau (p-tau181, p-tau217)
• Neurofilament light chain (NfL) - marker of neuronal injury

• MRI volumetry (hippocampal atrophy)
• FDG-PET (hypometabolism in temporoparietal cortex)
• Tau PET (optional for patient stratification)

Potential Biomarker Applications in This Trial

The EX039 Phase 2 trial may incorporate biomarker assessments:

Linking to NeuroWiki Biomarker Pages

For more detailed biomarker information, see:

• [Alzheimer's Biomarkers](/biomarkers/alzheimers-biomarkers) — Overview of AD biomarker categories
• [CSF Biomarker Panels](/biomarkers/csf-biomarker-panels) — CSF biomarker testing
• [Amyloid PET Imaging](/biomarkers/amyloid-pet-imaging) — Amyloid plaque imaging
• [ATN Classification](/biomarkers/atn-biomarker-classification-ad) — Biomarker-based disease staging

Competitive Landscape

Add-on Therapy Competition

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 |

Broader AD Therapeutic Competition

The AD therapeutic landscape is rapidly evolving:

Disease-Modifying Therapies (Approved):

• Lecanemab (Leqembi) — Anti-amyloid antibody
• Donanemab (Kisunla) — Anti-amyloid antibody

• Donepezil, Rivastigmine, Galantamine — AChEIs
• Memantine — NMDA antagonist

• Anti-tau antibodies (E2814, Bepranemab)
• BACE inhibitors (various)
• Neuroprotective agents (various)

Positioning of EX039

EX039's positioning depends on several factors:

Trial Site Network

Taiwan-Based Development

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

• Dr. Ching-Kuan Liu at Kaohsiung Medical University
• Established AD research program in Taiwan

Global Development Implications

If successful, subsequent trials would likely expand geographically:

Regulatory Pathway

Taiwan Regulatory Context

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

Future Global Regulatory Strategy

Successful Phase 2 results would support:

Post-Approval Requirements

If approved, standard post-marketing obligations would include:

• Pharmacovigilance monitoring
• Safety updates to regulatory agencies
• Potential confirmatory trials
• Quality control for manufacturing

Patient Perspectives

Treatment Burden

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

• Potential cognitive stabilization or improvement
• Maintain independence longer
• Reduced caregiver burden
• Delayed institutionalization

Access Considerations

If approved, access depends on:

Research Gaps and Future Directions

Unmet Needs in AD Treatment

This trial addresses several unmet needs:

Future Research Questions

Regardless of trial outcome, valuable insights will emerge:

Scientific Contribution

Regardless of regulatory outcome, this trial contributes to:

Trial Status (as of 2026-03)

• Overall Status: Recruiting
• Last Verified: February 2025
• Last Updated: February 26, 2025
• Primary Completion (Estimated): December 2026
• Study Completion (Estimated): February 2027

Relevance to NeuroWiki

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.

See Also

• [Excelsior Biopharma](/companies/excelsior) — Sponsor company page
• [Alzheimer's Disease](/diseases/alzheimers-disease) — Disease background
• [Clinical Trials Overview](/clinical-trials) — Index of clinical trials in NeuroWiki
• [AD Therapeutic Targets](/therapeutics/ad-therapeutic-pipeline) — Development pipeline
• [Acetylcholinesterase Inhibitors](/therapeutics/acetylcholinesterase-inhibitors) — Background on AChEIs
• [Cholinergic Signaling](/mechanisms/cholinergic-signaling-neurodegeneration) — Pathway details
• [Synaptic Plasticity in AD](/mechanisms/synaptic-plasticity-alzheimers) — Memory mechanisms

References