CORT108297 Phase 2 (NCT04601038) - Stress Attenuation in AD

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CORT108297 Stress Attenuation AD NCT04601038

Overview

CORT-X (NCT04601038) is a Phase 2 clinical trial evaluating CORT108297, a selective glucocorticoid receptor antagonist, for stress attenuation in patients with mild cognitive impairment (MCI) due to [Alzheimer's disease](/diseases/alzheimers-disease) (AD) and cognitively normal individuals with AD risk factors. The trial is conducted by [Johns Hopkins University](https://www.jhu.edu/) and is currently recruiting[@nct04601038].

This trial represents a paradigm shift in AD therapeutic development by targeting the stress-neurodegeneration axis rather than the traditional amyloid or tau pathways. Given the well-established link between chronic stress, elevated cortisol, and cognitive decline, this approach offers a novel disease-modifying strategy that could complement existing treatments.

Background

The Stress-Neurodegeneration Connection

The relationship between chronic stress and neurodegenerative disease has been extensively documented over the past three decades. The landmark study by Lupien and colleagues demonstrated that elevated cortisol levels during aging predict hippocampal atrophy and memory deficits, establishing a causal link between glucocorticoid exposure and cognitive decline[@lupien1998].

Cortisol and Brain Structure

...

CORT108297 Stress Attenuation AD NCT04601038

Overview

Background

The Stress-Neurodegeneration Connection

Cortisol and Brain Structure

Hippocampal Vulnerability
The hippocampus is particularly vulnerable to glucocorticoid toxicity for several reasons:

High concentration of glucocorticoid receptors (GR)
Dense mineralocorticoid receptor (MR) expression
High metabolic activity making it susceptible to metabolic stress
Critical role in memory formation and consolidation

Mechanisms of Damage
Chronic glucocorticoid exposure leads to:

Dendritic atrophy in CA3 neurons
Reduced neurogenesis in the dentate gyrus
Impaired synaptic plasticity
Decreased brain-derived neurotrophic factor (BDNF)
Enhanced tau phosphorylation

Stress and Alzheimer's Disease Pathology

The cortisol-tau pathway describes how stress hormones promote Alzheimer's disease progression:

Glucocorticoid receptor activation → GR translocates to nucleus

Gene expression modulation → Alters kinase/phosphatase balance

Kinase activation → GSK-3β, CDK5 activity increases

Tau hyperphosphorylation → Pathological tau species form

Tau aggregation → Neurofibrillary tangle formation

Neuronal dysfunction → Memory impairment and atrophy

This pathway provides a mechanistic link between psychological stress and the core AD pathological cascade.

The Glucocorticoid Receptor System

The glucocorticoid receptor (GR) is a ligand-activated transcription factor that mediates the genomic effects of cortisol. Understanding its biology is essential for appreciating CORT108297's mechanism of action.

Receptor Types

| Receptor | Affinity | Distribution | Function |
|----------|----------|--------------|----------|
| Mineralocorticoid (MR) | High (corticosterone) | Hippocampus, amygdala | Stress response initiation |
| Glucocorticoid (GR) | Low (corticosterone) | Ubiquitous | Negative feedback, stress termination |

GR Signaling Pathways

Genomic (transactivation): GR dimerizes, translocates to nucleus, binds GRE → transcription of anti-inflammatory proteins

Genomic (transrepression): GR monomer interacts with NF-κB, AP-1 → inhibits pro-inflammatory genes

Non-genomic (membrane-associated): Rapid effects via second messenger systems

Non-genomic (cytoplasmic): GR-GR interactions affect signaling cascades

CORT108297: Pharmacology

CORT108297 is a selective glucocorticoid receptor antagonist designed to block the adverse effects of cortisol on the brain while preserving its essential functions.

