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.
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.
| 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 |
¶ 11β-HSD1 and Brain Cortisol
11β-HSD1 is expressed in multiple brain regions, including the hippocampus, prefrontal cortex, and hypothalamus:
flowchart TD
A["Inactive Cortisone"] --> B["11β-HSD1"]
click B "/enzymes/11beta-hsd1" "11β-HSD1 Enzyme"
B --> C["Active Cortisol"]
click C "/biomarkers/cortisol" "Cortisol Biomarker"
C --> D["Glucocorticoid Receptors"]
D --> E["Gene Transcription"]
style D fill:#fff3e0,stroke:#333
style E fill:#fff3e0,stroke:#333
C --> F["Cortisol Excess"]
F --> G["Hippocampal Atrophy"]
F --> H["Cognitive Impairment"]
F --> I["Synaptic Dysfunction"]
F --> J["Neuroinflammation"]
style F fill:#ffcdd2,stroke:#333
style G fill:#ffcdd2,stroke:#333
style H fill:#ffcdd2,stroke:#333
style I fill:#ffcdd2,stroke:#333
style J fill:#ffcdd2,stroke:#333
K["Xanamem<br/>11β-HSD1 Inhibitor"] -->|"Inhibition"| B
click K "/therapeutics/xanamem" "Xanamem Therapeutic"
K --> L["Reduced Cortisol"]
L --> M["Neuroprotection"]
M --> N["Cognitive Preservation"]
style K fill:#f3e5f5,stroke:#333
style M fill:#c8e6c9,stroke:#333
style N fill:#c8e6c9,stroke:#333
Elevated brain cortisol contributes to Alzheimer's disease pathogenesis through multiple mechanisms:
- 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 shrinkage
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
- 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
| 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 |
- Cognitive function: Change from baseline in ADAS-Cog-14 at Week 26
- Safety: Incidence of adverse events (AEs) and serious adverse events (SAEs)
- 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
Xanamem has demonstrated efficacy in preclinical models:
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
The link between HPA axis dysfunction and AD is well-established[@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
Inhibiting 11β-HSD1 offers several advantages:
- 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
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
The inclusion of CSF biomarkers provides objective measures of target engagement:
- CSF cortisol: Direct measure of brain cortisol reduction
- Aβ42: Amyloid marker to confirm mechanism compatibility
- Total tau: Neurodegeneration marker
- p-tau181: Tau phosphorylation state
ADAS-Cog-14 was chosen as the primary cognitive endpoint because:
- 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.
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
Actinogen Medical is developing Xanamem with support from:
- Academic collaborators
- Clinical trial networks
- Potential pharmaceutical partnerships
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
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
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
Based on mechanism and previous trials:
- Generally mild and transient
- No significant liver enzyme elevations
- No effect on blood pressure or glucose
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
The glucocorticoid modulation approach may have applications in:
- Mild cognitive impairment (MCI)
- Treatment-resistant depression
- Post-traumatic stress disorder
- Other neurodegenerative conditions
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