NRTIs for Alzheimer's Disease - Phase 1 (NCT07210528)

Overview

This Phase 1 clinical trial investigates the repurposing of nucleoside reverse transcriptase inhibitors (NRTIs) — traditionally used for HIV treatment — for Alzheimer's disease. The trial is being conducted at National University Hospital Singapore and represents an innovative approach targeting the endogenous retroviral element hypothesis of neurodegeneration [1].

Trial Details

Overview

This Phase 1 clinical trial investigates the repurposing of nucleoside reverse transcriptase inhibitors (NRTIs) — traditionally used for HIV treatment — for Alzheimer's disease. The trial is being conducted at National University Hospital Singapore and represents an innovative approach targeting the endogenous retroviral element hypothesis of neurodegeneration [1].

Trial Details

| Parameter | Value |
|-----------|-------|
| Trial ID | NCT07210528 |
| Phase | Phase 1 |
| Status | Recruiting |
| Participants | 48 |
| Location | National University Hospital, Singapore |
| Intervention | Emtricitabine + Descovy (FTC/TDF) |
| Indication | Alzheimer's Disease |
| Sponsor | National University of Singapore |

Background and Rationale

The Viral Hypothesis of Alzheimer's Disease

The endogenous retroelement hypothesis proposes that human endogenous retroviruses (HERVs) may contribute to Alzheimer's disease pathogenesis. These are remnants of ancient viral infections incorporated into the human genome over millions of years of evolution [2].

Key HERVs Implicated in AD:

• HERV-K (HML-2): Most active endogenous retrovirus, expresses viral proteins in AD brain
• HERV-W: Associated with neuroinflammation and demyelination
• ERVWE1: Syncytin-1, involved in cell fusion and neuroinflammation

Evidence Supporting the Hypothesis

• Post-mortem brain studies show elevated HERV-K RNA and protein in AD temporal cortex
• HERV-K envelope proteins detected in neurons and glia of AD patients
• CSF HERV-K DNA levels correlate with disease severity

• HERV activation can trigger neuroinflammatory cascades
• Reverse transcriptase activity may interfere with amyloid processing
• Viral proteins may promote tau phosphorylation
• HERV-mediated IFN response drives chronic neuroinflammation

• AZT and other NRTIs reduce HERV-K expression in cell culture
• NRTI treatment decreases amyloid-beta production in vitro
• Animal models show reduced neuroinflammation with NRTI treatment

Rationale for NRTI Repurposing

NRTIs have several advantages for AD therapy:

Treatment Regimen

Drug Combination

• Emtricitabine (FTC): 200mg once daily
• Cytidine analog, incorporates into viral DNA causing chain termination
• Half-life: 10 hours, supporting once-daily dosing
• Generally well-tolerated with good CNS penetration
• Descovy (FTC/TDF): 200mg/25mg once daily
• Fixed-dose combination of emtricitabine and tenofovir alafenamide
• Improved renal and bone safety compared to older formulations
• Tenofovir alafenamide has enhanced lymphoid tissue penetration

Study Duration

• Treatment Period: 12 weeks
• Selected to balance efficacy assessment with safety monitoring
• Allows adequate time for biomarker changes to manifest
• Follow-up Period: 24 weeks
• Extended monitoring for safety and durability of effects
• Assesses whether benefits persist after treatment cessation

Inclusion Criteria

Key Eligibility Requirements

• Age: 50-80 years
• Diagnosis: Clinical diagnosis of Alzheimer's disease per NIA-AA criteria
• Cognitive Status: MMSE score 18-26 (mild to moderate AD)
• MRI Evidence: Neuroimaging consistent with AD pathology
• Stable Medications: No changes to AD medications for 4 weeks
• Capacity: Ability to provide informed consent

Exclusion Criteria

• HIV-positive status (known)
• Significant neurological disorders other than AD
• Active psychiatric conditions
• Severe medical conditions
• Prior NRTI exposure within 12 months

