AMDX-2011P Retinal Amyloid Tracer in Alzheimer's Disease

Overview

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AMDX-2011P is a novel retinal amyloid tracer being developed by Amydis Inc. for the non-invasive detection of amyloid deposits in the retina of Alzheimer’s disease patients. This Phase 2 clinical trial evaluates the safety, tolerability, pharmacokinetics, and biological activity of AMDX-2011P as a potential diagnostic tool for Alzheimer’s disease.

Trial Details

Study Objectives

Primary Objective

• Evaluate the safety and tolerability of AMDX-2011P in participants with Alzheimer’s disease

• Assess the incidence and severity of adverse events over 8 days following administration

Secondary Objectives

• Characterize plasma pharmacokinetics (Cmax, AUC over 2 hours)

• Evaluate biological activity of AMDX-2011P as a retinal tracer

• Assess detection of retinal amyloid deposits at 8 days post-administration

Eligibility Criteria

Key Inclusion Criteria

1. Confirmed diagnosis of Alzheimer’s disease

2. Positive amyloid beta PET scan indicating presence of amyloid pathology

3. Willingness to undergo APOE genotyping

4. Ability to fixate and complete retinal imaging procedures

Key Exclusion Criteria

1. Glaucoma or suspected glaucoma

2. Age-related macular degeneration (AMD)

3. Clinically significant laboratory abnormalities

4. Prolonged QTcF interval

5. Cardiac arrhythmia or significant ECG abnormalities

Study Design

This is a Phase 2, open-label, single-dose study conducted at a single site:

• Site: Associated Retina Consultants, Phoenix, Arizona, USA

• Contact: Matthew Lehman (info@amydis.com, 859-905-0402)

• Duration: 8-day observation period per participant

Mechanism of Action

AMDX-2011P is designed as a retinal amyloid tracer that:

1. Binds to retinal amyloid deposits — The compound selectively binds to amyloid-beta aggregates that accumulate in the retina of AD patients

2. Enables non-invasive imaging — Unlike PET imaging which requires brain scanning, retinal imaging is less invasive and more accessible

3. Provides amyloid detection — The tracer allows visualization and quantification of amyloid burden in the retina

Rationale for Retinal Amyloid Imaging

The retina offers several advantages for Alzheimer’s disease biomarker detection:

1. Direct visualization — The retina is an accessible part of the CNS that can be imaged non-invasively

2. Correlation with brain pathology — Retinal amyloid deposits correlate with cerebral amyloid burden

3. Earlier detection — Retinal changes may occur earlier than detectable brain changes

4. Repeated monitoring — Allows for easy repeated assessments over time

Significance for Alzheimer’s Disease

This trial represents an important step in Alzheimer’s disease diagnostics because:

1. Non-invasive alternative — Provides an alternative to PET imaging which is expensive and involves radiation exposure

2. Accessibility — Retinal imaging could be performed in outpatient settings

3. Trial enrichment — Could help identify patients with amyloid pathology for clinical trials

4. Disease monitoring — Potential for tracking disease progression and treatment response

Amyloid Biology Context

Amyloid-beta (Aβ) deposition is a hallmark pathological feature of Alzheimer’s disease:

• Amyloid Beta Peptide — The key protein fragment that aggregates into plaques

• Amyloid Cascade Hypothesis — The leading theoretical framework for AD pathogenesis

Related Pages

• Retinal Imaging in Neurodegeneration

• Optical Coherence Tomography in Neurodegeneration

• Amyloid PET Imaging — Current standard for amyloid detection

• APOE Genotyping for Neurodegenerative Disease Risk Assessment

• CSF Biomarkers in Neurodegeneration

• Plasma Biomarkers in Neurodegeneration

• P-tau 217 — Other emerging AD biomarker

• Clinical Trials Overview — Index of all clinical trials

• Alzheimer’s Disease

• Amydis Inc.

Amyydis Inc. - Company Background

Company Overview

Amydis Inc. is a privately held biotechnology company founded in 2014 with a focus on developing non-invasive diagnostics for neurodegenerative diseases. The company’s lead program targets retinal amyloid detection as a biomarker for Alzheimer’s disease.

