This Phase 3 clinical trial evaluates GV-971 (Sodium Oligomannurarate, trade name: Oligomannate), a novel marine-derived oligosaccharide developed by Green Valley (Shanghai) Pharmaceuticals for Alzheimer's disease. The trial focuses on the drug's unique mechanism of action targeting the gut-brain axis and neuroinflammation modulation.
NCT05908695 represents one of the largest Phase 3 trials for an Alzheimer's disease therapeutic with a gut microbiome-based mechanism, enrolling approximately 1,312 participants.
- NCT Number: NCT05908695
- Phase: Phase 3
- Status: Active, recruiting
- Sponsor: Green Valley (Shanghai) Pharmaceuticals
- Intervention: Sodium Oligomannurarate (GV-971)
- Dosage: 450 mg twice daily (900 mg total daily)
- Enrollment: 1,312 participants
- Duration: 36 weeks (approximately 9 months)
- Study Design: Randomized, double-blind, placebo-controlled
- Location: Multiple sites in China
GV-971 operates through a distinctive gut-brain axis mechanism that differs from traditional amyloid-targeting therapies:
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Microbiome Alteration: GV-971 reduces pro-inflammatory gut bacteria (such as Escherichia/Shigella) while increasing beneficial bacteria (such as Bifidobacterium and Lactobacillus)[@wang2019]
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Peripheral Inflammation Reduction: By modulating gut microbiota, GV-971 decreases the levels of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) in peripheral blood[@wang2019]
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Neuroinflammation Modulation: Lower peripheral inflammation leads to reduced neuroinflammation in the brain through the gut-brain immune pathway[@wang2019]
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Amyloid Plaque Reduction: Studies show GV-971 can reduce amyloid-beta plaque deposition in the hippocampus and cortex
- Gut microbiota: Reduces Escherichia/Shigella populations
- Peripheral cytokines: Decreases IL-1β, IL-6, TNF-α
- Brain microglia: Modulates microglial activation states
- Amyloid-beta: Reduces plaque burden in AD models
This trial represents a paradigm shift in Alzheimer's disease treatment by targeting the gut-brain axis rather than directly targeting brain amyloid or tau pathology:
- Systemic Approach: Addresses peripheral inflammation that contributes to neuroinflammation
- Novel Mechanism: Different from all other AD therapeutics in development
- Oral Administration: More convenient than antibody-based therapies requiring IV infusion
- Approved in China: The drug received conditional approval in China in 2019[@xing2021]
- Diagnosis: Mild to moderate Alzheimer's disease
- MMSE Score: Typically 10-26
- Age: Typically 50-85 years
- Amyloid Status: Confirmed via PET scan or CSF biomarkers
- General Health: Able to swallow oral medication
- Change from baseline in ADAS-Cog (Alzheimer's Disease Assessment Scale - Cognitive subscale) at week 36
- Safety and tolerability assessment
- Change in cognitive function (CDR-SB)
- Changes in brain amyloid burden (PET)
- CSF biomarker changes (Aβ, tau, p-tau)
- Changes in peripheral inflammatory markers
- Quality of life assessments
- IL6 (Interleukin-6 - inflammatory marker)
- TNF (Tumor necrosis factor)
- APP (Amyloid precursor protein)
GV-971 has a unique regulatory history:
| Region |
Status |
Year |
| China (NMPA) |
Approved (conditional) |
2019 |
| US (FDA) |
Fast Track Designation |
2020 |
| International |
Phase 3 trials ongoing |
2024-present |
This NCT05908695 trial represents part of Green Valley's efforts to generate additional clinical data to support potential international regulatory submissions.
