Trontinemab (RO7126209) Phase 3 Trial — TRONTIER 2 (NCT07170150) is a pivotal Phase 3 clinical trial evaluating trontinemab, an innovative anti-tau antibody with enhanced brain penetration, in patients with early symptomatic Alzheimer's disease. This trial represents a significant advancement in tau-directed immunotherapy for Alzheimer's disease, combining a novel mechanism of action with an advanced delivery technology designed to overcome one of the greatest challenges in CNS drug development: effective antibody delivery across the blood-brain barrier.
| Field |
Value |
| NCT ID |
NCT07170150 |
| Phase |
Phase 3 |
| Status |
Recruiting |
| Sponsor |
Hoffmann-La Roche |
| Acronym |
TRONTIER 2 |
| Start Date |
November 12, 2025 |
| Primary Completion |
June 7, 2028 |
| Enrollment |
800 participants |
| Study Design |
Randomized, double-blind, placebo-controlled |
| Treatment Duration |
72 weeks (18 months) |
| Follow-up |
28 weeks post-treatment |
TRONTIER 2 is a Phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group efficacy and safety study of trontinemab in participants with early symptomatic Alzheimer's disease (MCI to mild dementia due to AD). The trial employs a sophisticated design with multiple arms and extensive biomarker substudies.
| Arm |
Type |
Description |
Dose |
| Trontinemab Low Dose |
Experimental |
IV infusion of trontinemab |
TBD |
| Trontinemab High Dose |
Experimental |
IV infusion of trontinemab |
TBD |
| Placebo |
Placebo Comparator |
IV infusion of placebo |
N/A |
¶ Randomization
- Ratio: 1:1:1 (low dose : high dose : placebo)
- Stratification: By age, baseline cognitive status, and ApoE status
- Blinding: Double-blind maintained through all treatment and follow-up periods
Inclusion Criteria:
- Condition: Early symptomatic Alzheimer's disease (MCI to mild dementia due to AD)
- Age: 50-85 years
- MMSE: 20-28 (inclusive)
- Clinical Dementia Rating (CDR): 0.5 or 1.0
- Amyloid positivity: Confirmed by PET or CSF biomarkers
- Brain MRI: Consistent with AD, no significant vascular pathology
- Stable on background AD therapy (if applicable)
Exclusion Criteria:
- Significant psychiatric illness
- Active neurological disease other than AD
- History of stroke or significant vascular disease
- Contraindications to MRI
- Prior anti-tau immunotherapy
¶ Anti-Tau Antibody
Trontinemab (RO7126209) is an anti-tau antibody designed to target pathological tau protein in the brain. Tau protein is a microtubule-associated protein that, in Alzheimer's disease, becomes hyperphosphorylated, aggregates into neurofibrillary tangles (NFTs), and propagates throughout the brain in a predictable pattern that closely correlates with cognitive decline.
The tau protein undergoes several pathological modifications in Alzheimer's disease:
- Hyperphosphorylation: Abnormal phosphorylation at multiple sites (Ser202, Thr231, Ser396, etc.) reduces tau's ability to bind microtubules
- Oligomerization: Toxic soluble oligomers form before insoluble fibrils
- Fibril Formation: Paired helical filaments that constitute neurofibrillary tangles
- Propagation: Tau seeds spread trans-synaptically between neurons, contributing to disease progression
The "Braak staging" system describes the progression of tau pathology through the brain in a hierarchical manner, beginning in the entorhinal cortex and spreading to the hippocampus, limbic structures, and eventually throughout the neocortex.
The key innovation of trontinemab is the Brain Shuttle technology, which enhances delivery of the antibody across the blood-brain barrier (BBB). This approach aims to overcome the traditional challenge of limited CNS penetration for large molecule therapeutics.
