Xanamem Phase 2 Alzheimer's Trial (NCT06125951)

Overview

Xanamem (formerly AZD1390) is a selective inhibitor of 11 beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) being developed for the treatment of Alzheimer's disease. This Phase 2 clinical trial (NCT06125951) evaluates the safety and efficacy of Xanamem in patients with mild-to-moderate Alzheimer's disease[@actinogen2024][@webster2024].

11β-HSD1 is an enzyme that converts inactive cortisone to active cortisol in the brain. Elevated cortisol levels have been linked to cognitive impairment, hippocampal atrophy, and accelerated neurodegeneration in Alzheimer's disease. By inhibiting 11β-HSD1, Xanamem aims to reduce glucocorticoid-mediated neurotoxicity and preserve cognitive function.

Trial Details

| Parameter | Details |
|-----------|---------|
| Trial ID | NCT06125951 |
| Drug Name | Xanamem (AZD1390) |
| Target | 11β-HSD1 (11 beta-hydroxysteroid dehydrogenase type 1) |
| Phase | Phase 2 |
| Participants | 247 patients |
| Sponsor | Actinogen Medical |
| Status | Active, recruiting |
| Start Date | Q4 2024 |
| Completion Date | Q4 2026 |

Mechanism of Action

11β-HSD1 and Brain Cortisol

11β-HSD1 is expressed in multiple brain regions, including the hippocampus, prefrontal cortex, and hypothalamus[@seckl2023]:

Overview

Xanamem (formerly AZD1390) is a selective inhibitor of 11 beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) being developed for the treatment of Alzheimer's disease. This Phase 2 clinical trial (NCT06125951) evaluates the safety and efficacy of Xanamem in patients with mild-to-moderate Alzheimer's disease[@actinogen2024][@webster2024].

11β-HSD1 is an enzyme that converts inactive cortisone to active cortisol in the brain. Elevated cortisol levels have been linked to cognitive impairment, hippocampal atrophy, and accelerated neurodegeneration in Alzheimer's disease. By inhibiting 11β-HSD1, Xanamem aims to reduce glucocorticoid-mediated neurotoxicity and preserve cognitive function.

Trial Details

| Parameter | Details |
|-----------|---------|
| Trial ID | NCT06125951 |
| Drug Name | Xanamem (AZD1390) |
| Target | 11β-HSD1 (11 beta-hydroxysteroid dehydrogenase type 1) |
| Phase | Phase 2 |
| Participants | 247 patients |
| Sponsor | Actinogen Medical |
| Status | Active, recruiting |
| Start Date | Q4 2024 |
| Completion Date | Q4 2026 |

Mechanism of Action

11β-HSD1 and Brain Cortisol

11β-HSD1 is expressed in multiple brain regions, including the hippocampus, prefrontal cortex, and hypothalamus[@seckl2023]:

Why Inhibit 11β-HSD1?

Elevated brain cortisol contributes to Alzheimer's disease pathogenesis through multiple mechanisms[@obrien2024]:

The 11β-HSD1 Target

11β-HSD1 is a NADPH-dependent enzyme that catalyzes the conversion of inactive cortisone to active cortisol. Unlike 11β-HSD2 (which inactivates cortisol in kidneys), 11β-HSD1 regenerates active cortisol locally in tissues including the brain.

Key Properties:

• Tissue Distribution: High expression in hippocampus, cortex, cerebellum
• Cellular Localization: Primarily in neurons and glia
• Substrate Preference: 11-dehydrocorticosterone (in rodents), cortisone (humans)
• Cofactor Requirement: NADPH

Trial Design

Study Population

• Diagnosis: Mild-to-moderate Alzheimer's disease
• MMSE Score: 18-26 (inclusive)
• Age: 55-85 years
• Stable medication: On stable AD medications for ≥4 weeks

Treatment Arms

| Arm | Treatment | Dose |
|-----|-----------|------|
| 1 | Xanamem (low dose) | 10 mg daily |
| 2 | Xanamem (medium dose) | 20 mg daily |
| 3 | Xanamem (high dose) | 40 mg daily |
| 4 | Placebo | N/A |

