Allopregnanolone Regenerative Therapeutic for Alzheimer's Disease (NCT04838301)
Overview
Allopregnanolone (also known as allo, brexanolone, or SAGE-547) is a neurosteroid being developed as a regenerative therapeutic for mild Alzheimer's disease. This Phase 2 clinical trial (NCT04838301), conducted by the University of Arizona Center for Innovation in Brain Science, evaluates the safety, tolerability, and efficacy of intravenous allopregnanolone in patients with mild Alzheimer's disease[@brinton2022][@irwin2020].
Unlike conventional AD therapies that target amyloid or tau pathology, allopregnanolone takes a regenerative approach by promoting neurogenesis, protecting synapses, and supporting overall brain health. This represents a paradigm shift in AD therapeutics from disease modification to true regeneration of neural function[@neurosteroid2024].
Trial Overview
| Field | Value |
|-------|-------|
| NCT Number | NCT04838301 |
| Brief Title | Allopregnanolone Regenerative Therapeutic for Mild Alzheimer's Disease |
| Official Title | A Phase 2 Study of Allopregnanolone (Allo) as a Regenerative Therapeutic for Mild Alzheimer's Disease |
| Study Type | Interventional |
| Phase | Phase 2 |
| Enrollment | 200 participants |
| Status | Completed |
| Sponsor | University of Arizona |
| Collaborators | NIH National Institute on Aging (NIA) |
| Study Start | April 2021 |
| Primary Completion | December 2023 |
Study Design
...Allopregnanolone Regenerative Therapeutic for Alzheimer's Disease (NCT04838301)
Overview
Allopregnanolone (also known as allo, brexanolone, or SAGE-547) is a neurosteroid being developed as a regenerative therapeutic for mild Alzheimer's disease. This Phase 2 clinical trial (NCT04838301), conducted by the University of Arizona Center for Innovation in Brain Science, evaluates the safety, tolerability, and efficacy of intravenous allopregnanolone in patients with mild Alzheimer's disease[@brinton2022][@irwin2020].
Unlike conventional AD therapies that target amyloid or tau pathology, allopregnanolone takes a regenerative approach by promoting neurogenesis, protecting synapses, and supporting overall brain health. This represents a paradigm shift in AD therapeutics from disease modification to true regeneration of neural function[@neurosteroid2024].
Trial Overview
| Field | Value |
|-------|-------|
| NCT Number | NCT04838301 |
| Brief Title | Allopregnanolone Regenerative Therapeutic for Mild Alzheimer's Disease |
| Official Title | A Phase 2 Study of Allopregnanolone (Allo) as a Regenerative Therapeutic for Mild Alzheimer's Disease |
| Study Type | Interventional |
| Phase | Phase 2 |
| Enrollment | 200 participants |
| Status | Completed |
| Sponsor | University of Arizona |
| Collaborators | NIH National Institute on Aging (NIA) |
| Study Start | April 2021 |
| Primary Completion | December 2023 |
Study Design
Design Description
This is a multicenter, randomized, double-blind, placebo-controlled, parallel-group Phase 2 clinical trial evaluating the safety, tolerability, and efficacy of intravenous allopregnanolone in participants with mild Alzheimer's disease.
Allocation
Randomized, 1:1 allocation to treatment vs. placebo.
Intervention Model
Parallel group design with multiple dose cohorts.
Intervention
Drug: Allopregnanolone (Allo)
- Drug Name: Allopregnanolone (also known as Allo)
- Route: Intravenous infusion
- Dosing: Multiple dose levels evaluated across cohorts
- Duration: 12-week treatment period with follow-up
Placebo
Matched vehicle solution administered via identical infusion protocol.
Mechanism of Action
Allopregnanolone is a neurosteroid — a naturally occurring neuromodulator derived from progesterone that acts as a positive allosteric modulator of the GABA<sub>A</sub> receptor.
Key Mechanisms
GABAergic Modulation: Allopregnanolone enhances GABA<sub>A</sub> receptor function, the primary inhibitory neurotransmitter system in the brain. This modulation affects neuronal excitability, synaptic plasticity, and circuit function.
