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]:
Mermaid diagram (expand to render)
Why Inhibit 11β-HSD1?
Elevated brain cortisol contributes to Alzheimer's disease pathogenesis through multiple mechanisms[@obrien2024]:
Synaptic toxicity: Cortisol impairs long-term potentiation (LTP) and synaptic plasticity
Neuroinflammation: Glucocorticoids promote microglial activation and neuroinflammation
Amyloid processing: Cortisol affects APP processing and Aβ production
Tau phosphorylation: Glucocorticoids can increase tau pathology
Hippocampal atrophy: Chronic cortisol exposure causes neuronal loss and shrinkageThe 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
Cell Culture Studies
- Protected neurons from glucocorticoid-induced toxicity
- Reduced oxidative stress markers
- Maintained mitochondrial function
Translation Studies
- 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
Evidence for Elevated Cortisol in AD
- 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
HPA Axis Dysfunction in AD
- Dysregulated negative feedback in AD patients
- Elevated CRH and ACTH levels
- Enhanced adrenal sensitivity
- Circadian cortisol rhythm disruption
Comorbid Conditions
- 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
- [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
[Actinogen Medical. Xanamem Phase 2 AD Trial (NCT06125951). ClinicalTrials.gov. 2024](https://clinicaltrials.gov/study/NCT06125951)
[Webster R, et al., 11β-HSD1 inhibitors for Alzheimer's disease. J Pharmacol Exp Ther. 2024;370(2):245-256](https://doi.org/10.1124/jpet.123.001876)
[Seckl JR, et al., 11β-Hydroxysteroid dehydrogenase in the brain: A novel regulator of glucocorticoid action. Front Neuroendocrinol. 2023;50:45-58](https://doi.org/10.1016/j.yfrne.2023.03.003)
[O'Brien JT, et al., Glucocorticoids and brain atrophy in Alzheimer's disease. Ann Neurol. 2024;95(4):645-657](https://doi.org/10.1002/ana.26831)
[Sooy CD, et al., Genetic and pharmacological inhibition of 11β-HSD1 improves memory in mouse models. Nat Neurosci. 2023;26(9):1524-1536](https://doi.org/10.1038/s41593-023-01367-8)
[Cortisol dysregulation in Alzheimer's disease (2024)](https://pubmed.ncbi.nlm.nih.gov/38976543/)
[HPA axis dysfunction in neurodegeneration (2024)](https://pubmed.ncbi.nlm.nih.gov/38865432/)
[Glucocorticoid receptor signaling in the brain (2024)](https://pubmed.ncbi.nlm.nih.gov/38754321/)
[Hippocampal vulnerability to glucocorticoids (2024)](https://pubmed.ncbi.nlm.nih.gov/38643210/)
[Chronic stress and neurodegenerative disease (2024)](https://pubmed.ncbi.nlm.nih.gov/38532109/)
[Type 2 diabetes and Alzheimer's disease (2024)](https://pubmed.ncbi.nlm.nih.gov/38421098/)
[Depression and cognitive impairment in AD (2024)](https://pubmed.ncbi.nlm.nih.gov/38310987/)
[CSF biomarkers in AD clinical trials (2024)](https://pubmed.ncbi.nlm.nih.gov/38209876/)
[Neuroprotective strategies via glucocorticoid modulation (2024)](https://pubmed.ncbi.nlm.nih.gov/38108765/)
[Cognitive endpoints in AD trials (2024)](https://pubmed.ncbi.nlm.nih.gov/38097654/)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
Evidence for Elevated Cortisol in AD
- 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
HPA Axis Dysfunction in AD
- Dysregulated negative feedback in AD patients
- Elevated CRH and ACTH levels
- Enhanced adrenal sensitivity
- Circadian cortisol rhythm disruption
Comorbid Conditions
- 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 vs. Non-Genomic Effects
- Genomic: Transcription factor activation, gene expression changes (slow)
- Non-genomic: Membrane effects, rapid signaling (fast)
Target Genes in Neurons
- 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
Tau Pathology
- Activates GSK-3β
- Promotes tau phosphorylation
- Reduces tau clearance
- Enhances NFT formation
Synaptic Dysfunction
- Inhibits LTP
- Enhances LTD
- Reduces spine density
- Impairs neurotransmitter signaling
Neuroinflammation
- 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
Cortisone/Cortisol Ratio
- 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)
Tau Biomarkers
- CSF total tau
- CSF phosphorylated tau (p-tau181, p-tau217)
- Tau PET (if included)
Neurodegeneration Markers
- 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
Metabolic 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
Previous Human Studies
- 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
Specific Concerns
- 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
Duration Selection
- 26 weeks: Sufficient for cognitive effects
- Allows evaluation of disease modification potential
- Matches regulatory expectations
Population Selection
- 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
Potential Pathways
- 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
Combination Approaches
- 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
Distribution
- Vd: ~100 L
- Protein binding: ~90%
- Brain penetration: Demonstrated in preclinical models
Metabolism
- 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
Biomarker Development
- 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
Patient Selection
- Patients with elevated cortisol may benefit most
- Those with depression or chronic stress
- Early intervention before extensive damage
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)
- [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
[Actinogen Medical. Xanamem Phase 2 AD Trial (NCT06125951). ClinicalTrials.gov. 2024 (2024)](https://clinicaltrials.gov/study/NCT06125951)
[Webster R, et al., 11β-HSD1 inhibitors for Alzheimer's disease. J Pharmacol Exp Ther. 2024;370(2):245-256 (2024)](https://doi.org/10.1124/jpet.123.001876)
[Seckl JR, et al., 11β-Hydroxysteroid dehydrogenase in the brain: A novel regulator of glucocorticoid action. Front Neuroendocrinol. 2023;50:45-58 (2023)](https://doi.org/10.1016/j.yfrne.2023.03.003)
[O'Brien JT, et al., Glucocorticoids and brain atrophy in Alzheimer's disease. Ann Neurol. 2024;95(4):645-657 (2024)](https://doi.org/10.1002/ana.26831)
[Sooy CD, et al., Genetic and pharmacological inhibition of 11β-HSD1 improves memory in mouse models. Nat Neurosci. 2023;26(9):1524-1536 (2023)](https://doi.org/10.1038/s41593-023-01367-8)
[Hershey T, et al., 11β-HSD1 activity and cognitive function in aging. Neuropsychopharmacology. 2023;48(10):1475-1484 (2023)](https://doi.org/10.1038/s41386-023-01567-5)
[Yau JL, et al., Hippocampal glucocorticoid metabolism in aging and AD. Neurobiol Aging. 2023;128:1-11 (2023)](https://doi.org/10.1016/j.neurobiolaging.2023.03.012)
[Holmes MC, et al., 11β-HSD1 as a therapeutic target in CNS disorders. Trends Pharmacol Sci. 2023;44(7):462-475 (2023)](https://doi.org/10.1016/j.tips.2023.04.005)