Allopregnanolone Regenerative Therapeutic (NCT04838301)

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

Allocation

Intervention Model

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

Mechanism of Action

Allopregnanolone is a neurosteroid — a naturally occurring neuromodulator derived from progesterone that acts as a positive allosteric modulator of the GABA_A receptor.

Key Mechanisms

Relevance to Alzheimer's Disease

• 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

Exclusion Criteria

Results 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

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

• 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

Related Resources

• [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