remternetug-sc-genetic-ad-nct05552157

Remternetug SC for Dominantly Inherited Alzheimer's Disease (NCT05552157)

Overview

This Phase 2/3 clinical trial evaluates remternetug (LY3372993), administered subcutaneously, for the primary prevention of disease progression in individuals with Dominantly Inherited Alzheimer's Disease (DIAD). The trial is conducted through the DIAN-TU (Dominantly Inherited Alzheimer Network - Therapeutic trials) platform, led by Washington University School of Medicine in collaboration with the Alzheimer's Association, Eli Lilly and Company, and the National Institute on Aging (NIA)[@washington2024].

This represents a precision medicine approach targeting individuals with genetic forms of AD caused by autosomal dominant mutations in APP, PSEN1, or PSEN2 genes. Unlike trials in sporadic AD, this study enrolls individuals 25-11 years before predicted cognitive symptom onset, aiming to prevent or significantly delay disease progression.

Trial Details

Remternetug SC for Dominantly Inherited Alzheimer's Disease (NCT05552157)

Overview

This Phase 2/3 clinical trial evaluates remternetug (LY3372993), administered subcutaneously, for the primary prevention of disease progression in individuals with Dominantly Inherited Alzheimer's Disease (DIAD). The trial is conducted through the DIAN-TU (Dominantly Inherited Alzheimer Network - Therapeutic trials) platform, led by Washington University School of Medicine in collaboration with the Alzheimer's Association, Eli Lilly and Company, and the National Institute on Aging (NIA)[@washington2024].

This represents a precision medicine approach targeting individuals with genetic forms of AD caused by autosomal dominant mutations in APP, PSEN1, or PSEN2 genes. Unlike trials in sporadic AD, this study enrolls individuals 25-11 years before predicted cognitive symptom onset, aiming to prevent or significantly delay disease progression.

Trial Details

| Parameter | Value |
|-----------|-------|
| NCT Number | NCT05552157 |
| Trial Name | DIAN-TU-002 Master |
| Phase | Phase 2/Phase 3 |
| Status | RECRUITING |
| Sponsor | Washington University School of Medicine |
| Collaborators | Alzheimer's Association, Eli Lilly and Company, NIA |
| Enrollment | 280 participants |
| Enrollment Type | ESTIMATED |
| Study Type | INTERVENTIONAL |
| Intervention | Remternetug (LY3372993) subcutaneous |
| Control | Matching Placebo |
| Allocation | Randomized |
| Start Date | November 22, 2024 |
| Primary Completion | March 30, 2034 |
| Completion | August 30, 2034 |

Scientific Background

Dominantly Inherited Alzheimer's Disease (DIAD)

DIAD, also known as Autosomal Dominant Alzheimer's Disease (ADAD), is caused by inheriting a single mutated gene from one parent. The disease typically manifests at a predictable age, often 30-50 years younger than sporadic AD[@bateman2017].

| Gene | Protein | Chromosome | Key Mutations |
|------|---------|------------|---------------|
| [APP](/genes/app) | Amyloid Precursor Protein | 21 | Arctic, Swedish, Dutch, Flemish, Iowa |
| [PSEN1](/genes/psen1) | Presenilin 1 | 14 | Over 80 mutations |
| [PSEN2](/genes/psen2) | Presenilin 2 | 1 | Volga German, A79V |

DIAN Network Foundation

The Dominantly Inherited Alzheimer Network (DIAN) has established:

• Predictable onset: Individuals with DIAD mutations show biomarker changes 15-25 years before clinical symptoms
• Uniform pathology: Single gene mutation causes the disease
• Homogeneous biomarkers: Consistent amyloid and tau changes across mutation carriers
• Prevention opportunity: Treatment can begin before irreversible damage[@reitz2021]

Why Subcutaneous Administration?

Remternetug is typically administered intravenously (IV). This trial tests the subcutaneous (SC) formulation, which offers several advantages:

Study Design

This is a multicenter, randomized, double-blind, placebo-controlled, two-stage adaptive design platform trial.