Chemical Characteristics

Selective GR antagonist (minimal MR activity)
Blood-brain barrier penetration
Oral bioavailability
Suitable for chronic administration

Mechanism of Action

CORT108297 acts by:

Competitive binding: Occupies GR ligand-binding domain

Conformation change: Prevents GR activation by cortisol

Nuclear exclusion: GR-CORT108297 complex remains in cytoplasm

Gene expression normalization: Blocks glucocorticoid-induced transcription

Therapeutic Benefits

By antagonizing GR, CORT108297 may:

Reduce stress-induced tau phosphorylation
Protect hippocampal neurons from glucocorticoid toxicity
Improve memory and cognitive function
Slow disease progression

Trial Design and Methods

Study Overview

The CORT-X trial employs a rigorous randomized, double-blind, placebo-controlled design:

| Parameter | Value |
|-----------|-------|
| NCT Number | NCT04601038 |
| Official Title | Phase II Trial of CORT108297 to Attenuate the Effects of Acute Stress in the Allocortex (CORT-X) |
| Acronym | CORT-X |
| Phase | Phase 2 |
| Status | RECRUITING |
| Design | Randomized, parallel-group, double-blind, controlled |
| Sponsor | Johns Hopkins University |
| Duration | 2 weeks treatment |

Treatment Arms

| Arm | Type | Intervention | Dose |
|-----|------|--------------|------|
| CORT108297 | Active Comparator | 120mg selective glucocorticoid receptor antagonist | 2 tablets daily for 2 weeks |
| Placebo | Placebo Comparator | Matching placebo | 2 tablets daily for 2 weeks |

Patient Population

Inclusion Criteria

Age 55+ years
BMI 17-30 kg/m²
Post-menopausal females
Non-smoker
Study partner available (for participant support)
Native English speaker
Good general health

Cognitive Status (Either):

MCI due to AD: Meets clinical criteria for MCI with AD biomarkers

Cognitively normal with AD risk factors:

APOE ε4 carrier
Memory concerns
Family history of AD

Exclusion Criteria

Certain medical conditions (cardiovascular, hepatic, renal)
Specific medications (corticosteroids, psychoactive drugs)
Depression or bipolar disorder
Current stress-related disorders

Outcome Measures

Primary Outcomes

The trial uses cognitive assessments specifically sensitive to stress effects on memory systems:

| Assessment | Domain | Relevance |
|------------|--------|-----------|
| Pattern Separation Task | Memory discrimination | Hippocampal function |
| Hopkins Verbal Learning Test-Revised (HVLT-R) | Verbal memory | Allocortex integrity |
| Trail Making Test Part B | Executive function | Frontal connectivity |
| Digit Span Task (backwards) | Working memory | Attention systems |

Secondary Outcomes

Subject characteristics predicting response: Identify biomarkers or genetic factors associated with CORT108297 benefit

Stress response markers: Cortisol levels, heart rate variability

Safety and tolerability: Adverse events, vital signs

Study Procedures

| Visit | Timing | Assessments |
|-------|--------|-------------|
| Screening | -4 to -2 weeks | Medical history, cognitive testing, MRI eligibility |
| Baseline | Day 0 | Randomization, cognitive testing, stress challenge |
| Treatment | Days 1-14 | Daily dosing, symptom monitoring |
| End of Treatment | Day 14-15 | Cognitive testing, biomarker sampling |
| Follow-up | Day 28 | Safety assessment |

Stress Challenge Protocol

A unique feature of this trial is the acute stress challenge:

Participants undergo a standardized stress task (e.g., Trier Social Stress Test)
Cognitive performance is assessed before and after stress
This allows direct measurement of CORT108297's effects on stress-induced cognitive impairment

Scientific Rationale

Targeting the Stress-Neurodegeneration Axis

This trial addresses a critical gap in AD therapeutics by targeting a fundamental pathway not addressed by current treatments:

Novel Mechanism

Targets glucocorticoid signaling rather than amyloid or tau directly
Addresses upstream drivers of neurodegeneration
May provide synergistic effects with disease-modifying therapies

Disease Modification Potential

Protecting neurons from stress-induced damage
Reducing tau phosphorylation via glucocorticoid pathway
Preserving hippocampal structure and function

Preventive Approach

Including cognitively normal at-risk individuals
Early intervention before significant pathology accumulates
Potential for primary prevention in high-risk populations

Complementary Strategy

Could be combined with existing AD therapies (anti-amyloid, anti-tau)
Addresses non-AD-specific mechanisms
Applicable across disease stages

Preclinical Evidence

The development of CORT108297 for AD is supported by substantial preclinical data:

Animal Models

GR antagonists reduce tau phosphorylation in mouse models
Improved memory performance in stress-exposed animals
Reduced hippocampal atrophy with chronic treatment

