18F-OP-801 Ashvattha Neuroinflammation PET Imaging Trial

Overview

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18F-OP-801 (18F Hydroxyl Dendrimer) is an experimental PET (Positron Emission Tomography) imaging agent developed by Ashvattha Therapeutics for detecting neuroinflammation in the brain. This Phase 1/2 clinical trial evaluates the safety, biodistribution, and imaging characteristics of this novel radiotracer in participants with Alzheimer’s disease, Parkinson’s disease, Amyotrophic Lateral Sclerosis (ALS), Multiple Sclerosis (MS), and healthy volunteers

The key innovation of 18F-OP-801 is its selective uptake by activated microglia while sparing resting microglia, offering the potential to detect neuroinflammation at lower levels and earlier stages of neurodegenerative diseases. This represents a significant advancement over existing PET tracers for neuroinflammation, which generally cannot differentiate between microglial activation states

Trial Details

Sponsors and Collaborators

• Lead Sponsor: Ashvattha Therapeutics, Inc.

• Collaborators: UCSF, Stanford University, Mayo Clinic

Study Design

• Allocation: Non-randomized (imaging study)

• Intervention Model: Single group

• Masking: None (open-label imaging)

• Primary Purpose: Diagnostic (imaging biomarker)

Mechanism of Action

Neuroinflammation in Neurodegenerative Diseases

Neuroinflammation is a hallmark of multiple neurodegenerative diseases, driven primarily by activated microglia—the brain’s resident immune cells. In Alzheimer’s disease, Parkinson’s disease, ALS, and MS, neuroinflammation contributes to disease progression through:

• Cytokine release: Pro-inflammatory cytokines (IL-1β, TNF-α, IL-6) that damage neurons

• Oxidative stress: Reactive oxygen species that cause lipid peroxidation and DNA damage

• Excitotoxicity: Dysregulated glutamate signaling leading to calcium overload

• Protein aggregation: Enhanced aggregation of amyloid-beta, alpha-synuclein, and tau

• Synaptic dysfunction: Loss of synaptic connections and neuronal communication

18F-OP-801: Activated Microglia Targeting

18F-OP-801 is a hydroxyl dendrimer-based PET radiotracer designed to selectively bind to activated microglia and macrophages in the brain. The molecular targeting mechanism involves:

1. Dendrimer Structure: The hydroxyl-terminated dendrimer provides a highly branched scaffold that can be radiolabeled with fluorine-18

2. Microglial Specificity: The tracer is selectively taken up only by activated (not resting) microglia, offering superior specificity compared to existing TSPO-based tracers

3. Blood-Brain Barrier Penetration: Designed to cross the blood-brain barrier and reach target regions

4. Quantitative PET Signal: Provides quantitative biological information in vivo at very low radiotracer doses without pharmacological effects

Advantages Over Existing Neuroinflammation Tracers

Primary Outcomes

Safety and Tolerability

Primary Endpoint: Number of participants with treatment-emergent adverse events (TEAEs) from Day 1 to Day 15/18-29.

Safety assessment includes:

• Physical examinations

• Vital signs monitoring

• Laboratory tests (hematology, chemistry)

• ECG monitoring

• Adverse event recording

The trial monitors for any acute reactions to the radiotracer administration, as 18F-OP-801 is administered intravenously at very low mass doses typical of PET radiotracers.

Secondary Outcomes

Biodistribution

1. Whole body PET/MRI or PET/CT scans - Assessment of tracer distribution across organ systems

2. Clearance measurement - Pharmacokinetics of 18F-OP-801 elimination from the body

3. Time-activity curves - Quantitative analysis of tracer uptake over time

Neuroinflammation Imaging

4. Ability to detect neuroinflammation - PET signal intensity in regions of known neuroinflammation in:

   • Alzheimer’s disease participants

   • Parkinson’s disease participants

   • ALS participants

   • MS participants

   • Healthy volunteers (control)

5. Test/retest imaging repeatability - Reliability of the imaging signal on repeated administration

Biomarker Correlations

6. Plasma NfL correlation - Relationship between plasma neurofilament light chain (NfL) levels and 18F-OP-801 uptake in brain regions

7. Clinical scale correlations - Correlation between PET signal and clinical measures:

   • ALS: ALSFRS-R (Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised) / PUMNS (Progressive Upper Motor Neuron Scale)

   • Alzheimer’s: MMSE (Mini-Mental State Examination)

   • MS: EDSS (Expanded Disability Status Scale)

   • Parkinson’s: SE-ADL (Schwab and England Activities of Daily Living)

Scientific Rationale

Why Detect Neuroinflammation?

Neuroinflammation is both a consequence and a driver of neurodegeneration. In Alzheimer’s disease, microglial activation correlates with amyloid deposition and precedes clinical symptoms. In Parkinson’s disease, neuroinflammation accompanies alpha-synuclein pathology. In ALS, microglial activation is prominent throughout disease progression.

The ability to visualize and quantify neuroinflammation in vivo provides:

1. Diagnostic value: Earlier and more accurate diagnosis

2. Progression monitoring: Tracking disease advancement

3. Therapeutic target engagement: Measuring drug effects on inflammation

4. Patient stratification: Identifying patients with high neuroinflammation

5. Clinical trial enrichment: Selecting patients likely to respond to anti-inflammatory therapies

The Need for Better Tracers

Current neuroinflammation PET tracers target the 18 kDa translocator protein (TSPO), which is expressed in both activated and resting microglia, as well as in other cell types. This limitation leads to:

• Lower signal-to-noise ratios

• Inability to detect early/lower-level inflammation

• Variable binding due to TSPO polymorphisms

• Poor specificity for disease-specific neuroinflammation

18F-OP-801 addresses these limitations by targeting a more specific marker of activated microglia, potentially enabling earlier detection and more accurate quantification of neuroinflammation.

Clinical Sites

UCSF (University of California, San Francisco)

• Leading neuroscience research center

• Active neuroimaging program for neurodegenerative diseases

• Experienced in PET imaging clinical trials

Stanford University (Stanford, CA)

• Center for neurodegenerative disease research

• Advanced PET/MRI imaging capabilities

• Collaborative neuroscience programs

Mayo Clinic Jacksonville (Jacksonville, FL)

• Comprehensive neurodegenerative disease program

• Clinical trial expertise

• PET imaging infrastructure

Future Directions

Therapeutic Development Implications

The development of 18F-OP-801 as a neuroinflammation biomarker enables:

1. Anti-inflammatory therapy development - Clinical trials can now measure target engagement of anti-inflammatory drugs

2. Patient selection - Identifying patients with elevated neuroinflammation for targeted therapies

3. Combination therapy monitoring - Assessing effects of disease-modifying therapies on neuroinflammation

Expansion Potential

Successful development of 18F-OP-801 could support:

• Phase 3 registration trials

• Companion diagnostic development

• Expansion to additional neurodegenerative indications

• Use in clinical practice for diagnosis and monitoring

Related Pages

• Neuroinflammation Overview

• Microglia in Neurodegeneration

• Alzheimer’s Disease

• Parkinson’s Disease

• Amyotrophic Lateral Sclerosis (ALS)

• Multiple Sclerosis

• PET Imaging in Neurodegeneration

• Neuroinflammation Biomarkers

• Ashvattha Therapeutics