Neurogenesis Promotion: Preclinical studies demonstrate that allopregnanolone stimulates hippocampal neurogenesis — the birth of new neurons in the dentate gyrus. This is particularly relevant for AD, where neurogenesis is impaired.
White Matter Integrity: Evidence suggests allopregnanolone promotes oligodendrocyte differentiation and myelination, potentially protecting white matter integrity compromised in AD.
Anti-inflammatory Effects: Neurosteroids exhibit anti-inflammatory properties that may contribute to neuroprotection.
Neurotrophic Support: Allopregnanolone has been shown to increase brain-derived neurotrophic factor (BDNF) expression, supporting neuronal survival and plasticity.Relevance to Alzheimer's Disease
The regenerative therapeutic approach targets multiple pathological features of AD:
- Amyloid and tau pathology do not fully account for cognitive decline. Neuronal loss and synaptic dysfunction are key drivers, which regenerative mechanisms like neurogenesis may address.
- The hippocampus, critical for memory, shows early vulnerability in AD and is a primary site of adult neurogenesis that allopregnanolone may enhance.
Primary Outcomes
Primary Safety Endpoint
- Incidence and severity of adverse events (AEs)
- Changes in vital signs, laboratory values, and ECG parameters
- Incidence of treatment-emergent serious adverse events (SAEs)
Primary Efficacy Endpoints
- Change in cognitive function as measured by ADAS-Cog
- Change in functional status as measured by ADAS-Activities of Daily Living
- Brain structure changes via MRI volumetry
Secondary Outcomes
- CSF biomarkers of neurodegeneration and neuroinflammation
- Glucose metabolism via PET imaging
- White matter integrity via diffusion tensor imaging (DTI)
- Mood and behavioral assessments
- Pharmacokinetic profiling
Eligibility Criteria
Inclusion Criteria
Age 55-85 years
Diagnosis of mild Alzheimer's disease (MMSE 18-26)
Clinical dementia rating (CDR) of 0.5 or 1.0
Stable on permitted AD medications (cholinesterase inhibitors, memantine) for ≥3 months
Able to undergo MRI and PET imaging
Caregiver available to accompany to visitsExclusion Criteria
Major psychiatric disorder (depression, schizophrenia, bipolar)
History of seizures
Significant cerebrovascular disease
Other neurodegenerative conditions
Active malignancy
Severe medical conditions precluding participationResults and Findings
This trial represents a significant effort in developing regenerative therapies for AD that move beyond symptom modification to address underlying neuronal loss and dysfunction[@regeneration2024].
Key Publications
- Brinton RD et al. "Allopregnanolone as a regenerative therapeutic for Alzheimer's disease." Ann Neurol. 2022.
- Irwin RW et al. "Allopregnanolone preclinical and clinical data for Alzheimer's disease." Neurobiology of Disease. 2020.
Clinical Development History
Allopregnanolone (also known as allo, brexanolone, or SAGE-547) has undergone extensive clinical development for neurological indications:
- Phase 1 studies (2015-2017): Established safety, tolerability, and pharmacokinetics in healthy volunteers and AD patients
- Phase 2 studies (2018-2020): Demonstrated signal detection in cognitive endpoints
- Phase 2/3 (NCT04838301): Currently completing evaluation in mild AD patients
- FDA approval: Brexanolone (Zulresso) is already FDA-approved for postpartum depression, providing regulatory precedent for safety
Neurosteroid Biology
Allopregnanolone is an endogenous neurosteroid derived from progesterone through the cholesterol side-chain cleavage pathway[@progesterone2024]. It is synthesized de novo in the brain, primarily in glial cells, and acts as a potent positive allosteric modulator of GABA-A receptors.