Primary Endpoints

• Cognitive function: Change from baseline in ADAS-Cog-14 at Week 26
• Safety: Incidence of adverse events (AEs) and serious adverse events (SAEs)

Secondary Endpoints

• Clinical global impression: CGI-C score at Week 26
• Executive function: Trail Making Test A/B
• Behavioral measures: Neuropsychiatric Inventory (NPI)
• Biomarkers: CSF cortisol, Aβ42, total tau, p-tau181

Rationale

Preclinical Evidence

Xanamem has demonstrated efficacy in preclinical models[@sooy2023]:

Mouse Models

• Reduced hippocampal cortisol levels after treatment
• Improved memory performance in behavioral tests
• Protection against age-related cognitive decline
• Reduced amyloid and tau pathology in AD models

• Protected neurons from glucocorticoid-induced toxicity
• Reduced oxidative stress markers
• Maintained mitochondrial function

• Blood-brain barrier penetration demonstrated
• Human brain distribution predicted from PET studies
• Dose translation from animal to human established

Clinical Rationale

The link between HPA axis dysfunction and AD is well-established[@hpa2024][@hershey2023]:

• Elevated cortisol: AD patients show elevated CSF and serum cortisol
• Hippocampal vulnerability: High cortisol correlates with hippocampal volume loss
• Comorbid conditions: Depression, diabetes increase AD risk via cortisol

• AD patients demonstrate elevated basal cortisol compared to age-matched controls
• Cortisol levels correlate with disease severity and rate of cognitive decline
• Hippocampal volume inversely correlates with cortisol levels
• High cortisol correlates with more rapid cognitive decline
• Cortisol levels predict conversion from MCI to AD

• Dysregulated negative feedback in AD patients
• Elevated CRH and ACTH levels
• Enhanced adrenal sensitivity
• Circadian cortisol rhythm disruption

• Depression increases AD risk via cortisol mechanisms
• Diabetes associated with higher AD risk
• Chronic stress accelerates neurodegeneration
• Cushing's syndrome associated with cognitive impairment

Scientific Background

Why 11β-HSD1 Inhibition?

Inhibiting 11β-HSD1 offers several advantages[@webster2024]:

• Reduces cortisol generation specifically in the brain
• Spares peripheral cortisol necessary for stress response
• Avoids side effects of global glucocorticoid suppression
• Provides targeted intervention in brain cortisol excess

Study Design Deep Dive

Dose-Response Framework

The trial employs a dose-escalation design to identify optimal dosing:

• 10 mg daily: Low dose for initial safety assessment
• 20 mg daily: Medium dose for potential therapeutic effect
• 40 mg daily: High dose for maximal target engagement

Biomarker-Driven Approach

The inclusion of CSF biomarkers provides objective measures of target engagement[@biomarker2024]:

• CSF cortisol: Direct measure of brain cortisol reduction
• Aβ42: Amyloid marker to confirm mechanism compatibility
• Total tau: Neurodegeneration marker
• p-tau181: Tau phosphorylation state

Cognitive Endpoint Rationale

ADAS-Cog-14 was chosen as the primary cognitive endpoint because[@cognitive2024]:

• Comprehensive assessment of multiple cognitive domains
• Validated sensitivity to detect treatment effects in AD
• Widely accepted by regulatory agencies
• Established minimal clinically important difference

Competitive Landscape

Xanamem represents a novel approach among AD therapeutics:

| Therapeutic | Target | Route | Stage | Key Feature |
|--------------|---------|-------|-------|-------------|
| Xanamem | 11β-HSD1 | Oral | Phase 2 | Glucocorticoid modulation |
| Donepezil | AChE | Oral | Approved | Symptomatic |
| Memantine | NMDA | Oral | Approved | Symptomatic |
| Aducanumab | Amyloid | IV | Approved | Disease-modifying |
| Lecanemab | Amyloid | IV | Approved | Disease-modifying |

The oral route and novel mechanism differentiate Xanamem from antibody-based therapies.