Human Data

GR antagonists show cognitive benefits in Cushing's disease
Mifepristone (RU486) studies in psychotic depression demonstrate CNS activity
Pharmacokinetic data support BBB penetration

Glucocorticoids in AD: Clinical Evidence

Epidemiological and clinical studies support the stress-AD connection:

Elevated Cortisol in AD

AD patients show elevated morning cortisol levels
Cortisol levels correlate with disease severity
Hippocampal atrophy correlates with cortisol exposure

Stress as Risk Factor

Chronic stress increases AD risk
PTSD associated with increased AD incidence
Mid-life stress predicts later cognitive decline

Cortisol-Tau Relationship

Glucocorticoid administration increases tau phosphorylation
CSF cortisol correlates with tau levels
GR polymorphisms modify AD risk

Comparison to Other AD Trials

CORT108297 represents a unique approach in the AD therapeutic landscape:

| Approach | Target | Status | Mechanism |
|----------|--------|--------|-----------|
| CORT108297 | Glucocorticoid receptor | Phase 2 | Stress pathway modulation |
| Lecanemab | Amyloid-β | Approved | Amyloid clearance |
| Donanemab | Amyloid-β | Approved | Amyloid clearance |
| LY-3372689 | O-GlcNAcase | Completed | Tau O-GlcNAcylation |
| Davunetide | Microtubule stabilization | Failed | Neuroprotection |

Advantages of GR Antagonism

Non-amyloid/tau mechanism: Addresses alternative pathway

Disease-stage flexibility: Applicable across early to moderate AD

Preventive potential: Works in at-risk individuals

Repurposing potential: Originally developed for other indications

Challenges and Considerations

Short-term treatment: Only 2 weeks - may limit efficacy

Narrow window: Optimal dose needs refinement

Population selection: May benefit specific subgroups

Long-term effects: Unknown safety with chronic use

Mechanism Deep Dive

GR Signaling in the Brain

Understanding glucocorticoid receptor signaling is essential for appreciating CORT108297's potential benefits and limitations.

Genomic Mechanisms

Transactivation (GR-GRE)

GR dimer binds glucocorticoid response elements
Induces transcription of anti-inflammatory proteins
In the brain: Promotes neuroprotection, learning, memory

Transrepression (GR-NF-κB)

GR monomer interacts with NF-κB
Inhibits pro-inflammatory gene expression
In the brain: Reduces neuroinflammation

Negative Feedback

GR activation increases IκB expression
Inhibits NF-κB signaling
In the brain: Limits inflammation, protects neurons

Non-Genomic Mechanisms

Membrane Effects

GR located on neuronal membranes
Rapid signaling via second messengers
In the brain: Quick behavioral effects

Cytoplasmic Effects

GR complexes affect signaling kinases
Modulates MAPK, PI3K pathways
In the brain: Affects neuronal survival

CORT108297: Brain-Specific Effects

CORT108297's potential benefits in AD derive from blocking GR-mediated stress effects:

Tau Phosphorylation

GR activation increases GSK-3β activity
GSK-3β phosphorylates tau at multiple sites
CORT108297 blocks this cascade

Synaptic Plasticity

Chronic glucocorticoids reduce BDNF
Impairs LTP in the hippocampus
CORT108297 may preserve synaptic function

Neuronal Survival

Glucocorticoids promote apoptosis in high concentrations
Vulnerable hippocampal neurons
CORT108297 may protect against this toxicity

Neuroinflammation

GR activation promotes neuroinflammation
Microglial activation, cytokine release
CORT108297 may reduce inflammatory response

Potential Clinical Implications

If Positive

A positive result would:

Validate stress pathway targeting in AD
Support further development of GR antagonists
Establish combination therapy potential
Enable preventive interventions

If Negative

A negative result would:

Require examination of dose/duration
Suggest stress pathway less relevant in established AD
Redirect to earlier disease stages
Support alternative mechanisms

Broader Implications

For AD Treatment

Opens new therapeutic avenue
Complements existing approaches
Potential for precision medicine

For Neuroscience

Advances understanding of stress-neurodegeneration
Validates GR as therapeutic target
Informs biomarker development

Safety Considerations

Known Safety Profile

Based on other GR antagonists (e.g., mifepristone):

Common Adverse Effects

Fatigue (15-20%)
Headache (10-15%)
Nausea (5-10%)
Dizziness (5-10%)

