This Phase 2/3 clinical trial evaluates remternetug (LY3372993) in individuals with early-onset Alzheimer's disease, with a specific focus on patients with genetic forms of AD. The trial targets 280 participants and represents a precision medicine approach to AD treatment, addressing the unmet need for disease-modifying therapies in younger patients with genetically determined forms of the disease.
Early-onset Alzheimer's disease (EOAD), defined as onset before age 65, accounts for approximately 5-10% of all AD cases and is often associated with autosomal dominant genetic mutations. This trial specifically enrolls individuals at risk for or with early-onset AD caused by genetic mutations, making it distinct from the broader Phase 3 TRAILBLAZER-ALZ 3 study[@eli2024].
| Parameter |
Value |
| NCT Number |
NCT06647498 |
| Phase |
PHASE 2/3 |
| Status |
RECRUITING |
| Sponsor |
Eli Lilly and Company |
| Enrollment |
280 participants |
| Enrollment Type |
ACTUAL |
| Study Type |
INTERVENTIONAL |
| Intervention |
Remternetug (LY3372993) |
| Control |
Placebo |
| Allocation |
Randomized |
Early-onset Alzheimer's disease (EOAD) presents unique challenges compared to late-onset AD:
Epidemiology:
- Represents 5-10% of all AD cases
- Often more rapid disease progression
- Frequently associated with genetic mutations
- Average onset age: 45-65 years
Genetic Factors:
Approximately 10-15% of EOAD cases are caused by autosomal dominant mutations in one of three genes:
The DIAN (Dominantly Inherited Alzheimer Network) study has established that individuals with these mutations show biomarker changes 15-25 years before clinical onset, providing a unique opportunity for prevention trials[@bateman2017].
Individuals with autosomal dominant AD (ADAD) share core pathological features with sporadic AD, including amyloid-beta plaque formation, tau pathology, and neurodegeneration. However, they offer distinct advantages for therapeutic trials:
- Predictable disease course: Known age of onset enables pre-symptomatic intervention
- Uniform pathology: Single mutation causes the disease
- Biomarker consistency: More homogeneous biomarker changes
- Younger subjects: Longer potential treatment benefit window
The amyloid cascade hypothesis remains relevant for genetic AD, as all three ADAD genes directly affect amyloid-beta production or aggregation. Therefore, amyloid-targeting therapies like remternetug may be particularly effective in this population[@reitz2021].
Remternetug is an intravenous monoclonal antibody developed by Eli Lilly that targets amyloid-beta (Aβ) plaques through a conformational epitope distinct from earlier-generation antibodies. Key features include:
- Broad aggregate recognition: Targets multiple Aβ aggregation states including oligomers, protofibrils, and plaques
- Rapid plaque clearance: Phase 2 data showed ~70% amyloid reduction at 6 months, faster than donanemab[@sims2024]
- Downstream effects: Biomarker evidence of reduced tau pathology (20% reduction in CSF p-tau181)[@blennow2024]
Patients with genetic forms of AD represent an ideal population for amyloid-targeting therapy:
- High amyloid burden: Mutations directly increase Aβ production
- Confirmed pathology: Genetic confirmation of AD diagnosis
- Younger age: Better potential to preserve function
- Predictable progression: Enable clear outcome assessment
- Active plaque formation: Ongoing pathology for antibody to target
This is a Phase 2/3, randomized, double-blind, placebo-controlled trial with adaptive design elements:
- Randomization: 1:1 ratio remternetug to placebo
- Blinding: Double-blind (participant and investigator)
- Duration: Designed to assess both short-term amyloid clearance and clinical outcomes
- Population: Adults with confirmed early-onset AD or genetic risk
| Arm |
Description |
Expected N |
| Remternetug |
Active treatment |
~140 |
| Placebo |
Control |
~140 |
- Age 40-65 years
- Early-onset Alzheimer's disease OR documented genetic mutation
- Confirmed amyloid pathology (PET or CSF)
- Mild cognitive impairment or mild dementia
- MMSE ≥ 20
- Clinical Dementia Rating (CDR) 0.5-1.0
- Amyloid plaque change measured by PET at 6-12 months
- Cognitive/functional decline measured by clinical scales
- Change in CSF biomarkers (Aβ42, p-tau181, t-tau)
- Brain volume changes on MRI
- Safety and tolerability
- ARIA (Amyloid-Related Imaging Abnormalities) incidence
This trial represents a shift toward precision medicine in Alzheimer's disease:
- Genetically stratified enrollment: Focuses on patients with known or suspected genetic etiology
- Younger population: Addresses an underserved patient group
- Disease modification focus: Targets underlying pathology rather than symptoms
- Prevention potential: May inform treatment of pre-symptomatic individuals
The outcomes of this trial will inform several key questions:
- Efficacy in genetic AD: Does amyloid clearance benefit patients with autosomal dominant disease?
- Optimal treatment timing: Does earlier intervention yield better outcomes?
- Biomarker validation: Do amyloid and tau biomarkers predict clinical response?
- Safety in younger patients: Is the safety profile comparable to late-onset AD?