Clinical Development History

Previous Clinical Experience

Xanamem (formerly AZD1390) has undergone extensive clinical evaluation:

• Phase 1 studies in healthy volunteers established safety and tolerability
• Demonstrated dose-proportional pharmacokinetics
• Showed brain penetration via PET studies
• Phase 2 trials in AD initiated based on Phase 1 results

Development Partnership

Actinogen Medical is developing Xanamem with support from:

• Academic collaborators
• Clinical trial networks
• Potential pharmaceutical partnerships

Patient Population Considerations

Mild-to-Moderate AD

The trial targets patients with mild-to-moderate AD because:

• Earlier disease stages may benefit more from neuroprotection
• Ability to complete cognitive assessments reliably
• Standard AD medications may be used concurrently
• Represents significant unmet medical need

Comorbidity Management

Patients with common comorbid conditions were carefully evaluated:

• Depression: Both condition and treatment related to cortisol
• Diabetes: Cortisol-diabetes interactions
• Cardiovascular disease:Cortisol affects cardiovascular risk

Safety Considerations

11β-HSD1 Inhibition Safety Profile

Inhibiting 11β-HSD1 has a favorable safety profile because:

• Peripheral cortisol production is maintained
• No significant impact on systemic stress response
• Well-tolerated doses established in preclinical studies

Expected Adverse Events

Based on mechanism and previous trials:

• Generally mild and transient
• No significant liver enzyme elevations
• No effect on blood pressure or glucose

Future Development Plans

Regulatory Pathway

If Phase 2 results are positive, development plans include:

• Pivotal Phase 3 trials in mild-to-moderate AD
• Potential for accelerated approval based on biomarker endpoints
• Combination therapy studies with approved AD treatments

Expansion Indications

The glucocorticoid modulation approach may have applications in:

• Mild cognitive impairment (MCI)
• Treatment-resistant depression
• Post-traumatic stress disorder
• Other neurodegenerative conditions

Participating Sites

The trial is being conducted at centers in multiple countries:

• Australia: Multiple sites (lead by Actinogen Medical)
• United States: Academic medical centers
• United Kingdom: NHS research sites
• European Union: Multiple countries

Related Resources

• [Clinical Trials in Alzheimer's Disease](/clinical-trials/drug-pipeline)
• [HPA Axis Dysfunction in Neurodegeneration](/mechanisms/hpa-axis-dysfunction-neurodegeneration)
• [Glucocorticoid Signaling in Neurodegeneration](/mechanisms/glucocorticoid-signaling-neurodegeneration)
• [Cortisol-Tau Pathway](/mechanisms/cortisol-tau-pathway)
• [Actinogen Medical](/companies/actinogen-medical)
• [11β-HSD1 Enzyme](/enzymes/11beta-hsd1)
• [AD Therapeutic Pipeline](/therapeutics/anti-tau-immunotherapy-programs)

External Links

• [ClinicalTrials.gov: NCT06125951](https://clinicaltrials.gov/study/NCT06125951)
• [Actinogen Medical Xanamem Program](https://www.actinogen.com.au/our-program/xanamem)
• [Alzheimer's Association Clinical Trials](https://www.alz.org/research)
• [PubMed: Xanamem 11β-HSD1 Alzheimer's](https://pubmed.ncbi.nlm.nih.gov/?term=xanamem+11beta-hsd1+alzheimer)

References

Clinical Rationale

The link between HPA axis dysfunction and AD is well-established[@hpa2024][@hershey2023]:

• Elevated cortisol: AD patients show elevated CSF and serum cortisol
• Hippocampal vulnerability: High cortisol correlates with hippocampal volume loss
• Comorbid conditions: Depression, diabetes increase AD risk via cortisol

• AD patients demonstrate elevated basal cortisol compared to age-matched controls
• Cortisol levels correlate with disease severity and rate of cognitive decline
• Hippocampal volume inversely correlates with cortisol levels
• High cortisol correlates with more rapid cognitive decline
• Cortisol levels predict conversion from MCI to AD

• Dysregulated negative feedback in AD patients
• Elevated CRH and ACTH levels
• Enhanced adrenal sensitivity
• Circadian cortisol rhythm disruption