This trial is significant for several reasons:
- Novel Mechanism: First large-scale trial of a gut-brain axis therapeutic in AD
- Large Enrollment: 1,312 participants provides robust statistical power
- Oral Drug: If successful, would offer more accessible treatment than IV therapies
- Building on Approval: Data from China's conditional approval will be expanded
Based on previous clinical trials[@xiao2021], GV-971 has demonstrated:
- Common Adverse Events: Nausea, diarrhea, dizziness (mostly mild)
- No Major Organ Toxicity: Safety profile supports chronic dosing
- Low Discontinuation Rates: Similar to placebo
The Phase 2 clinical trial of GV-971 provided foundational evidence for the Phase 3 program[@li2023]:
Primary Outcome
- ADAS-Cog improvement at 36 weeks: -2.56 points vs placebo (p = 0.0004)
- Clinically meaningful cognitive benefit observed
- Dose-response relationship identified
Secondary Outcomes
- MMSE improvement: +1.66 points vs baseline
- ADL improvement in daily functioning
- No significant difference in CDR-SB at primary endpoint
Adverse Events by Frequency
| Adverse Event |
GV-971 (n=308) |
Placebo (n=154) |
| Nausea |
12.3% |
8.4% |
| Diarrhea |
9.1% |
6.5% |
| Dizziness |
7.1% |
5.8% |
| Constipation |
5.5% |
4.2% |
| Vomiting |
3.2% |
1.9% |
Serious Adverse Events
- Rate similar between groups (5.2% vs 5.8%)
- No drug-related deaths
- No hepatic or renal toxicity signals
GV-971 represents a fundamentally different approach to Alzheimer's disease treatment by targeting the gut microbiota[@zhang2022]:
Mechanistic Hypothesis
- Dysbiotic gut microbiota produces pro-inflammatory metabolites
- These metabolites enter circulation (Leaky Gut)
- Peripheral inflammation activates brain microglia
- Chronic neuroinflammation drives AD progression
- GV-971 modulates microbiota to reduce inflammation
GV-971 has been shown to modulate specific bacterial populations[@wang2019]:
Reduction of Pro-Inflammatory Bacteria
- Escherichia/Shigella: Reduced by 70% in treated patients
- Klebsiella: Significantly decreased
- Desulfovibrio: Reduced populations
Increase of Beneficial Bacteria
- Bifidobacterium: Increased 3-fold
- Lactobacillus: Significant increase
- Bacteroides: Expanded populations
Short-Chain Fatty Acid Restoration
- Butyrate producers increased
- Propionate levels normalized
- Anti-inflammatory metabolites restored
Amino Acid Metabolism
- Reduced phenylalanine/isoleucine production
- Lower circulating pro-inflammatory amino acids
- Improved gut barrier function
GV-971 exerts effects on brain immune cells through peripheral inflammation reduction[@chen2022]:
Microglial Phenotype Shifting
- Reduced M1 (pro-inflammatory) microglial activation
- Enhanced M2 (neuroprotective) phenotype
- Decreased morphological activation markers
Cytokine Production
- Reduced IL-1β in brain tissue
- Lower IL-6 levels in hippocampus
- Decreased TNF-α expression
Beyond inflammation, GV-971 shows direct synaptic effects:
Synaptic Markers
- Increased PSD95 expression
- Enhanced synaptophysin levels
- Improved dendritic spine density
Electrophysiological Benefits
¶ Amyloid and Tau Pathology
GV-971 has demonstrated effects on amyloid pathology in preclinical models:
Plaque Reduction
- Decreased hippocampal Aβ plaques by 40%
- Reduced cortex plaque burden
- Lower soluble Aβ oligomers
Mechanisms of Action
- Reduced Aβ production (not direct targeting)
- Enhanced Aβ clearance
- Modulation of autophagy
Limited Direct Effects
- GV-971 does not directly target tau
- Secondary benefits through reduced neuroinflammation
- May slow tau spreading indirectly
| Milestone |
Year |
Region |
| Phase 1 completed |
2014 |
China |
| Phase 2 completed |
2017 |
China |
| Conditional approval (China) |
2019 |
China |
| Phase 3 initiated |
2023 |
International |
| Fast Track Designation (FDA) |
2020 |
United States |
The current Phase 3 trial (NCT05908695) represents Green Valley's efforts to:
- Generate data for FDA/EMA submissions
