Alzheimer Disease, Early Onset
Conditions
Keywords
Alzheimer's Disease
Brief summary
This is a Phase 1b, multicenter, randomized, placebo-controlled, double-blind, multiple ascending dose (MAD) study to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of DNL628 in participants with early Alzheimer's disease (AD), defined as mild cognitive impairment, or mild AD with biomarker evidence of amyloid positivity. Note: In the Netherlands, this study includes an open-label extension.
Interventions
DRUGDNL628
Multiple ascending doses
DRUGPlacebo
Multiple ascending doses
Sponsors
Denali Therapeutics Inc.
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Masking description
Sponsor staff directly interacting with the site (clinical operations and medical monitor) will be blinded but may be unblinded if necessary to ensure participant safety.
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * BMI of ≥18 to \< 32 kg/m2 and body weight of ≥45 kg * Have a diagnosis of probable AD dementia based on NIA AA 2011 criteria, including amnestic or nonamnestic presentation at screening * Have supportive evidence of AD pathology via historical records or laboratory testing at screening for amyloid positivity * Have AD severity defined as the following at screening: * A Clinical Dementia Rating global score of 0.5 or 1 * A Mini-Mental State Examination score of 20 to 30 (inclusive) Key
Exclusion criteria
* Have clinically significant neurological or cognitive disorders affecting the CNS other than AD, as determined by the investigator * Have clinically significant psychiatric conditions * Have any history of unstable or poorly controlled endocrine, pulmonary, cardiovascular, gastrointestinal, hepatic, hematological, or other significant medical condition that, in the opinion of the investigator, may interfere with the completion or interpretation of study assessment * Have had a malignancy within 5 years before screening, except fully resected basal cell carcinoma or other malignancies (such as prostate cancer) at low risk of recurrence, depending on investigator and medical monitor agreement * Have had previous anti amyloid or anti tau immunotherapy (including active immunization) * Note: ADAD participants who have participated in previous passive anti-amyloid immunotherapy \> 6 months previously will be allowed, contingent on investigator and Sponsor agreement * Have had previous exposure to gene therapy
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Incidence and severity of treatment-emergent adverse events (TEAEs) throughout the double-blind period | 37 weeks |
Secondary
| Measure | Time frame |
|---|---|
| PK parameter: Maximum concentration (Cmax) of DNL628 in plasma | 37 weeks |
| PK Parameter: Time to reach maximum concentration (tmax) of DNL628 in plasma | 37 weeks |
| PK Parameter: Minimum concentration (Cmin) of DNL628 in plasma | 37 weeks |
| PK Parameter: Area under the concentration-time curve (AUC) from time zero to time of last measurable concentration (AUClast) of DNL628 in plasma | 37 weeks |
| PK Parameter: AUC from time 0 to the end of the dosing interval (AUCτ) of DNL628 in plasma | 37 weeks |
| PK Parameter: terminal elimination half-life (t1/2) of DNL628 in plasma | 37 weeks |
| PK Parameter: Accumulation ratio of DNL628 in plasma | 37 weeks |
| Change from baseline in total tau and ptau181 as measured in CSF | 25 weeks |
Countries
Netherlands, United Kingdom
Contacts
CONTACTClinical Trials at Denali Therapeutics
STUDY_DIRECTORMedical Monitor
Denali Therapeutics
Outcome results
None listed