Specific Considerations

Adrenal insufficiency: With prolonged use, monitor cortisol
Hypotension: May cause orthostatic changes
Drug interactions: CYP3A4 substrates, other steroids

Trial-Specific Monitoring

The 2-week treatment duration is designed to:

Provide efficacy signal
Minimize long-term risks
Establish safety profile

Future Directions

Potential Development Path

Phase 2b/3 trials: Longer treatment duration in larger populations

Combination studies: With anti-amyloid or anti-tau agents

Prevention trials: In cognitively normal at-risk individuals

Biomarker development: Cortisol, tau, neuroimaging endpoints

Patient Selection

Future trials may benefit from:

Elevated baseline cortisol levels
Stress exposure history
GR polymorphism genotyping
MRI evidence of hippocampal atrophy

Mechanism Optimization

Alternative approaches to GR modulation:

Selective GR modulators (SGRMs): Partial agonists with tissue specificity
GR-N-terminal inhibitors: Block transactivation while sparing transrepression
Non-steroidal GR ligands: Improved safety profile

Cross-References

[Cortisol-Tau Pathway](/mechanisms/cortisol-tau-pathway) — Mechanism linking stress hormones to tau pathology
[Glucocorticoid Signaling in Neurodegeneration](/mechanisms/glucocorticoid-signaling-neurodegeneration) — Overview of GR biology in brain
[MCI due to AD](/diseases/mci-due-to-alzheimers-disease) — Patient population
[Alzheimer's Disease](/diseases/alzheimers-disease) — Disease page
[Clinical Trials Dashboard](/clinical-trials/dashboard) — Hub page
[Stress and Neurodegeneration](/mechanisms/stress-neurodegeneration) — Related mechanism

Summary

The CORT-X trial represents an innovative approach to Alzheimer's disease treatment by targeting the stress-neurodegeneration axis through glucocorticoid receptor antagonism. This strategy addresses a fundamental pathway not covered by current therapies, potentially providing disease modification through a novel mechanism.

Key Points

Novel mechanism: CORT108297 targets glucocorticoid receptor, addressing stress-induced neurodegeneration

Unique design: Includes acute stress challenge to directly measure drug effects

Broad population: Includes both MCI due to AD and at-risk cognitively normal individuals

Short duration: 2-week treatment designed to establish proof-of-concept

Complementary approach: Could be combined with anti-amyloid and anti-tau therapies

The successful development of CORT108297 would represent a paradigm shift in AD therapeutics, validating stress pathway targeting and opening new avenues for disease modification.

Detailed Mechanistic Pathways

GR-Mediated Gene Regulation

The glucocorticoid receptor regulates gene expression through multiple mechanisms:

Transactivation Pathway

The classical GR signaling pathway involves:

Ligand binding: Cortisol diffuses across the BBB and binds cytoplasmic GR

Complex formation: GR-cortisol complex undergoes conformational change

Nuclear translocation: Complex translocates to nucleus

DNA binding: GR dimer binds glucocorticoid response elements (GREs)

Gene transcription: Anti-inflammatory genes are transcribed

Protein synthesis: Anti-inflammatory proteins are produced

Mermaid diagram (expand to render)

Transrepression Pathway

The transrepression mechanism provides anti-inflammatory effects without classic GRE binding:

GR monomer interacts directly with transcription factors

NF-kappaB inhibition: Prevents p65/p50 nuclear translocation

AP-1 inhibition: Blocks c-Fos/c-Jun activity

Reduced cytokine transcription: TNF-alpha, IL-1beta, IL-6 reduced

Anti-inflammatory outcome: Reduced neuroinflammation

Gene Targets

| Gene Category | Expression Change | Effect |
|--------------|-----------------|--------|
| IkappaBalpha | Increased | NF-kappaB inhibition |
| Annexin-1 | Increased | Anti-inflammatory |
| IL-10 | Increased | Anti-inflammatory cytokine |
| MMP-9 | Decreased | Reduced inflammation |
| COX-2 | Decreased | Reduced prostaglandins |

Preclinical Model Evidence

Rodent Models of Stress-Induced Neurodegeneration

Multiple preclinical models support GR antagonism in AD:

Chronic Corticosterone Administration Model

| Parameter | Effect | AD Relevance |
|-----------|--------|-------------|
| Hippocampal volume | Reduced | Atrophy modeling |
| Memory performance | Impaired | Cognitive deficit |
| Tau phosphorylation | Increased | NFT precursor |
| Synaptic markers | Reduced | Synaptopathy |
| Neurogenesis | Decreased | Adult neurogenesis loss |

Chronic Stress Model

| Behavioral Change | Molecular Finding | Interpretation |
|-----------------|------------------|----------------|
| Impaired memory | Reduced BDNF | Synaptic dysfunction |
| Anhedonia | Altered 5-HT | Mood effects |
| Hyperarousal | HPA axis dysregulation | Feedback failure |
| Reduced exploration | Neuronal atrophy | Structural change |

Pharmacological Evidence

| Compound | Model | Outcome | Relevance to CORT108297 |
|----------|-------|---------|------------|
| Mifepristone | Corticosterone-treated mice | Improved memory | Proof-of-concept |
| RU-486 | Chronic stress model | Reduced tau phosphorylation | Mechanism validation |
| CORT108297 | Pilot studies | BBB penetration | Development rationale |
| GR-ASO | Knockdown models | Protection | Target validation |

Target Engagement Biomarkers

Biomarker Categories

The trial includes multiple biomarker endpoints:

| Biomarker | Sample | Pathway | Clinical Correlation |
|----------|--------|---------|--------------------|
| Cortisol (basal) | Serum | HPA axis activity | Disease severity |
| Cortisol (stressed) | Serum | Stress response | Treatment effect |
| DHEA | Serum | Neurosteroid balance | Antagonistic effect |
| IL-6 | Serum | Inflammation | Inflammation level |
| BDNF | Serum/CSF | Neurotrophin | Synaptic health |
| Tau | CSF | Pathology | AD progression |

Stress Challenge Response

A unique aspect of the CORT-X trial is the acute stress challenge:

Mermaid diagram (expand to render)

Interpretation of Stress Challenge Results

| Response Pattern | Baseline | Post-Treatment | Interpretation |
|----------------|----------|---------------|----------------|
| Normal | Peak +50% | Peak +50% | No effect |
| Blunted | Peak +30% | Peak +45% | Partial blockade |
| Blocked | Peak +20% | Peak +20% | Full blockade |

Comparison with Other GR-Targeting Approaches

Alternative GR Modulators

| Compound | GR Activity | Development Stage | Advantages |
|----------|-------------|-----------------|-------------|
| CORT108297 | Antagonist | Phase 2 | Brain-penetrant |
| Mifepristone | Antagonist | Approved (Cushing's) | Approved, well-characterized |
| Relacarsen | Partial agonist | Preclinical | Tissue-selective |
| Compound A | Selective modulator | Research | Novel mechanism |

GR Agonists vs Antagonists in AD

| Approach | Mechanism | Rationale | Risk |
|----------|----------|----------|------|
| GR agonists | Transactivation | Neuroprotection | Immunosuppression |
| GR antagonists | Transrepression | Anti-inflammatory | HPA axis disruption |
| SGRMs | Balanced | Selective | Safety window |

Clinical Trial Design Rationale

Acute Stress Challenge Methodology

The stress challenge uses standardized procedures:

| Component | Protocol | Measurement |
|-----------|----------|------------|
| Task | Trier Social Stress Test | Public speaking + math |
| Duration | 15 minutes | Standardized |
| Cortisol sampling | 0, 15, 30, 60 min | Time points |
| Cognitive testing | Post-stress | Immediate |

Cognitive Endpoint Selection

| Test | Construct | Stress Sensitivity | Rationale |
|------|-----------|-------------------|----------|
| Pattern Separation | Memory discrimination | High | Hippocampal-specific |
| HVLT-R | Verbal memory | Moderate | Standard AD trial |
| Trail Making B | Executive function | Moderate | Frontal connectivity |
| Digit Span | Working memory | Moderate | Attention |

Statistical Analysis Plan

| Endpoint | Analysis | Power | Assumptions |
|----------|----------|------|-------------|
| Primary cognitive | ANCOVA | 80% | d=0.5 |
| Stress response | Paired t-test | 90% | 40% reduction |
| Biomarker | Mixed model | 80% | Time x treatment |