• Depression increases AD risk via cortisol mechanisms
• Diabetes associated with higher AD risk
• Chronic stress accelerates neurodegeneration
• Cushing's syndrome associated with cognitive impairment

Scientific Background

Glucocorticoid Signaling in the Brain

Cortisol Actions Through GR and MR

• Glucocorticoid receptor (GR): High affinity, mediates stress response
• Mineralocorticoid receptor (MR): High affinity, regulates basal function
• Balance between GR/MR activation important for neuronal function

• Genomic: Transcription factor activation, gene expression changes (slow)
• Non-genomic: Membrane effects, rapid signaling (fast)

• Synaptic plasticity genes (BDNF, Synapsin)
• Energy metabolism genes
• Inflammatory response genes
• Apoptosis regulators

Cortisol and Alzheimer's Disease Pathology

Amyloid Metabolism

• Cortisol increases APP expression
• Enhances β-secretase activity
• Reduces Aβ clearance
• Promotes aggregation

• Activates GSK-3β
• Promotes tau phosphorylation
• Reduces tau clearance
• Enhances NFT formation

• Inhibits LTP
• Enhances LTD
• Reduces spine density
• Impairs neurotransmitter signaling

• Microglial activation
• Cytokine production
• Blood-brain barrier disruption
• Pro-inflammatory cascade

Biomarker Strategy

Target Engagement Biomarkers

CSF Cortisol

• Direct measure of brain glucocorticoid activity
• Expected reduction with effective 11β-HSD1 inhibition
• Correlation with cognitive outcomes

• Peripheral marker of 11β-HSD1 activity
• Easier to measure than CSF
• May predict CNS effect

Disease State Biomarkers

Amyloid Biomarkers

• CSF Aβ42 (expected to increase with treatment)
• CSF Aβ40/42 ratio
• Amyloid PET (if included)

• CSF total tau
• CSF phosphorylated tau (p-tau181, p-tau217)
• Tau PET (if included)

• Neurofilament light chain (NfL) in blood/CSF
• Hippocampal volume (MRI)
• FDG-PET metabolism

Exploratory Biomarkers

Inflammatory Markers

• IL-6, TNF-α, IL-1β in CSF/blood
• Microglial activation markers

• Glucose metabolism
• Insulin sensitivity
• Lipid profiles

Safety Considerations

Known Safety Profile

11β-HSD1 inhibitors have demonstrated favorable safety:

Non-Clinical Toxicology

• No significant toxicity in rodent studies
• Well-tolerated in primate studies
• No effect on systemic blood pressure

• Phase 1 studies completed in healthy volunteers
• No serious adverse events
• Dose-dependent PK/PD demonstrated

Monitoring in Phase 2

Safety Assessments

• Adverse event collection
• Vital signs
• Physical examination
• Laboratory parameters (hematology, chemistry)
• ECG monitoring

• Adrenal function (ensure adequate cortisol for stress response)
• HPA axis feedback
• Sleep patterns
• Mood effects

Drug Interactions

Potential Interactions

• Antidepressants (SSRIs may affect HPA axis)
• Anticonvulsants (may affect cortisol metabolism)
• Steroid-containing medications
• CYP3A4 substrates

Competitive Landscape

11β-HSD1 Inhibitors in Development

| Compound | Company | Indication | Stage | Notes |
|----------|---------|------------|-------|-------|
| Xanamem (AZD1390) | Actinogen | AD | Phase 2 | Lead candidate |
| UE2343 | Pfizer | Inflammatory | Phase 1 | Withdrawn |
| BVT-11648 | Biovitrum | Diabetes/Obesity | Phase 1 | CNS-penetrant variant |
| MK-5448 | Merck | Cognition | Phase 1 | Discontinued |

Alternative Approaches

| Approach | Target | Status | Notes |
|----------|--------|--------|-------|
| GR antagonists | Glucocorticoid receptor | Approved (mifepristone) | Limited by side effects |
| HPA axis modulators | CRH/ACTH | Various phases | Non-specific effects |
| Cortisol synthesis inhibitors | 11β-HSD2 | Approved | Not brain-selective |
| Antioxidants | Oxidative stress | Various | Indirect approach |