Design Schematic

Treatment Arms

| Stage | Arm | Description | Administration |
|-------|-----|-------------|----------------|
| Stage 1 | Remternetug (Active) | Anti-amyloid antibody | SC every 12 weeks |
| Stage 1 | Matching Placebo | Control | SC every 12 weeks |
| Stage 2 | Remternetug Open Label | All participants | SC every 12 weeks |

Adaptive Design Features

• Two-stage: Stage 1 evaluates efficacy vs placebo; Stage 2 allows open-label extension
• Pre-planned analyses: Multiple interim analyses to assess futility or efficacy
• Sample size re-estimation: Adaptive sample size adjustments based on observed effect size

Inclusion Criteria (Key)

Genetic Requirements

• Confirmed carrier of pathogenic mutation in APP, PSEN1, or PSEN2 gene
• OR at-risk individual with family history of DIAD mutation
• Must have documented family mutation status

Timing Requirement

• -25 to -11 years from predicted age of cognitive symptom onset
• Based on family history and mutation-specific onset prediction

Clinical Requirements

• Cognitively normal (Clinical Dementia Rating Sum of Boxes = 0)
• Has a study partner (collateral informant)
• Fluency in DIAN-TU approved languages
• Adequate visual and auditory abilities
• Stable medications for non-excluded conditions

Age Requirement

• 18 years or older

Exclusion Criteria (Key)

| Category | Exclusion |
|----------|-----------|
| Neurological | Significant neurological disease other than DIAD |
| Psychiatric | Suicidal ideation, major depression |
| Vascular | History of stroke, cerebral hemorrhage |
| Substance | Alcohol/substance use disorder (DSM-V) |
| Imaging | Brain MRI abnormalities |
| Cardiovascular | Uncontrolled hypertension, cardiovascular complications |
| Hepatic/Renal | Abnormal liver function, severe renal impairment |
| Infectious | HIV, Hepatitis B or C |
| Medications | Immunosuppressive medications within 90 days |
| Anticoagulants | Current use of anticoagulants |
| Prior Treatment | Aβ monoclonal antibody within 6 months |
| Investigational | Other investigational treatments within 3 months |
| Special | "Dutch" APP E693Q mutation carriers |

Outcome Measures

Primary Endpoints

| Stage | Measure | Timeframe |
|-------|--------|----------|
| Stage 1 | Change in amyloid accumulation (PET) vs placebo | Baseline to Week 208 |
| Stage 2 | Effect on downstream AD biomarkers | Stage 2 Week 208 |

Secondary Endpoints

• Cognitive change: Memory, executive function, language assessments
• Functional status: Clinical Dementia Rating (CDR)
• Brain volume: MRI hippocampal and whole brain volume
• CSF biomarkers: Aβ42, total tau, phosphorylated tau
• Safety: ARIA incidence, adverse events
• Pharmacokinetics: Drug levels in blood

Therapeutic Rationale

Remternetug Mechanism

Remternetug is an anti-amyloid monoclonal antibody that:

Why Primary Prevention?

Treating individuals before symptoms offers advantages:

• Preserved neuronal function: No irreversible synaptic loss
• Normal cognition: Treatment targets earliest pathology
• Maximum benefit: Greatest potential to delay or prevent onset
• Cleaner readouts: No confounding from symptomatic treatment

SC Formulation Benefits

| Aspect | IV Formulation | SC Formulation |
|--------|---------------|---------------|
| Dosing frequency | Every 4 weeks | Every 12 weeks |
| Administration | Infusion center | Local clinic or home |
| Visit duration | 2-4 hours | 15-30 minutes |
| Healthcare cost | Higher | Lower |
| Patient burden | Greater | Reduced |

Safety Profile

Expected Risks

Based on remternetug IV data:

| Risk | Frequency | Management |
|------|-----------|-------------|
| ARIA-E (edema) | 15-25% | MRI monitoring, dose pause |
| ARIA-H (hemorrhage) | 5-10% | MRI monitoring |
| Injection site reactions | 10-20% | SC-specific |
| Headache | 10-15% | Supportive care |
| Infusion reactions | 5-8% | Pre-medication |