Biosynthetic Pathway
Mermaid diagram (expand to render)
GABA-A Receptor Pharmacology
Allopregnanolone binds to a distinct recognition site on the GABA-A receptor that is separate from the benzodiazepine binding site[@gabaa2024]. This site has the following properties:
- Potentiation: Allopregnanolone potentiates GABA currents at concentrations as low as 10-100 nM
- Direct activation: At higher concentrations, it can directly activate GABA-A receptors
- Subunit specificity: Preferentially enhances receptors containing δ or α subunits
- Tolerance: Unlike benzodiazepines, allopregnanolone does not produce tolerance with repeated dosing
Hippocampal Neurogenesis
Adult hippocampal neurogenesis occurs in the dentate gyrus throughout life and is essential for memory formation and cognitive flexibility[@neurogenesis2024]. In AD:
- Neurogenesis is reduced by 50% or more in AD patients
- This reduction correlates with cognitive impairment
- Enhancing neurogenesis may restore cognitive function
Allopregnanolone promotes neurogenesis through:
- Increased proliferation of neural progenitor cells
- Enhanced survival of newly generated neurons
- Improved dendritic integration
- Promotion of learning and memory formation
Neuroinflammatory Pathways
Chronic neuroinflammation is a hallmark of AD pathogenesis[@neuroinflammation2024]. Allopregnanolone exerts anti-inflammatory effects through:
- Reduced microglial activation
- Decreased pro-inflammatory cytokine production
- Enhanced anti-inflammatory mediator expression
- Modulation of NLRP3 inflammasome activity
Mitochondrial Protection
Mitochondrial dysfunction is an early event in AD pathogenesis[@mitochondria2024]. Allopregnanolone protects mitochondria through:
- Enhanced mitochondrial biogenesis
- Improved electron transport chain function
- Reduced reactive oxygen species production
- Protection against mitochondrial apoptosis
Epigenetic Regulation
Allopregnanolone influences gene expression through epigenetic mechanisms[@epigenetic2024]:
- Modulation of histone acetylation
- Regulation of DNA methylation patterns
- Control of non-coding RNA expression
- These effects may contribute to long-term therapeutic benefits
BDNF and Neurotrophic Support
Brain-derived neurotrophic factor (BDNF) is critical for neuronal survival and synaptic plasticity[@bdnf2024]. Allopregnanolone:
- Increases BDNF expression in the hippocampus
- Enhances TrkB signaling
- Promotes synaptic spine formation
- Improves learning and memory consolidation
White Matter and Oligodendrocytes
White matter integrity is compromised in AD, contributing to cognitive decline[@white2024]. Allopregnanolone supports white matter health through:
- Promotion of oligodendrocyte precursor differentiation
- Enhanced myelination
- Protection against demyelination
- Preservation of white matter microstructure
Synaptic Plasticity
Synaptic dysfunction is a key mediator of cognitive decline in AD[@synapse2024]. Allopregnanolone enhances synaptic plasticity through:
- Long-term potentiation (LTP) facilitation
- Improved synaptic vesicle dynamics
- Enhanced receptor trafficking
- Protection against excitotoxicity
Comparison to Other AD Therapeutics
| Therapeutic | Mechanism | Administration | Stage | Key Feature |
|-------------|-----------|----------------|-------|-------------|
| Allopregnanolone | GABA-A modulation + regeneration | IV infusion | Phase 2/3 | Regenerative |
| Donepezil | AChE inhibition | Oral | Approved | Symptomatic |
| Aducanumab | Anti-amyloid antibody | IV monthly | Approved | Disease-modifying |
| Lecanemab | Anti-amyloid antibody | IV biweekly | Approved | Disease-modifying |
| Allo | Regenerative + neuroprotection | IV | Phase 2 | Multi-target |
Future Directions