- Engineered Fc fragment: The antibody is engineered with a modified Fc region that binds to transferrin receptor (TfR) on brain endothelial cells
- Receptor-mediated transcytosis: The antibody-TfR complex is internalized and transported across the endothelial cell
- Release into brain parenchyma: The antibody is released into the brain interstitium
- Target engagement: The antibody binds to pathological tau in the brain
- Increased brain exposure: Up to 10-20x higher brain concentrations compared to conventional antibodies
- Reduced peripheral exposure: Lower doses may achieve therapeutic brain levels
- Improved target engagement: Better occupancy of tau targets in the brain
- Potential for lower dosing: Reduced risk of peripheral side effects
In preclinical models, the Brain Shuttle technology demonstrated:
- Enhanced brain uptake in non-human primates
- Reduced plaque-bound antibody in periphery
- Improved distribution throughout brain parenchyma
- Maintained target engagement in tau pathology models
The first-in-human study of trontinemab showed promising results:
- Safety: Generally well-tolerated with no dose-limiting toxicities
- Pharmacokinetics: Extended half-life supporting less frequent dosing
- Target engagement: Dose-dependent reduction in CSF tau species
- Biomarker signals: Encouraging effects on neurodegeneration markers
- ARIA: Low rates of amyloid-related imaging abnormalities (ARIA)
- Change from baseline to Week 72 in Clinical Dementia Rating, Sum of Boxes (CDR-SB)
The CDR-SB is a validated global measure of cognition and function that assesses six domains: memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care. A change of 0.5-1.0 points is considered clinically meaningful in early AD populations.
- ADAS-Cog-13: Alzheimer's Disease Assessment Scale - Cognitive subscale (13-item version)
- MMSE: Mini-Mental State Examination
- NCTR-ERB: Neuropsychological Test Battery with Emotional Recognition
- ADCS-ADL: Alzheimer's Disease Cooperative Study - Activities of Daily Living
- iADRS: Integrated Alzheimer's Disease Rating Scale (composite of cognitive and functional)
- Brain amyloid load: Amyloid PET (Centiloid scale)
- Brain tau load: Tau PET (subset of participants)
- CSF biomarkers:
- Phosphorylated tau (p-tau181)
- Total tau
- Neurogranin (synaptic marker)
- Aβ42/40 ratio
- Blood biomarkers:
- ARIA-E/E: Amyloid-related imaging abnormalities - edema/effusion
- ARIA-H: Amyloid-related imaging abnormalities - hemorrhage
- Infusion reactions: Rate and severity
- Anti-drug antibodies: Immunogenicity assessment
- Adverse events: Comprehensive safety monitoring
- Brain volume: MRI volumetric measures (hippocampus, ventricles)
- Connectivity: Resting-state fMRI
- Digital biomarkers: Smartphone-based cognitive assessments
- Pharmacogenomics: ApoE genotype effects on response
¶ Positioning in AD Therapeutic Landscape
Trontinemab represents a next-generation approach in the AD therapeutic pipeline:
- Complementary to anti-amyloid therapies: While lecanemab and donanemab target amyloid, trontinemab targets downstream tau pathology
- Potential for combination: May eventually be combined with amyloid-targeted approaches
- Earlier intervention: Focus on early AD population may provide maximal benefit
- Enhanced delivery: Brain Shuttle may improve efficacy through better brain penetration
Tau immunotherapy faces several challenges that trontinemab's design addresses:
- BBB penetration: Brain Shuttle technology specifically addresses this
- Target specificity: Trontinemab targets pathological tau specifically
- Off-target effects: Engineered Fc reduces peripheral binding
- Immunogenicity: Humanized antibody design minimizes immune response
| Approach |
Company |
Stage |
Mechanism |
| Trontinemab (RO7126209) |
Roche |
Phase 3 |
Anti-tau antibody with Brain Shuttle |
| Semorinemab |
Genentech |
Phase 2 |
Anti-tau antibody |
| Tilavonemab |
AbbVie |
Phase 2 |
Anti-tau antibody |
| JNJ-63733657 |
Janssen |
Phase 1 |
Anti-tau antibody |
| BIIB080 |
Biogen |
Phase 1 |
Anti-tau ASO |
The trial is being conducted at multiple sites globally, including in the United States, United Kingdom, Germany, France, Spain, Italy, Japan, South Korea, Australia, and Canada. For current site information, visit ClinicalTrials.gov.
Major academic medical centers and private research sites across the country
- United Kingdom: Multiple NHS trusts and private hospitals
- Europe: Sites in Germany (Charité, etc.), France, Spain, Italy
- Asia-Pacific: Japan, South Korea, Australia
- Extension studies: Planned to assess long-term safety and efficacy
- Open-label phases: Potential for participants to receive active treatment
- Anti-amyloid combination: Rationale for combining with approved anti-amyloid antibodies
- Small molecule combinations: Potential with symptomatic treatments
- Patient selection: Refinement of biomarker-based patient selection
- Response prediction: Identification of predictors of treatment response
- Monitoring: Development of real-time biomarker monitoring approaches