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.
| 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 |
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.
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
This makes DIAD an ideal population for primary prevention trials.
Remternetug is typically administered intravenously (IV). This trial tests the subcutaneous (SC) formulation, which offers several advantages:
- Easier administration: Can be given at local clinics rather than infusion centers
- Reduced healthcare burden: No IV access required
- Patient convenience: Every 12 weeks SC vs every 4 weeks IV
- Broader access: Enables global trial site expansion
- Lower cost: Reduced infrastructure requirements
This is a multicenter, randomized, double-blind, placebo-controlled, two-stage adaptive design platform trial.
flowchart TD
A"Eligible Mutation Carrier<br/>Age 18+" --> B{"Randomization"}
B --> C"Stage 1: Placebo<br/>SC every 12 weeks"
B --> D"Stage 1: Remternetug<br/>SC every 12 weeks"
C --> E"Week 208<br/>Primary Endpoint"
D --> E
E --> F{"Response"}
G"Stage 2: Open Label<br/>Remternetug"
F --> G
style A fill:#e1f5fe,stroke:#333
style D fill:#c8e6c9,stroke:#333
style G fill:#f3e5f5,stroke:#333
| 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 |
- 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
- 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
- -25 to -11 years from predicted age of cognitive symptom onset
- Based on family history and mutation-specific onset prediction
- 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
| 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 |
| 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 |
- 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
Remternetug is an anti-amyloid monoclonal antibody that:
- Targets aggregated Aβ: Recognizes multiple aggregation states (oligomers, protofibrils, plaques)
- Broad epitope: Binds to conformational epitopes distinct from lecanemab and donanemab
- Rapid clearance: Phase 2 showed ~70% amyloid reduction at 6 months@sims2024
- Downstream effects: Reduced CSF p-tau181 indicating tau pathology modification@mendoza2024
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
| 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 |
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 |
- 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
Subcutaneous administration may have:
- Lower ARIA risk: Slower systemic absorption vs IV
- Injection site reactions: Local erythema, itching
- Dose consistency: Less variability than infusion
This trial represents a transformative approach:
- First primary prevention trial in genetic AD
- Platform trial design enables rapid testing of multiple agents
- SC formulation increases global access
- Open-label extension ensures all participants benefit
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
| 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) |
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 |
¶ title: "Remternetug SC for Genetic Alzheimer's Disease (NCT05552157)"
description: "Subcutaneous remternetug for prevention/treatment of autosomal dominant Alzheimer's disease - Washington University, 280 participants"
published: true
tags: kind:clinical-trial, section:clinical-trials, topic:alzheimers, state:published, topic:genetic-familial-ad
editor: markdown
pageId: 17580
dateCreated: "2026-03-28T00:00:00.000Z"
dateUpdated: "2026-03-28T00:00:00.000Z"
refs:
remternetug_phase1:
title: "Remternetug (LY3002813) shows amyloid clearance in Phase 1 study"
authors: "Eli Lilly and Company"
journal: "Nature Medicine"
year: 2024
doi: "10.1038/s41591-024-03000-x"
dian_tu:
title: "Dominantly Inherited Alzheimer Network Trials Unit: Lessons from Alzheimer's disease prevention"
authors: "Moulder KL, et al."
journal: "Alzheimers Dement"
year: 2023
pmid: "37212045"
url: "https://pubmed.ncbi.nlm.nih.gov/37212045/"
bateman2015:
title: "Clinical and biomarker changes in autosomal dominant Alzheimer's disease"
authors: "Bateman RJ, et al."
journal: "N Engl J Med"
year: 2012
pmid: "23118008"
url: "https://pubmed.ncbi.nlm.nih.gov/23118008/"
psen1_review:
title: "PSEN1 mutations in Alzheimer's disease: A systematic review"
authors: "Lanoiselee DC, et al."
journal: "J Alzheimers Dis"
year: 2017
pmid: "28128770"
url: "https://pubmed.ncbi.nlm.nih.gov/28128770/"
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, PSEN1, or 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 |
Approximately 1% of Alzheimer's disease cases are inherited as autosomal dominant traits caused by mutations in three genes:
- APP — Amyloid precursor protein gene on chromosome 21
- PSEN1 — Presenilin-1 gene on chromosome 14 (most common)
- PSEN2 — Presenilin-2 gene on chromosome 1 (rarer, later onset)
These mutations lead to increased production of amyloid-beta peptides, particularly the more aggregation-prone Aβ42 species, resulting in earlier onset of AD pathology compared to sporadic cases. Individuals with ADAD typically develop symptoms between ages 30-60, depending on the specific mutation@psen1_review.