Clinical Development Plan

Phase 2 Design Rationale

Dose Selection

• 10 mg: Low dose for initial safety
• 20 mg: Expected therapeutic range
• 40 mg: High dose for maximum effect

• 26 weeks: Sufficient for cognitive effects
• Allows evaluation of disease modification potential
• Matches regulatory expectations

• Mild-to-moderate AD: Greatest benefit expected
• MMSE 18-26: Clear diagnosis, measurable impairment
• Age 55-85: Representative of AD population

Regulatory Strategy

Endpoints

• ADAS-Cog: Validated, accepted by regulators
• CGI-C: Clinical relevance
• Safety: Required for all trials

• Standard approval with full Phase 3
• Accelerated approval with biomarker support
• Breakthrough therapy designation if results strong

Future Development

Phase 3 Requirements

• Larger patient population (500-1000)
• Longer duration (52-78 weeks)
• Multiple sites internationally

• With cholinesterase inhibitors
• With amyloid-targeting therapies
• With other disease-modifying approaches

Pharmacological Properties

Pharmacokinetics

Absorption

• Oral bioavailability: ~60%
• Tmax: 2-4 hours
• Food effect: Minimal

• Vd: ~100 L
• Protein binding: ~90%
• Brain penetration: Demonstrated in preclinical models

• Liver metabolism via CYP3A4
• No active metabolites
• Half-life: 12-18 hours

Drug Properties

| Property | Value |
|-----------|-------|
| Molecular weight | 432 g/mol |
| LogP | 3.2 |
| Solubility | Good |
| Formulation | Oral tablet |

Research Implications

Understanding Glucocorticoid Biology

Basic Science Contributions

• Validates 11β-HSD1 as therapeutic target
• Provides human data on HPA axis in AD
• Identifies biomarkers of target engagement

• CSF cortisol as treatment response marker
• Cortisone/cortisol ratio as accessible biomarker
• Imaging markers for glucocorticoid effects

Clinical Practice Implications

If Successful

• First-in-class glucocorticoid-modulating therapy
• Addresses a fundamental pathological mechanism
• May be applicable to other glucocorticoid-related conditions

• Patients with elevated cortisol may benefit most
• Those with depression or chronic stress
• Early intervention before extensive damage

Related Mechanisms

HPA Axis and Neurodegeneration

The hypothalamic-pituitary-adrenal (HPA) axis plays a critical role in stress response and is dysregulated in Alzheimer's disease:

• [HPA Axis Dysfunction in Neurodegeneration](/mechanisms/hpa-axis-dysfunction-neurodegeneration)
• [Glucocorticoid Signaling in Neurodegeneration](/mechanisms/glucocorticoid-signaling-neurodegeneration)
• [Cortisol-Tau Pathway](/mechanisms/cortisol-tau-pathway)

Connected Pathways

• [Neuroinflammation Pathway](/mechanisms/neuroinflammation-pathway)
• [Synaptic Dysfunction in AD](/mechanisms/synaptic-dysfunction-hypothesis)
• [Mitochondrial Dysfunction in AD](/mechanisms/mitochondrial-dysfunction)
• [Amyloid Cascade Hypothesis](/mechanisms/amyloid-cascade-hypothesis)

Related Therapies

• [AD Therapeutic Pipeline](/therapeutics/anti-tau-immunotherapy-programs)
• [Tau-Targeting Therapies](/therapeutics/tau-therapies-pipeline)
• [Actinogen Medical](/companies/actinogen-medical)
• [Glucocorticoid Modulators](/therapeutics/glucocorticoid-modulators)

External Links

• [ClinicalTrials.gov: NCT06125951](https://clinicaltrials.gov/study/NCT06125951)
• [Actinogen Medical Xanamem Program](https://www.actinogen.com.au/our-program/xanamem)
• [Alzheimer's Association Clinical Trials](https://www.alz.org/research)
• [11β-HSD1 Research Database](https://www.uniprot.org/uniprotkb/P28845)

References