DNL628 Phase 1 AD Trial (NCT07328451) — Denali Tau ASO
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DNL628 Phase 1 Trial in Early Alzheimer's Disease (NCT07328451)
DNL628 is an [antisense oligonucleotide](/therapeutics/antisense-oligonucleotide-therapy-neurodegeneration) (ASO) targeting tau ([MAPT](/genes/mapt)) mRNA, developed by [Denali Therapeutics](/companies/denali-therapeutics) using the company's proprietary Oligonucleotide Trafficking Vehicle (OTV) technology for enhanced blood-brain barrier (BBB) penetration. It is currently in Phase 1b clinical development for early Alzheimer's disease under NCT07328451.
DNL628 Phase 1 Trial in Early Alzheimer's Disease (NCT07328451)
DNL628 is an [antisense oligonucleotide](/therapeutics/antisense-oligonucleotide-therapy-neurodegeneration) (ASO) targeting tau ([MAPT](/genes/mapt)) mRNA, developed by [Denali Therapeutics](/companies/denali-therapeutics) using the company's proprietary Oligonucleotide Trafficking Vehicle (OTV) technology for enhanced blood-brain barrier (BBB) penetration. It is currently in Phase 1b clinical development for early Alzheimer's disease under NCT07328451.
Trial Overview
Mermaid diagram (expand to render)
| Attribute | Details | |-----------|---------| | NCT Number | NCT07328451 | | Phase | Phase 1b | | Status | Recruiting (as of 2026) | | Sponsor | Denali Therapeutics | | Indication | Early Alzheimer's disease (MCI due to AD or mild AD dementia) | | Mechanism | Tau ASO — reduces MAPT mRNA and protein | | Delivery | OTV (Oligonucleotide Trafficking Vehicle) for BBB penetration | | Route | Intrathecal (IT) injection | | Enrollment | 68 participants (estimated) |
Mechanism of Action
DNL628 is designed to reduce tau protein production through an antisense mechanism:
Target: MAPT mRNA — the gene encoding the [Tau protein](/proteins/tau)
ASO design: Single-stranded oligonucleotide that binds complementary sequence in MAPT pre-mRNA, recruiting RNase H for catalytic degradation of the target mRNA
Downstream effects: Reduced intracellular tau leads to less extracellular tau release, decreased tau aggregation, and reduced spread of pathological tau
BBB penetration: The OTV technology is designed to cross the blood-brain barrier and distribute to CNS neurons, enabling a potential peripheral (IV) delivery approach for ASOs that traditionally require intrathecal administration
OTV Technology
[Denali's OTV platform](/companies/denali-therapeutics) is a key differentiator:
Transferrin receptor (TfR) binding: OTV molecules are designed to engage TfR on the luminal side of brain endothelial cells, facilitating transcytosis across the BBB
CNS neuron targeting: After transcytosis, OTV-ASOs distribute widely in neurons throughout the brain
Reduced dosing frequency: Enhanced CNS exposure may enable less frequent dosing compared to conventional ASOs
Applies to multiple CNS programs: Denali's LRRK2 ASO (DNL351) and other programs also use OTV delivery
Clinical Development Rationale
Tau as a Therapeutic Target in AD
Tau pathology ([neurofibrillary tangles](/proteins/tau)) strongly correlates with cognitive decline in AD, even more than amyloid burden in many studies[@tau_aso_general]:
Braak staging of NFT pathology correlates with clinical severity
Tau PET imaging shows patterns of spread that mirror clinical progression
Reducing tau has been shown to improve cognition in multiple animal models
Two other tau ASO programs (Ionis/BIIB080 for AD, NIO752 for PSP) have shown target engagement in humans
DNL628's key differentiation is the OTV delivery technology, which may provide superior CNS exposure and distribution compared to conventional ASOs[@otv_tech].
Trial Design
Phase 1 Study Structure
Based on the NCT07328451 protocol, this is a multicenter, randomized, placebo-controlled, double-blind, multiple ascending dose (MAD) study:
Part A (if applicable): Single ascending dose cohorts
Part B: Multiple ascending dose (MAD) cohorts receiving multiple doses of DNL628
Primary objectives: Safety and tolerability of DNL628
Secondary objectives: Pharmacokinetics in plasma and CSF, pharmacodynamics (CSF biomarkers including total tau and p-tau181)
Pharmacokinetics: CSF and plasma concentrations of DNL628 over time
Pharmacodynamics: Change from baseline in CSF biomarkers
Cognitive: Change from baseline on ADAS-Cog13 and CDR-SB at 3, 6, 12 months
Patient Population
Inclusion: Diagnosis of probable AD dementia (NIA-AA 2011 criteria), amyloid positivity confirmed at screening, Clinical Dementia Rating (CDR) global score of 0.5 or 1, MMSE score of 20-30, BMI 18-32 kg/m2, body weight ≥45 kg
Amyloid confirmation: Confirmed amyloid pathology via PET or CSF (centiloid > 20)
Exclusion: Other neurodegenerative conditions, significant psychiatric conditions, other causes of cognitive impairment, prior anti-amyloid or anti-tau immunotherapy, prior gene therapy exposure
Biomarker Strategy
DNL628 trials incorporate a comprehensive biomarker panel:
| Biomarker | Target | Utility | |-----------|-------|---------| | CSF total tau | Target engagement | Reduced after ASO treatment (dose-dependent) | | CSF p-tau181 | Disease modification | Tracking tau phosphorylation reduction | | CSF p-tau217 | Disease modification | Highly specific for AD tauopathy | | CSF NfL | Neuroaxonal injury | Monitoring for off-target effects | | Tau PET (MK-6240) | Disease spread | Imaging tau burden changes at higher doses |
Denali's CNS ASO Pipeline
DNL628 is part of Denali's broader CNS oligonucleotide strategy:
DNL351 (LRRK2 ASO): Phase 2 in [Parkinson's disease](/diseases/parkinsons-disease) for G2019S LRRK2 mutation carriers
DNL692 (RIPK1 ASO): Preclinical for ALS and Frontotemporal Dementia
Partnered with Biogen: Collaboration on tau ASO programs (BIIB080/IONIS-MAPT) includes options on Denali's tau ASO pipeline
Connection to Denali Company Page
[Denali Therapeutics](/companies/denali-therapeutics) is a precision neuroscience company founded by former Genentech executives, with a focus on developability and delivery technologies for large molecules and oligonucleotides in neurodegeneration.
Cross-Links
[Denali Therapeutics](/companies/denali-therapeutics) — Company page](/therapeutics)