Monitoring Protocol

• Baseline MRI: Establish pre-treatment baseline
• Periodic MRI: At Weeks 12, 24, 52, and per protocol
• Clinical assessment: Every 12 weeks
• Safety labs: Regular monitoring

SC-Specific Considerations

Subcutaneous administration may have:

• Lower ARIA risk: Slower systemic absorption vs IV
• Injection site reactions: Local erythema, itching
• Dose consistency: Less variability than infusion

Significance

For DIAD Community

This trial represents a transformative approach:

Broader Implications

Understanding remternetug efficacy in DIAD will inform:

• Sporadic AD prevention: Can the approach generalize?
• Optimal treatment timing: When to start treatment?
• Biomarker validation: Do amyloid/tau biomarkers predict clinical outcomes?
• Precision medicine: Genetic stratification in AD trials

Comparison to Other Trials

| Trial | Population | Formulation | Company |
|-------|------------|-------------|---------|
| NCT05552157 | DIAD (genetic) | SC | Washington Univ/Eli Lilly |
| NCT06647498 | EOAD | IV | Eli Lilly |
| NCT06653153 | Early AD | IV | Eli Lilly (TRAILBLAZER-ALZ 3) |

Locations

Trial sites across multiple countries:

| Region | Countries |
|-------|-----------|
| North America | US, Canada, Mexico, Puerto Rico |
| South America | Argentina, Colombia |
| Europe | France, Germany, Italy, Netherlands, Spain, UK |
| Oceania | Australia, New Zealand |

Related Resources

• [DIAN-TU-001](/clinical-trials/dian-tu-001) - Previous DIAN platform trial
• [Remternetug Entity Page](/entities/remternetug)
• [APP Gene](/genes/app)
• [PSEN1 Gene](/genes/psen1)
• [PSEN2 Gene](/genes/psen2)
• [Amyloid Cascade Hypothesis](/mechanisms/amyloid-cascade-hypothesis)
• [Dominantly Inherited Alzheimer Network](https://dian.wustl.edu/)
• [ClinicalTrials.gov Record](https://clinicaltrials.gov/study/NCT05552157)

Remternetug SC for Genetic Alzheimer's Disease (NCT05552157)

Overview

NCT05552157 is a clinical trial evaluating the subcutaneous (SC) formulation of remternetug (LY3002813) in individuals with genetic forms of Alzheimer's disease, specifically those with autosomal dominant mutations in [APP](/genes/app), [PSEN1](/genes/psen1), or [PSEN2](/genes/psen2). This trial represents a precision medicine approach targeting hereditary AD, sponsored by Washington University School of Medicine.

| Attribute | Value |
|-----------|-------|
| NCT Number | NCT05552157 |
| Intervention | Remternetug (LY3002813) subcutaneous injection |
| Sponsor | Washington University School of Medicine |
| Phase | Phase 2 |
| Status | RECRUITING |
| Participants | 280 |
| Start Date | September 2022 |
| Completion | 2028 |

Background: Genetic Alzheimer's Disease

Autosomal Dominant Alzheimer's Disease (ADAD)

Approximately 1% of Alzheimer's disease cases are inherited as autosomal dominant traits caused by mutations in three genes:

• [APP](/genes/app) — Amyloid precursor protein gene on chromosome 21
• [PSEN1](/genes/psen1) — Presenilin-1 gene on chromosome 14 (most common)
• [PSEN2](/genes/psen2) — Presenilin-2 gene on chromosome 1 (rarer, later onset)

DIAN Observational Study

This trial builds on the Dominantly Inherited Alzheimer Network (DIAN) observational study, which has been tracking individuals with ADAD mutations since 2008. DIAN has established that:

• Amyloid accumulation begins 20-25 years before clinical symptoms
• Tau PET changes appear ~10 years before symptoms
• Neurodegeneration detectable ~5 years before onset[@bateman2015]

Trial Design

Study Type

This is a Phase 2, randomized, double-blind, placebo-controlled clinical trial evaluating the safety, tolerability, and efficacy of subcutaneous remternetug in pre-symptomatic and symptomatic individuals with ADAD.

