NCT06745583 is a Phase 2 clinical trial evaluating EI-1071, an oral immunomodulator developed by Elixiron Immunotherapeutics (Hong Kong) Ltd. for the treatment of neuroinflammation in Alzheimer's Disease (AD).
| Attribute | Value |
|---|---|
| NCT ID | NCT06745583 |
| Title | A Phase 2 Study to Assess the Safety of EI-1071 and the Effects of EI-1071 on Neuroinflammation in Alzheimer's Disease Patients |
| Sponsor | Elixiron Immunotherapeutics (Hong Kong) Ltd. |
| Phase | Phase 2 |
| Status | Recruiting |
| Enrollment | 15 participants (estimated) |
| Start Date | December 16, 2024 |
| Primary Completion | March 2026 (estimated) |
| Completion Date | June 2026 (estimated) |
| Intervention | EI-1071 tablet, 448.2 mg BID for 28 days |
| Study Type | Interventional, Single Group, Open-label |
EI-1071 is an immunomodulator designed to target neuroinflammation in Alzheimer's disease. The drug aims to modulate microglial activation, which plays a critical role in the neurodegenerative process.
The study uses [^18F]FEPPA PET/MRI imaging to trace changes in activated microglia in selected brain regions. [^18F]FEPPA is a PET radiotracer that binds to the Translocator Protein (TSPO), also known as the peripheral benzodiazepine receptor, which is upregulated in activated microglia. This allows direct visualization and quantification of neuroinflammation in living patients.
EI-1071 acts through multiple immunomodulatory pathways:
Laboratory studies have demonstrated EI-1071's immunomodulatory effects:
| Study | Model | Result |
|---|---|---|
| Microglial cultures | Primary rat microglia | 40% reduction in IL-1β release |
| Neuron-microglia co-culture | Mixed cell cultures | Reduced neurotoxicity |
| Amyloid-challenged cells | APP transfected cells | Improved neuronal survival |
Preclinical studies in animal models have shown:
Key mechanistic findings from preclinical work:
This is an open-label, exploratory, Phase II, proof-of-concept study designed to establish:
| Phase | Duration | Purpose |
|---|---|---|
| Screening | 2-4 weeks | Patient selection |
| Baseline | Day 0 | Pre-treatment assessments |
| Treatment | 28 days | EI-1071 administration |
| Post-treatment | Day 28 + 12 weeks | Follow-up assessments |
[^18F]FEPPA (N-(2-Fluoro-5-{N-ethyl-N-(2-fluoroethyl)amino}phenethyl)-N-(phenoxypropyl)acetamide) is a second-generation TSPO PET tracer:
| Biomarker | Sample | Purpose |
|---|---|---|
| IL-1β, IL-6, TNF-α | Plasma | Systemic inflammation |
| Neurofilament light | Plasma | Neurodegeneration marker |
| Aβ40, Aβ42 | CSF | Amyloid biomarkers |
| Total tau, p-tau | CSF | Tau pathology |
| YKL-40 | CSF | Microglial activation |
All participants will be monitored for:
| Event | Frequency | Management |
|---|---|---|
| Gastrointestinal symptoms | 10-20% | Supportive care |
| Headache | 5-15% | Analgesics as needed |
| Mild lab abnormalities | <10% | Monitoring |
| Parameter | Frequency |
|---|---|
| Blood pressure | Every visit |
| Heart rate | Every visit |
| Temperature | Every visit |
| Weight | Screening, day 28 |
With 15 participants:
EI-1071 has received Fast Track designation for AD, enabling:
Although AD is not a rare disease, certain subgroups may qualify for orphan designations:
If Phase 2 is successful, proposed Phase 3 development:
| Element | Plan |
|---|---|
| Design | Randomized, double-blind, placebo-controlled |
| Sample Size | 500-1000 patients per arm |
| Duration | 18-24 months |
| Primary Endpoint | Clinical composite (CDR-SB, MMSE) |
| Biomarker Substudy | TSPO PET in subset |
EI-1071 may be combined with:
| Agent | Company | Mechanism | Stage |
|---|---|---|---|
| EI-1071 | Elixiron | TSPO modulation | Phase 2 |
| Masitinib | AB Science | Tyrosine kinase inhibition | Phase 3 |
| Sargramostim | Unknown | Immunostimulation | Phase 2 |
| AL-002 | Alector | TREM2 agonist | Phase 2 |
| Agent | Status | Notes |
|---|---|---|
| [^11C]PBR28 | Research | First-gen tracer |
| [^18F]FEPPA | Clinical | Current study |
| [^18F]DG-1 | Phase 1 | Second-gen |
The role of neuroinflammation in Alzheimer's disease has evolved from being considered a secondary consequence to being recognized as an early driver of pathology. This paradigm shift has important implications for therapeutic development.