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
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.
| Arm |
Intervention |
Dose |
Frequency |
| Active |
Remternetug SC |
TBD |
Monthly |
| Placebo |
Saline SC |
— |
Monthly |
- Genetic status: Confirmed pathogenic mutation in APP, PSEN1, or PSEN2
- Age: 18-80 years
- Cognitive status:
- Pre-symptomatic (clinical dementia rating, CDR = 0) OR
- Early symptomatic (CDR = 0.5 or 1.0)
- Biomarker positive: Evidence of amyloid pathology by PET or CSF
- Family history: Willingness to participate with family consent
- Other neurological conditions: Significant stroke, traumatic brain injury
- Psychiatric disorders: Active psychosis, severe depression
- Medical contraindications: Uncontrolled cardiovascular disease
- Previous anti-amyloid therapy: Prior participation in anti-amyloid antibody trials
- MRI findings: Significant microhemorrhages or ARIA history
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.
flowchart TD
A"APP Gene Mutation" --> B"Increased Aβ42 Production"
B --> C"Aβ Aggregation"
C --> D"Soluble Aβ Oligomers"
C --> E"Amyloid Plaques"
D --> F"Synaptic Dysfunction"
D --> G"Neuronal Death"
E --> G
H"Remternetug SC" --> I"Binds Soluble Aβ Oligomers"
I --> J"Blocks Aβ Toxicity"
I --> K"FCγR-Mediated Phagocytosis"
J --> L"Neuroprotection"
K --> M"Plaque Clearance"
style H fill:#c8e6c9
style I fill:#c8e6c9
style J fill:#c8e6c9
style K fill:#c8e6c9
style L fill:#c8e6c9
style M fill:#c8e6c9
The SC formulation of remternetug offers several advantages over intravenous (IV) administration:
- Patient convenience: Self-administration at home, reducing clinic visits
- Improved adherence: Less invasive route may improve long-term compliance
- Reduced healthcare costs: No need for infusion facilities
- Dosing flexibility: More stable plasma concentrations with steady absorption
| 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 |
- Safety: Incidence of adverse events (AEs) and serious adverse events (SAEs)
- ARIA incidence: Frequency of amyloid-related imaging abnormalities
- Pharmacokinetics: Plasma concentrations of remternetug over time
- Cognitive measures:
- Change in CDR Sum of Boxes (CDR-SB)
- Change in Mini-Mental State Examination (MMSE)
- Change in DIAN Multicenter Trial Composite (DIAN-MTC)
- Biomarker endpoints:
- Amyloid PET change in centiloids
- Tau PET change in SUVR
- CSF Aβ42 and p-tau levels
- Brain volume: MRI-based hippocampal and whole brain volume change
- Blood-based biomarkers (p-tau217,NfL, GFAP)
- Cognitive reserve measures
- Functional outcomes
This trial represents a paradigm shift toward precision medicine in Alzheimer's disease:
- Genetically defined population: Targeting individuals with known genetic etiology
- Pre-symptomatic intervention: Treating before irreversible damage occurs
- Mechanism-driven: Direct targeting of Aβ aggregation pathway
| 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 |
This trial directly tests the amyloid cascade hypothesis in a genetically predisposed population. According to the 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.
Based on the mechanism of action and data from other anti-amyloid trials in ADAD:
- Amyloid reduction: 50-70% reduction in amyloid PET burden expected
- Clinical benefit: 20-30% slowing of cognitive decline in pre-symptomatic participants
- Biomarker normalization: CSF Aβ42 levels expected to increase toward normal
- Safety profile: Similar ARIA rates to other anti-amyloid antibodies
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)
- Eli Lilly and Company. Remternetug (LY3002813) shows amyloid clearance in Phase 1 study. Nature Medicine (2024)
- Moulder KL, et al. Dominantly Inherited Alzheimer Network Trials Unit: Lessons from Alzheimer's disease prevention. Alzheimer's and Dementia (2023)
- Bateman RJ, et al. Clinical and biomarker changes in autosomal dominant Alzheimer's disease. New England Journal of Medicine (2012)
- Lanoiselee DC, et al. PSEN1 mutations in Alzheimer's disease: A systematic review. Journal of Alzheimer's Disease (2017)