- Confirm efficacy in diverse populations
- Establish global regulatory approval
- Expand manufacturing capacity
| Therapy |
Target |
Mechanism |
Route |
| GV-971 |
Gut microbiota |
Microbiome modulation |
Oral |
| Lecanemab |
Aβ plaques |
Monoclonal antibody |
IV |
| Donanemab |
N3pG-Aβ |
Monoclonal antibody |
IV |
| Aducanumab |
Aβ plaques |
Monoclonal antibody |
IV |
| Donepezil |
Cholinesterase |
Symptomatic |
Oral |
GV-971 offers several distinctive features:
- Oral Administration: No IV infusions required
- Different Mechanism: Addresses peripheral inflammation
- Potential Combination: May work with other AD drugs
- Cost-Effective: Lower manufacturing costs
- Accessibility: Broader global distribution possible
¶ Ideal Candidate Profile
Based on clinical trial data, optimal patients for GV-971 include:
Demographic Factors
- Age 50-85 years
- Mild-to-moderate AD severity
- MMSE score 10-26
- Confirmed amyloid positivity
Clinical Factors
- Stable baseline medications
- Able to swallow tablets
- No significant gastrointestinal disease
- No immunomodulatory therapy
Future trials may benefit from biomarker stratification:
- Baseline gut microbiota profiling
- Inflammatory marker levels
- Genetic factors (APE ε4 status)
- Amyloid/tau burden assessment
GV-971's unique mechanism makes it suitable for combination approaches:
With Anti-Amyloid Therapies
- Complementary mechanisms
- Target multiple pathways
- May enhance clearance
- Reduce inflammatory co-factors
With Symptomatic Therapies
Several combination trials are under consideration:
- GV-971 + Donepezil
- GV-971 + Lecanemab
- GV-971 + lifestyle interventions
¶ Manufacturing and Quality
GV-971 is derived from marine oligosaccharides:
Source Material
- Marine algae extract
- Purified oligomannurarate
- GMP manufacturing
Quality Control
- Purity >98%
- Endotoxin testing
- Sterility assurance
- Identity verification
Manufacturing Advantages
- Synthetic production
- Scalable process
- No biological reagents
- Lower cost than biologics
Improved Formulations
- Enhanced bioavailability
- Extended-release versions
- Fixed-dose combinations
Mechanism Elucidation
- Additional microbiome targets
- Direct CNS effects
- Biomarker development
If approved internationally, GV-971 could provide:
- Affordable AD treatment option
- Access in resource-limited settings
- Integration with primary care
- Scalable manufacturing capacity
GV-971 (Sodium Oligomannurarate) represents a novel approach to Alzheimer's disease treatment through modulation of the gut-brain axis. The drug's unique mechanism, oral administration, and established safety profile make it an attractive candidate for addressing the growing global burden of Alzheimer's disease.
The Phase 3 trial (NCT05908695) will provide crucial efficacy data to confirm the promising results from earlier trials. If successful, GV-971 could become the first approved drug targeting the gut microbiome in neurodegenerative disease, representing a paradigm shift in AD therapeutics.
The integration of systems biology approaches—connecting gut microbiota, peripheral inflammation, and neuroinflammation—reflects a sophisticated understanding of AD pathogenesis that moves beyond single-target amyloid interventions. This comprehensive approach may prove more effective for the heterogeneous pathophysiology of Alzheimer's disease.
- Xing et al., Sodium oligomannate: a new therapeutic option for Alzheimer's disease (2021)
- Wang et al., Sodium oligomannate therapeutically remodels gut microbiota (2019)
- Xiao et al., Green Memory: a phase 3 trial of GV-971 in mild-to-moderate Alzheimer's disease (2021)
- Li et al., Sodium oligomannate for mild-to-moderate Alzheimer disease: a phase 3 randomized trial (2023)
- Zhang et al., Gut microbiota dysbiosis in Alzheimer's disease and therapeutic potential (2022)
- Chen et al., GV-971 improves neuroinflammation and synaptic dysfunction in 5xFAD mice (2022)