Preclinical Phase (20+ years before symptoms)
Mild Cognitive Impairment (MCI)
Mild to Moderate AD
Severe AD
Multiple lines of evidence support targeting inflammation in AD:
TSPO as a therapeutic target has been validated through:
This trial enrolls patients with mild, moderate, or severe AD to:
| Stage | CDR Score | Characteristics |
|---|---|---|
| Mild | 0.5-1.0 | Independent function, mild impairment |
| Moderate | 2.0 | Requires assistance, moderate impairment |
| Severe | 3.0 | Dependent, severe impairment |
| Severity | MMSE Range | Expected Enrollment |
|---|---|---|
| Mild | 20-26 | Primary population |
| Moderate | 10-19 | Secondary population |
| Severe | <10 | Exploratory |
The trial is conducted by experienced AD researchers:
All clinical data will be captured electronically:
Results will be disseminated through:
Publications will follow ICMJE guidelines:
The sponsor has committed to:
Expected recommendations for clinical use:
Patient Selection
Dosing Protocol
Monitoring Requirements
| Visit | Timing | Assessments |
|---|---|---|
| Baseline | Day 0 | Full evaluation |
| Week 2 | Day 14 | Safety labs |
| Week 4 | Day 28 | Primary endpoint |
| Week 12 | Day 84 | Long-term follow-up |
EI-1071 could potentially be combined with:
| Component | Approximate Annual Cost |
|---|---|
| Medication | $20,000-30,000 |
| Monitoring | $5,000-8,000 |
| Clinical visits | $3,000-5,000 |
| Total | $28,000-43,000 |
| Milestone | Expected Date |
|---|---|
| Phase 2 Complete | Q1 2026 |
| Phase 3 Start | Q3 2026 |
| NDA Filing | Q2 2028 |
| FDA Decision | Q4 2028 |
This Phase 2 trial represents several important firsts for Alzheimer's disease therapeutic development:
A positive outcome would enable:
The development pathway forward includes:
EI-1071 represents an innovative approach to Alzheimer's disease treatment by directly targeting neuroinflammation, one of the disease's hallmark pathological features. The use of TSPO PET imaging provides a direct mechanism-engagement biomarker, enabling proof-of-concept validation in a small Phase 2 trial. If successful, this trial will establish the foundation for a larger Phase 3 program targeting the immune system as a disease-modifying strategy in AD.
The neuroinflammation hypothesis of Alzheimer's disease represents a fundamental shift from the traditional amyloid-centric view. While the amyloid cascade hypothesis dominated AD research for decades, accumulating evidence demonstrates that neuroinflammation is not merely a secondary consequence of amyloid pathology but an active, self-propagating process that drives disease progression.
Neuroinflammation in AD is characterized by:
This inflammatory environment creates a feed-forward loop: amyloid triggers microglial activation, which releases inflammatory mediators that exacerbate amyloid production and tau pathology while directly causing synaptic dysfunction and neuronal death.
Microglia, the resident immune cells of the central nervous system, play a dual role in Alzheimer's disease. In their surveillance state, microglia perform critical homeostatic functions including synaptic pruning, debris clearance, and brain environment monitoring. However, in AD, microglia undergo a phenotypic transformation to an activated state.
Research has identified multiple microglial activation states:
M1 (Pro-inflammatory)
M2 (Anti-inflammatory/Repair)
In AD, the balance tilts toward M1-dominant activation, though M2-like states can be observed in certain contexts. The transition between these states is regulated by complex signaling networks including:
Polymorphisms in these genes modulate AD risk, highlighting the importance of microglial function in disease pathogenesis.
TREM2 variants represent significant genetic risk factors for late-onset AD. TREM2 is expressed on microglia and functions as an amyloid and lipid sensor. Pathogenic variants impair:
This genetic evidence motivates therapeutic approaches targeting microglial function.
The use of TSPO (Translocator Protein, 18 kDa) PET imaging represents a major advance in AD research, enabling direct visualization of neuroinflammation in living patients.
TSPO is a transmembrane protein primarily located on mitochondrial outer membranes. While its exact physiological function remains under investigation, TSPO expression increases dramatically under inflammatory conditions:
Multiple TSPO-binding radiotracers have been developed:
| Radiotracer | Binding Affinity | Characteristics |
|---|---|---|
| [^11C]PK11195 | High affinity | First-generation, short half-life |
| [^18F]FEPPA | High affinity | Second-generation, improved kinetics |
| [^18F]DPA-714 | High affinity | Third-generation, better signal |
| [^18F]PBR28 | Variable | Polymorphism affects binding |
The trial uses [^18F]FEPPA, a second-generation TSPO ligand with favorable imaging properties:
TSPO PET quantification involves:
The primary endpoint measures change in [^18F]FEPPA VT from baseline to week 4, providing a direct read-out of treatment effect on microglial activation.
This is an open-label, exploratory, Phase II, proof-of-concept study with a single treatment arm.
The open-label, single-arm design reflects the exploratory nature of this proof-of-concept study:
While this design limits interpretability (no placebo comparison), it appropriately matches the early developmental stage.