Arms

| Arm | Intervention | Dose | Frequency |
|-----|--------------|------|-----------|
| Active | Remternetug SC | TBD | Monthly |
| Placebo | Saline SC | — | Monthly |

Key Inclusion Criteria

• Pre-symptomatic (clinical dementia rating, CDR = 0) OR
• Early symptomatic (CDR = 0.5 or 1.0)

Key Exclusion Criteria

Mechanism of Action

Remternetug is a humanized monoclonal antibody designed to target soluble amyloid-beta aggregates, particularly oligomers and protofibrils, which are considered the most neurotoxic species in AD pathogenesis. This mechanism differs from earlier antibodies that primarily targeted monomeric Aβ or insoluble plaques.

Subcutaneous Administration Advantages

The SC formulation of remternetug offers several advantages over intravenous (IV) administration:

Comparison to IV Formulation

| Feature | SC Formulation | IV Formulation |
|---------|----------------|----------------|
| Bioavailability | ~60-70% | 100% |
| Administration | Home-based | Clinic infusion |
| Visit frequency | Monthly | Monthly |
| Infusion time | Subcutaneous injection | 30-60 minutes |
| Storage | Refrigerated | Professional handling |

Endpoints

Primary Endpoints

Secondary Endpoints

• Change in CDR Sum of Boxes (CDR-SB)
• Change in Mini-Mental State Examination (MMSE)
• Change in DIAN Multicenter Trial Composite (DIAN-MTC)

• Amyloid PET change in centiloids
• Tau PET change in SUVR
• CSF Aβ42 and p-tau levels

Exploratory Endpoints

• Blood-based biomarkers (p-tau217,NfL, GFAP)
• Cognitive reserve measures
• Functional outcomes

Scientific Significance

Precision Medicine for ADAD

This trial represents a paradigm shift toward precision medicine in Alzheimer's disease:

Comparison to Other Prevention Trials

| Trial | Population | Intervention | Status |
|-------|------------|--------------|--------|
| DIAN-TU | ADAD mutation carriers | Anti-amyloid antibodies | Completed |
| API (API-AD) | PSEN1 mutation carriers | Crenezumab | Completed |
| A4 Study | Sporadic elevated amyloid | Solanezumab | Completed |
| NCT05552157 | ADAD mutation carriers | Remternetug SC | Recruiting |

Integration with Amyloid Cascade Hypothesis

This trial directly tests the amyloid cascade hypothesis in a genetically predisposed population. According to the [Amyloid Cascade Hypothesis](/mechanisms/amyloid-cascade-hypothesis), accumulation of Aβ in the brain initiates a pathological cascade leading to tau aggregation, neurodegeneration, and cognitive decline. By treating individuals with ADAD mutations—where Aβ overproduction is the primary driver—this trial provides a rigorous test of the hypothesis.

Expected Outcomes

Based on the mechanism of action and data from other anti-amyloid trials in ADAD:

Trial Sites

The trial is conducted at multiple DIAN-affiliated sites with expertise in genetic Alzheimer's disease:

• Washington University School of Medicine (St. Louis, MO) — Lead site
• Massachusetts General Hospital (Boston, MA)
• University of Pittsburgh (Pittsburgh, PA)
• University of California, Los Angeles (Los Angeles, CA)
• Banner Alzheimer's Institute (Phoenix, AZ)

Cross-References

• [Remternetug Anti-Amyloid Antibody for Alzheimer's Disease](/clinical-trials/remternetug-anti-amyloid-alzheimers) — IV formulation
• [APP Gene](/genes/app) — Amyloid precursor protein
• [PSEN1 Gene](/genes/psen1) — Presenilin-1
• [PSEN2 Gene](/genes/psen2) — Presenilin-2
• [Amyloid Cascade Hypothesis](/mechanisms/amyloid-cascade-hypothesis)
• [APP Amyloid Pathway](/mechanisms/app-amyloid-pathway)
• [Anti-Amyloid Therapeutics](/therapeutics/anti-amyloid-therapeutics)

References