Technology Platform

Retinal Amyloid Detection:

• Proprietary fluorescent compounds that bind to amyloid deposits

• Designed for visualization via standard retinal imaging devices

• Non-invasive alternative to PET imaging

• Potentially lower cost than brain PET

Pipeline Programs:

• AMDX-2011P: Lead candidate for Alzheimer’s disease (Phase 2)

• Early-stage programs for other neurodegenerative conditions

• Potential companion diagnostics for therapeutic development

Funding and Partnerships

• Raised Series A funding in 2016

• Received NIH grants for Alzheimer’s diagnostic development

• Strategic partnership discussions ongoing

• Investigator-initiated trials at academic centers

Amyloid Biology and Retinal Deposition

Amyloid-Beta in Alzheimer’s Disease Pathogenesis

The amyloid-beta peptide is central to Alzheimer’s disease pathology:

APP Processing:

• Amyloid precursor protein (APP) is a transmembrane protein

• Beta-secretase (BACE1) cleaves APP to generate C99 fragment

• Gamma-secretase cleaves C99 to release amyloid-beta peptides

• Aβ40 and Aβ42 are most common species

Aβ Aggregation:

• Aβ42 is more aggregation-prone than Aβ40

• Forms soluble oligomers, then fibrils, then plaques

• Oligomers are considered most toxic

• Plaques are pathological hallmark but may be protective

Amyloid Cascade Hypothesis:

• Aβ accumulation is the initiating event

• Leads to tau pathology, neurodegeneration, cognitive decline

• Supported by genetic evidence (APP, PSEN1, PSEN2 mutations)

• Therapeutic targeting of Aβ has had mixed results

Retinal Amyloid Deposition

Evidence for Retinal Aβ:

• Retinal amyloid deposits documented in AD patients

• Correlate with brain amyloid burden on PET

• May precede cognitive symptoms

• Detectable via specialized imaging

Advantages of Retinal Detection:

• Direct access to CNS tissue (retina is brain-derived)

• Non-invasive imaging possible

• High resolution imaging available

• May allow earlier detection than brain imaging

Challenges:

• Quantification methods still developing

• Correlation with brain amyloid not perfect

• Standardization of imaging protocols needed

• Sensitivity compared to PET still being established

Study Design and Methodology

Phase 2 Study Design

NCT06514001 Details:

• Single-center, open-label study

• Single ascending dose design

• 25 participants with confirmed AD

• 8-day observation period

Study Phases:

1. Screening (Day -28 to -1):

   • Confirm AD diagnosis

   • Verify positive amyloid PET

   • Complete baseline assessments

   • Obtain informed consent

   • Safety laboratory evaluation

   • APOE genotyping

2. Baseline (Day -7):

   • Complete physical examination

   • Baseline retinal imaging (pre-dose)

   • Vital signs and ECG

   • Confirm eligibility

3. Dosing (Day 1):

   • Administer AMDX-2011P (100 mg IV)

   • Monitor vital signs

   • Collect PK samples

   • Observe for acute reactions

4. Observation (Days 1-8):

   • Daily vital signs

   • Adverse event monitoring

   • Retinal imaging at Day 8

   • PK sampling schedule

5. Follow-up (Day 14, Day 28):

   • Safety assessment

   • Final study visit

Imaging Protocol

Retinal Imaging Methods:

• Fundus photography

• Optical coherence tomography (OCT)

• Confocal scanning laser ophthalmoscopy (cSLO)

• Adaptive optics (research settings)

Imaging Timepoints:

• Pre-dose baseline

• Day 8 post-dose (primary endpoint)

• Safety follow-up imaging

Image Analysis:

• Semi-quantitative amyloid detection

• Comparison to baseline

• Central reading by qualified ophthalmologist

Pharmacokinetic Sampling

PK Parameters to Evaluate:

• Cmax (maximum concentration)

• AUC (area under curve)

• Tmax (time to maximum)

• Half-life

• Clearance

Sample Collection:

• Blood samples at multiple timepoints

• Plasma separation within 30 minutes

• Storage at -80°C

• Bioanalysis by validated LC-MS/MS

Safety and Tolerability Assessment

Safety Endpoints

Primary Safety Variables:

• Incidence of adverse events (AEs)

• Serious adverse events (SAEs)

• Changes in vital signs

• Laboratory abnormalities

• ECG changes

• Ocular examination findings

Adverse Event Classification:

• Severity (mild, moderate, severe)

• Relationship to study drug (unrelated, possibly related, probably related, definitely related)

• Expected vs. unexpected

• Serious vs. non-serious

Expected Adverse Events

Based on Compound Class:

• Injection site reactions (mild)

• Headache

• Nausea

• Transient visual changes

• Hypersensitivity reactions (rare)

Monitoring Plan:

• Continuous vital sign monitoring

• Pre- and post-dose ophthalmologic exams

• Daily safety laboratory evaluation

• Full physical examination at end of study

Safety Stopping Rules

Criteria for Study Interruption:

• More than 2 participants with drug-related severe AEs

• Any drug-related SAE

• Clinically significant laboratory abnormality

• Ocular safety signals

Biological Activity and Validation

Retinal Amyloid Detection

Detection Method:

• Fluorescent signal from bound compound

• Quantification of signal intensity

• Comparison to established thresholds

• Correlation with PET amyloid burden

Expected Findings:

• Detectable signal in amyloid-positive retinas

• Minimal signal in controls

• Dose-response relationship

• Correlation with PET SUVR

Amyloid PET Correlation

PET Imaging Standard:

• Standardized Uptake Value Ratio (SUVR)

• Centiloid scale for standardization

• Posterior cingulate/precuneus region

• Threshold: Centiloid >20 considered positive

Correlation Analysis:

• Compare retinal signal to PET SUVR

• Evaluate sensitivity and specificity

• Assess predictive value

• Determine optimal detection threshold

Biomarker Validation

Biomarker Qualification:

• Analytical validation of detection method

• Clinical validation in target population

• Correlation with clinical endpoints

• Establishment of reference ranges

Diagnostic Significance

Alzheimer’s Disease Diagnostics Landscape

Current Diagnostic Challenges:

• Definitive diagnosis requires brain autopsy

• Clinical diagnosis has limited sensitivity/specificity

• Biomarkers improving but accessibility issues

• Need for early, accessible detection methods

Available Biomarker Tests:

• CSF Aβ42/tau ratio (invasive, specialized)

• Plasma Aβ and p-tau (emerging, accessible)

• Amyloid PET (expensive, radiation, limited access)

• FDG-PET for neurodegeneration

• Structural MRI for atrophy

Role of Retinal Imaging

Potential Advantages:

• Non-invasive (vs. LP for CSF)

• No radiation (vs. PET)

• Lower cost potential

• Accessible in ophthalmology settings

• Repeatable for monitoring

Limitations:

• Less established than PET

• Technical challenges in quantification

• Not yet validated for clinical use

• Requires specialized expertise

Clinical Utility

Potential Applications:

1. Screening: Identify individuals needing confirmatory testing

2. Diagnosis support: Add evidence for clinical diagnosis

3. Monitoring: Track amyloid burden over time

4. Therapeutic monitoring: Assess treatment response

5. Research enrichment: Identify amyloid-positive for trials

Implementation Considerations:

• Required imaging expertise

• Equipment availability

• Training for interpretation

• Standardized protocols

• Quality assurance

Future Development Plans

Phase 3 Registration Trial

Design Considerations:

• Larger sample size (hundreds to thousands)

• Multi-center international study

• Confirm sensitivity and specificity

• Compare to standard of care

• Regulatory submissions

Endpoints:

• Diagnostic accuracy (sensitivity, specificity)

• Positive/negative predictive values

• Inter-reader reliability

• Safety in broader population

Companion Diagnostic Potential

Therapeutic Development Integration:

• Patient selection for anti-amyloid trials

• Treatment response monitoring

• Safety monitoring for amyloid-related effects

• Combination with therapeutic candidates

Pharmaceutical Partnerships:

• CRO partnerships for large-scale studies

• Pharma collaboration for trial enrollment

• Diagnostic-therapeutic co-development

• Regulatory strategy alignment

Broader Applications

Other Neurodegenerative Diseases:

• Parkinson’s disease (alpha-synuclein in retina)

• Dementia with Lewy bodies

• Vascular dementia

• Frontotemporal dementia

• Amyotrophic lateral sclerosis

Screening Applications:

• At-risk population screening

• Population-based testing

• Primary care integration

• Teleophthalmology potential

Regulatory Considerations

FDA Pathway

Diagnostic Device Classification:

• Class II medical device (if cleared)

• Requires 510(k) or De Novo submission

• Predicate device needed (or novel pathway)

• Clinical performance data required

Development Pathway:

• Breakthrough Device designation (potential)

• Parallel review with FDA and CMS

• Collaboration with professional societies

• Coverage determination discussions

Reimbursement Strategy

Medicare Coverage:

• LCD (Local Coverage Determination) process

• LCDD (Laboratory) vs. diagnostic imaging

• Evidence development pathway

• Clinical utility demonstration needed

Private Payers:

• Medical necessity documentation

• CPT code development

• Reasonable and customary rates

• Prior authorization processes

Competitive Analysis

Other Retinal Diagnostics

Comparison to PET

Advantages over Amyloid PET:

• Lower cost (~100 vs. ~3000)

• No radiation exposure

• Faster (minutes vs. hours)

• More accessible

• Repeatable

Disadvantages vs. Amyloid PET:

• Less established

• Limited validation data

• May have lower sensitivity

• Technical expertise required

Molecular Imaging Mechanism

Fluorescence Detection Technology

AMDX-2011P utilizesfluorescence imaging to detect retinal amyloid deposits following intravenous administration:

Fluorescence Properties:

• Excitation wavelength: Optimized for retinal imaging devices

• Emission wavelength: Near-infrared for enhanced tissue penetration

• Quantum yield: High brightness for sensitive detection

• Photostability: Stable signal during imaging acquisition

Imaging Acquisition:

1. Baseline fundus photography prior to tracer administration

2. Day 8 post-administration imaging session

3. Semi-quantitative fluorescence analysis

4. Comparison with established retinal imaging biomarkers

Amyloid Binding Kinetics

The binding characteristics of AMDX-2011P determine detection sensitivity:

Association Kinetics:

• Rapid binding to amyloid aggregates

• High affinity (nanomolar Kd range)

• Slow off-rate for stable signal

• Preference for oligomeric and fibrillar species

Selectivity Profile:

• High selectivity for Aβ aggregates over monomers

• Minimal binding to other retinal proteins

• No significant lipofuscin interaction

• Preserved specificity in degenerating retina

Correlation with Brain Amyloid

The retinal amyloid burden correlates with cerebral pathology:

Cross-Sectional Correlation:

• Retinal Aβ correlates with PET amyloid burden

• Correlations strongest in mild-moderate disease stages

• Retinal imaging may reflect global brain amyloid load

• Regional specificity being investigated

Temporal Relationship:

• Retinal changes may precede brain changes in some cases

• Parallel disease progression in retina and brain

• Potential for earlier detection via retina

Clinical Validation Pathway

Regulatory Considerations

The development pathway addresses regulatory requirements:

Diagnostic Device Classification:

• Combination drug-device product

• Requires both drug and device clearance

• Companion diagnostic framework

• Biomarker validation requirements

Clinical Utility Requirements:

• Demonstration of clinical impact

• Integration with standard of care

• Reimbursement pathway

• Clinical decision support utility

Comparison with Other Retinal Approaches

Market Potential

Target Population:

• 6 million AD patients in US

• 55 million globally

• Early detection priority population

• Clinical trial enrichment

Competitive Advantages:

• Non-invasive detection alternative

• Reduced healthcare costs

• Population-wide screening potential

• Primary care implementation

Implementation Considerations

Healthcare System Integration:

• Ophthalmology practice settings

• Neurology referral pathways

• Primary care screening programs

• Clinical trial sites

Cost-Effectiveness:

• Reduced compared to PET imaging

• Population screening feasibility

• Early intervention enablement

• Care pathway optimization

Technical Specifications

Formulation Details

AMDX-2011P Formulation:

• Concentration: 100 mg single bolus

• Route: Intravenous injection

• Volume: 10 mL

• Vehicle: Sterile saline

Imaging System Requirements

Compatible Devices:

• Confocal scanning laser ophthalmoscopy (cSLO)

• Fundus camera with fluorescence capability

• Specialized retinal amyloid imaging systems

• Adaptive optics systems (research)

Image Analysis:

• Semi-quantitative scoring

• Quantitative fluorescence measurement

• Machine learning analysis

• Automated detection algorithms

Research Gaps and Future Directions

Unresolved Questions

Scientific Questions:

1. What is the exact composition of retinal amyloid?

2. How does retinal amyloid differ from brain amyloid?

3. What drives amyloid deposition in retina?

4. Can retinal amyloid be cleared therapeutically?

Clinical Questions:

1. Will retina-based detection replace PET?

2. How often should screening occur?

3. What is the prognostic value?

4. Can treatment response be monitored?

Planned Studies

Future Clinical Development:

Companion Diagnostic Development

Integration with Therapeutics:

• Anti-amyloid antibody combination

• Patient selection for trials

• Treatment response monitoring

• Treatment discontinuation decisions

Cross-Links

• Retinal Biomarkers for Alzheimer’s Disease

• Amyloid PET Imaging

• Retinal Imaging

• Optical Coherence Tomography

• Amyloid-Beta

• APOE Genotyping

• CSF Biomarkers

• Blood Biomarkers

• P-tau 217