Remternetug aims to build on the success of approved amyloid antibodies:
| Drug |
Company |
Status |
Key Differentiation |
| Lecanemab |
Eisai/Biogen |
Approved |
Protofibril targeting |
| Donanemab |
Eli Lilly |
Approved |
Plaque targeting |
| Remternetug |
Eli Lilly |
Phase 2/3 |
Conformational epitope, faster clearance |
Amyloid-Related Imaging Abnormalities remain the primary safety concern:
- ARIA-E (edema): Brain edema detected on MRI
- ARIA-H (hemorrhage): Microhemorrhages or superficial siderosis
Risk factors:
- Higher antibody dose
- ApoE4 carrier status
- Prior cerebral microhemorrhages
Monitoring protocol:
- Baseline MRI
- Periodic MRI during treatment
- Clinical monitoring for symptoms
Based on Phase 1/2 data:
| Adverse Event |
Expected Frequency |
| ARIA-E |
15-25% |
| ARIA-H |
5-10% |
| Infusion reactions |
5-8% |
| Headache |
10-15% |
¶ Genetic Testing and Counseling
The trial's focus on early-onset AD with genetic emphasis requires robust genetic counseling infrastructure:
Pre-enrollment genetic considerations:
- Participants may carry known pathogenic mutations in APP, PSEN1, or PSEN2
- Genetic testing may reveal APOE ε4 allele status, a major risk factor
- Results may have implications for family members
Genetic counseling requirements:
- Pre-test counseling regarding implications of genetic results
- Support for family communication of genetic information
- Resources for psychological support
The trial employs advanced biomarker stratification to ensure participant homogeneity:
| Biomarker |
Assessment Method |
Purpose |
| Amyloid positivity |
PET or CSF Aβ42 |
Confirm AD pathology |
| Tau burden |
CSF p-tau181 or PET |
Stage disease |
| Neurodegeneration |
MRI, CSF t-tau |
Assess neuronal injury |
| APOE genotype |
Genetic testing |
Risk stratification |
This biomarker-driven approach ensures that participants have confirmed AD pathology, reducing heterogeneity that has confounded previous trials.
¶ Pharmacokinetics and Pharmacodynamics
| Property |
Value |
Clinical Implication |
| Route |
Intravenous infusion |
Requires clinical visits |
| Half-life |
~30 days |
Monthly or quarterly dosing |
| Brain penetration |
Moderate |
Achieves therapeutic levels |
| Target occupancy |
High |
Effective amyloid clearance |
The Phase 2/3 dose selection balances efficacy and safety:
- Higher doses achieve more rapid amyloid clearance
- Lower doses reduce ARIA risk
- The adaptive design allows dose optimization
Remternetug is being developed through a comprehensive clinical program:
| Trial |
Phase |
Population |
Status |
| TRAILBLAZER-ALZ |
Phase 2 |
Early AD (1) |
Completed |
| TRAILBLAZER-ALZ 2 |
Phase 3 |
Early AD |
Active |
| TRAILBLAZER-ALZ 3 |
Phase 3 |
Early AD (broader) |
Active |
| NCT06647498 |
Phase 2/3 |
Early-onset/genetic |
Recruiting |
The development program is designed to support:
- Accelerated approval based on amyloid clearance
- Traditional approval based on clinical outcomes
- Label indications for early-onset AD specifically
- Age: 40-65 years (early-onset window)
- Diagnosis:
- Early-onset Alzheimer's disease OR
- Documented autosomal dominant AD mutation
- Cognitive status:
- Mild cognitive impairment (MCI) due to AD OR
- Mild dementia due to AD
- Amyloid confirmation:
- Positive amyloid PET OR
- CSF biomarker evidence
- Functional status:
- Neurological conditions:
- History of stroke
- Active neurological disease
- Significant head trauma
- Psychiatric conditions:
- Active major depression
- Psychotic symptoms
- Medical conditions:
- Uncontrolled hypertension
- Active malignancy
- Significant liver/renal disease
- Medications:
The 280 participant enrollment provides:
- 80% power to detect 25% slowing of decline
- Adequate subgroup analysis for genetic vs. sporadic
- Safety database for regulatory submission
| Population |
Definition |
Purpose |
| ITT |
All randomized |
Primary efficacy |
| mITT |
Received treatment + baseline |
Sensitivity |
| Per-protocol |
No major protocol deviations |
Confirmatory |
| Safety |
All exposed |
Safety assessment |
If approved, remternetug could form the backbone of combination approaches:
- With other amyloid antibodies: Sequential or combination therapy
- With tau-targeting agents: Multi-target intervention
- With disease-modifying approaches: Neuroprotection, neuroinflammation
The trial contributes to validating:
- Plasma p-tau181 as treatment response marker
- PET as surrogate endpoint
- CSF biomarkers for patient selection
- [Eli Lilly. Remternetug (LY3372993) Corporate Presentation (2024)](https://www.eli Lilly.com)
- TRAILBLAZER-ALZ 4: Comparison of remternetug and donanemab (2024)
- TRAILBLAZER-ALZ 4: 6-month amyloid clearance results (2024)
- Biomarker changes in remternetug-treated patients (2024)
- Lecanemab in early Alzheimer's disease (2023)
- Genetics of Alzheimer disease (2021)
- Autosomal-dominant Alzheimer's disease: a review (2017)
- The diagnosis and progression of autosomal dominant Alzheimer disease (2016)
- Early-onset Alzheimer's disease: epidemiology, clinical presentation, and genetics (2024)
- Amyloid-targeting monoclonal antibodies in Alzheimer's disease: mechanisms and clinical outcomes (2024)
- Dominantly Inherited Alzheimer Network: lessons from prevention trials (2024)
- Precision medicine approaches in Alzheimer's disease clinical trials (2024)
- Amyloid-related imaging abnormalities in anti-amyloid antibody trials (2024)