Outcome Measures

Primary Endpoints

• Safety and Tolerability: Adverse event monitoring throughout study
• Standard safety labs (CBC, chemistry, liver/renal function)
• Physical examinations and vital signs
• ECG monitoring
• Assessment of treatment-emergent adverse events
• Adverse Events Monitoring:
• Frequency and severity of all adverse events
• Serious adverse events
• Discontinuations due to adverse events

Secondary Endpoints

• Cognitive Assessment:
• MMSE: Serial cognitive screening
• ADAS-Cog: Primary cognitive endpoint in many AD trials
• Montreal Cognitive Assessment (MoCA): Complementary cognitive measure
• CSF Biomarkers:
• Amyloid-beta 40 and 42: Key markers of amyloid pathology
• Total tau: Marker of neurodegeneration
• Phosphorylated tau (p-tau181): AD-specific tau pathology
• PET Imaging:
• Amyloid PET: Florbetapir or florbetaben to assess amyloid burden
• Quantitative SUVR measurements

Mechanism of Action

NRTI Effects in AD

• NRTIs inhibit reverse transcriptase activity
• Prevent retrotransposition of HERV sequences
• Reduce formation of viral-like DNA species

• Lower HERV activation decreases innate immune stimulation
• Reduced type I interferon response
• Decreased pro-inflammatory cytokine production

• Evidence suggests NRTIs may affect amyloid precursor protein processing
• May reduce amyloid-beta production or aggregation
• Potential effects on amyloid clearance mechanisms

• Neuroprotective effects observed in some models
• May preserve neuronal function and connectivity

Singapore Research Context

National University Hospital (NUH)

The trial is conducted at one of Singapore's premier research institutions:

Research Capabilities:

• State-of-the-art neuroimaging facilities
• Dedicated clinical research unit
• Experienced AD research team
• Access to Singapore's multi-ethnic population

Singapore's AD Research Landscape

Singapore has emerged as a key site for AD clinical research:

• Well-established clinical trial infrastructure
• Strong government support for neuroscience research
• Strategic location bridging Asian and Western research networks
• Rapid patient recruitment capabilities

Comparison with Other Repurposing Approaches

| Drug | Original Use | AD Target | Stage |
|------|-------------|-----------|-------|
| Emtricitabine/Descovy | HIV | Retroelements | Phase 1 |
| Lovotib | Antifungal | Tau aggregation | Phase 2 |
| Metformin | Diabetes | Multiple | Phase 2/3 |
| Losartan | Hypertension | Vascular | Phase 3 |
| Statins | Cholesterol | Neuroinflammation | Phase 3 |

Potential Benefits and Risks

Potential Benefits

• Novel mechanism targeting unaddressed pathway
• Established safety profile from HIV indication
• Potential for disease modification
• Combination with existing therapies

Potential Risks

• Off-target effects on cellular polymerases
• Mitochondrial toxicity (though minimized with modern NRTIs)
• Limited efficacy if HERV hypothesis incorrect
• Unknown optimal dosing for AD

Future Implications

If Successful

• Proof of concept for viral hypothesis of AD
• Novel therapeutic class for AD
• Potential for combination with amyloid/tau-targeted therapies
• Broader application to other neurodegenerative diseases

If Unsuccessful

• Would not definitively disprove viral hypothesis
• May need different NRTI or combination
• Suggests need for more direct antiviral approaches
• Highlights complexity of AD pathogenesis

Summary

This Phase 1 trial represents an innovative approach to Alzheimer's disease treatment based on the endogenous retroelement hypothesis. By repurposing established HIV drugs, the study tests whether suppressing HERV activation can modify AD progression. With 48 participants over 12 weeks of treatment followed by 24 weeks of follow-up, this trial will provide initial safety and efficacy data for this novel therapeutic approach [1][2].

References

See Also

• [Alzheimer's Disease Drug Pipeline](/clinical-trials/drug-pipeline)
• [Neuroinflammation in AD](/mechanisms/neuroinflammation-alzheimers)
• [Amyloid-Targeting Therapies](/therapeutics/amyloid-targeting-therapies)
• [Singapore Neuroscience Research](/institutions/nus)