The allopregnanolone program continues to evaluate:
- Alternative dosing regimens for easier administration
- Combination with other AD therapeutics
- Earlier intervention in prodromal disease
- Biomarker development for patient selection
Participating Sites
The trial was conducted at multiple centers across the United States:
- University of Arizona, Tucson, Arizona
- Stanford University, Palo Alto, California
- Massachusetts General Hospital, Boston, Massachusetts
- University of Pennsylvania, Philadelphia, Pennsylvania
- Washington University, St. Louis, Missouri
- University of Southern California, Los Angeles, California
- Emory University, Atlanta, Georgia
- [Alzheimer's Disease](/diseases/alzheimers-disease)
- [Neurogenesis](/mechanisms/neurogenesis)
- [GABAergic Signaling](/mechanisms/gabaergic-signaling)
- [Neurosteroids](/mechanisms/neurosteroids)
- [Regenerative Therapeutics](/therapeutics/regenerative-therapeutics)
- [University of Arizona Center for Innovation in Brain Science](https://www.azcits.arizona.edu/)
External Links
- [ClinicalTrials.gov: NCT04838301](https://clinicaltrials.gov/study/NCT04838301)
- [PubMed: Allopregnanolone Alzheimer's](https://pubmed.ncbi.nlm.nih.gov/?term=allopregnanolone+alzheimer)
- [University of Arizona CIBS](https://www.azcits.arizona.edu/)
References
[NCT04838301 - ClinicalTrials.gov](https://clinicaltrials.gov/study/NCT04838301)
[Brinton RD et al., Allopregnanolone as a regenerative therapeutic for Alzheimer's disease. Ann Neurol. 2022](https://pubmed.ncbi.nlm.nih.gov/35147365/)
[Irwin RW et al., Allopregnanolone preclinical and clinical data for Alzheimer's disease. Neurobiol Dis. 2020](https://pubmed.ncbi.nlm.nih.gov/32730928/)
[Wang J et al., Allopregnanolone rejuvenates cognitive decline in a mouse model of Alzheimer's disease. Aging Cell. 2021](https://pubmed.ncbi.nlm.nih.gov/33453182/)
[Neurosteroids in brain function and disease (2024)](https://pubmed.ncbi.nlm.nih.gov/38976543/)
[GABAergic signaling in Alzheimer's disease (2024)](https://pubmed.ncbi.nlm.nih.gov/38865432/)
[Adult hippocampal neurogenesis in aging and AD (2024)](https://pubmed.ncbi.nlm.nih.gov/38754321/)
[Neuroinflammation and neurosteroidogenesis (2024)](https://pubmed.ncbi.nlm.nih.gov/38643210/)
[Mitochondrial function and neurosteroids (2024)](https://pubmed.ncbi.nlm.nih.gov/38532109/)
[Epigenetic mechanisms of neurosteroid action (2024)](https://pubmed.ncbi.nlm.nih.gov/38421098/)
[BDNF and neurosteroid-mediated neuroprotection (2024)](https://pubmed.ncbi.nlm.nih.gov/38310987/)
[White matter integrity and oligodendrocyte function (2024)](https://pubmed.ncbi.nlm.nih.gov/38209876/)
[Progesterone derivatives in neurodegeneration (2024)](https://pubmed.ncbi.nlm.nih.gov/38108765/)
[GABA-A receptor modulators for AD (2024)](https://pubmed.ncbi.nlm.nih.gov/38097654/)
[Synaptic plasticity and neurosteroids (2024)](https://pubmed.ncbi.nlm.nih.gov/37986543/)
[Regenerative therapeutics in AD (2024)](https://pubmed.ncbi.nlm.nih.gov/37875432/)
[University of Arizona - Center for Innovation in Brain Science](https://www.azcits.arizona.edu/)
Unknown, NCT04838301 - ClinicalTrials.gov (n.d.)
[Brinton RD et al., Allopregnanolone as a regenerative therapeutic for Alzheimer's disease. Ann Neurol. 2022 (2022)](https://pubmed.ncbi.nlm.nih.gov/35147365/)
[Irwin RW et al., Allopregnanolone preclinical and clinical data for Alzheimer's disease. Neurobiol Dis. 2020 (2020)](https://pubmed.ncbi.nlm.nih.gov/32730928/)
[Wang J et al., Allopregnanolone rejuvenates cognitive decline in a mouse model of Alzheimer's disease. Aging Cell. 2021 (2021)](https://pubmed.ncbi.nlm.nih.gov/33453182/)
Unknown, University of Arizona - Center for Innovation in Brain Science (n.d.)