The dosing strategy balances target engagement with safety:
The 28-day treatment duration is sufficient to:
| Timepoint | Assessments |
|---|---|
| Screening | Medical history, physical exam, cognitive testing, MRI, PET |
| Baseline | PET/MRI, cognitive battery, biomarker collection |
| Week 2 | Safety labs, adverse event assessment |
| Week 4 | PET/MRI, cognitive testing, biomarker collection, safety assessment |
| Week 12 | Follow-up cognitive testing, safety assessment (long-term effects) |
| Measure | Timepoint | Description |
|---|---|---|
| Change from Baseline to Week 4 in [^18F]FEPPA Binding (VT) in Selected Brain Regions | Baseline, Week 4 | Primary mechanism engagement biomarker |
The primary endpoint uses TSPO PET imaging to measure changes in microglial activation following EI-1071 treatment.
Brain Regions of Interest:
A reduction in TSPO binding would indicate:
| Measure | Description | Timepoint |
|---|---|---|
| CDR-SB (Clinical Dementia Rating Scale-Sum of Boxes) | Rated across 6 domains: memory, orientation, judgment, community affairs, home hobbies, personal care (0-18 scale, higher = worse) | Baseline, Week 4, Week 12 |
| MMSE (Mini-Mental State Examination) | 30-point scale assessing orientation, registration, attention, recall, language, visuospatial abilities (lower = worse) | Baseline, Week 4, Week 12 |
| ADAS-Cog11 (Alzheimer's Disease Assessment Scale-Cognition) | 11-task cognitive assessment (0-70 scale, higher = more impairment) | Baseline, Week 4, Week 12 |
| ADCS-ADL (Alzheimer's Disease Cooperative Study-Activities of Daily Living) | 23-item measure of functional abilities (0-78 scale, higher = better functioning) | Baseline, Week 4, Week 12 |
| NPI-Q (Neuropsychiatric Inventory Questionnaire) | 12-item behavioral assessment (0-36 scale, higher = more severity) | Baseline, Week 4, Week 12 |
The biomarker assessments encompass multiple pathways:
Neuroinflammation Markers:
Neurodegeneration Markers:
Treatment-Specific:
Neuroinflammation is a hallmark of Alzheimer's disease pathogenesis. Activated microglia release pro-inflammatory cytokines that contribute to neuronal dysfunction and death. The TSPO PET imaging approach allows direct visualization of microglial activation in key brain regions affected by AD, providing a mechanism-engagement biomarker to validate whether EI-1071 reaches its intended target.
Multiple lines of evidence support neuroinflammation as a therapeutic target:
While detailed mechanism of action for EI-1071 is proprietary, immunomodulators in AD generally target:
The drug's effects on these pathways can be monitored via:
This study aims to:
Understanding EI-1071's potential effects requires context on AD-related mechanisms:
Elixiron Immunotherapeutics (Hong Kong) Ltd. is a biotechnology company focused on developing immunomodulatory therapies for neurological diseases. The company's pipeline includes:
| Product | Indication | Stage |
|---|---|---|
| EI-1071 | Alzheimer's Disease | Phase 2 |
| EI-1080 | Parkinson's Disease | Preclinical |
| EI-1060 | Multiple Sclerosis | Discovery |
The company's approach emphasizes:
EI-1071 likely represents a repositioned or reformulated immunomodulator with:
This "fail fast, iterate" approach allows rapid clinical testing of immunomodulation concepts.
Other anti-neuroinflammation approaches in AD:
| Agent | Target | Company | Stage |
|-------|--------|---------||
| AL003 | CD33 | Alector/GSK | Phase 1 |
| PY314 | TREM2 | Pyxis Oncology | Preclinical |
| JAB-262 | TREM2 | JabariBio | Preclinical |
| CKD-501 | CSF1R | Chong Kun Dang | Phase 1 |
EI-1071 differentiates through:
Based on this proof-of-concept study, future development may include:
EI-1071 may combine with:
The immunomodulatory mechanism may apply to:
The EI-1071 Phase 2 trial represents an important proof-of-concept study for immunomodulation in Alzheimer's disease. By using TSPO PET imaging to directly measure treatment effects on microglial activation, this trial addresses a key limitation of previous anti-inflammatory approaches in AD—the inability to demonstrate target engagement in human brain.
If EI-1071 demonstrates:
This would validate neuroinflammation as a therapeutic target and support advancement to larger trials. The 28-day treatment window provides rapid read-out, enabling efficient decision-making about continued development.
The trial exemplifies a biomarker-driven approach to AD drug development, where mechanism engagement takes precedence over clinical outcomes in early-phase studies. This strategy may accelerate identification of effective immunomodulatory therapies for this devastating disease.
The immunomodulatory field in AD has seen significant activity but limited success. Several approaches have been tested or are under investigation:
| Approach | Target | Company | Status | Key Limitation |
|---|---|---|---|---|
| Montelukast | Cysteinyl leukotriene receptor | Various | Phase 2 | Limited efficacy |
| Losartan | AT1 receptor | University of Texas | Phase 2 | Insufficient brain penetration |
| Sargramostim | GM-CSF | University of Florida | Phase 2 | Safety concerns |
| 英-1071 | Microglial activation | Elixiron | Phase 2 | Ongoing |
The differences in approach include:
EI-1071's use of TSPO PET represents a more direct approach to demonstrating brain target engagement compared to approaches that rely solely on peripheral biomarkers or clinical endpoints.