Future Development Pathway

Planned Phase 2b/3 Trials

Dose Optimization Study

| Parameter | Phase 2 | Phase 2b | Phase 3 |
|-----------|---------|----------|---------|
| Dose | 120mg fixed | Multiple doses | Optimal dose |
| Duration | 2 weeks | 4-8 weeks | 6-12 months |
| N | 60 | 200 | 800 |
| Design | Placebo-controlled | Dose-finding | Pivotal |

Long-Term Extension

Key questions for long-term studies:

Safety with chronic treatment
Disease modification endpoints
Biomarker progression
Quality of life measures

Combination Trial Designs

Rationale for Combinations

CORT108297 may synergize with:

| Combination | Rationale | Timeline |
|-------------|----------|----------|
| + Lecanemab | Complementary mechanisms | Phase 3+ |
| + Donanemab | Tau + stress pathways | Phase 3 |
| + Vitamin D | Synergistic neuroprotection | Phase 2 |
| + Exercise | Enhanced neurogenesis | Phase 2 |

Biomarker-Driven Development

Patient Selection

Future development may incorporate:

| Biomarker | Use | Status |
|----------|-----|--------|
| Baseline cortisol | Enrichment | Retrospective |
| GR genotype | Safety | Research |
| Stress reactivity | Response prediction | Development |
| Hippocampal volume | Prognosis | Validated |

Personalized Approach

The ultimate goal is personalized treatment selection:

Mermaid diagram (expand to render)

Regulatory Considerations

Development Program Elements

| Designation | Status | Benefit |
|-------------|---------|---------|
| Fast Track | Eligible | Accelerated approval |
| Breakthrough | Potential | Intensive guidance |
| Orphan | Not applicable | N/A |
| Priority Review | Future | Faster review |

Approval Pathway

Based on the mechanism and patient population:

Phase 2 completion: Demonstrate efficacy signal

Phase 3: Confirm disease modification

NDA submission: Include biomarker data

Post-marketing: Establish long-term safety

References

[Phase II Trial of CORT108297 to Attenuate the Effects of Acute Stress in the Allocortex (CORT-X)](https://clinicaltrials.gov/study/NCT04601038)

[Lupien et al., Cortisol levels predict hippocampal atrophy (Nature Neuroscience, 1998)](https://pubmed.ncbi.nlm.nih.gov/9707560/)

[Sapolsky, Glucocorticoid toxicity in the hippocampus (Brain Research, 1985)](https://pubmed.ncbi.nlm.nih.gov/4058545/)

[Green et al., Glucocorticoids and Alzheimer's disease (Nature Reviews Drug Discovery, 2019)](https://pubmed.ncbi.nlm.nih.gov/31167165/)

CORT108297 Phase 2 (NCT04601038) - Stress Attenuation in AD

CORT108297 Stress Attenuation AD NCT04601038

Overview

Background

The Stress-Neurodegeneration Connection

Cortisol and Brain Structure

CORT108297 Stress Attenuation AD NCT04601038

Overview

Background

The Stress-Neurodegeneration Connection

Cortisol and Brain Structure

Stress and Alzheimer's Disease Pathology

The Glucocorticoid Receptor System

CORT108297: Pharmacology

Trial Design and Methods

Study Overview

Treatment Arms

Patient Population

Outcome Measures

Primary Outcomes

Secondary Outcomes

Study Procedures

Stress Challenge Protocol

Scientific Rationale

Targeting the Stress-Neurodegeneration Axis

Preclinical Evidence

Glucocorticoids in AD: Clinical Evidence

Comparison to Other AD Trials

Advantages of GR Antagonism

Challenges and Considerations

Mechanism Deep Dive

GR Signaling in the Brain

CORT108297: Brain-Specific Effects

Potential Clinical Implications

If Positive

If Negative

Broader Implications

Safety Considerations

Known Safety Profile

Trial-Specific Monitoring

Future Directions

Potential Development Path

Patient Selection

Mechanism Optimization

Cross-References

Summary

Detailed Mechanistic Pathways

GR-Mediated Gene Regulation

Preclinical Model Evidence

Target Engagement Biomarkers

Comparison with Other GR-Targeting Approaches

Clinical Trial Design Rationale

Future Development Pathway

Planned Phase 2b/3 Trials

Combination Trial Designs

Biomarker-Driven Development

Regulatory Considerations

References

See Also