Study to Evaluate DNL747 in Subjects With Alzheimer's Disease

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple oral doses of DNL747 in subjects with Alzheimer's disease when administered for 29 days in a cross-over design

Detailed Description
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This is a Phase 1b randomized, placebo-controlled, double-blind, crossover study to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of DNL747 in subjects with Alzheimer's disease (AD)

Official Title
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A Multicenter, Randomized, Placebo-Controlled, Double-Blind, Phase 1b Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of DNL747 in Subjects With Alzheimer's Disease

Conditions
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Alzheimer Disease

Intervention / Treatment
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* Drug: DNL747
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Women of non-childbearing potential and men, aged 55-85 years AD diagnosis based on the 2011 National Institute on Aging-Alzheimer's Association Guidelines Supportive evidence for diagnosis of AD based upon positive CSF Aβ42 test, or documented history of positive amyloid-specific PET scan Screening MMSE score of 16-26 points Screening CDR Global Score of 0.5-1.0 Availability of a person (caregiver) who, in the investigator's judgment, has frequent and sufficient contact with the participant and is able to provide accurate information regarding the participant's cognitive and functional abilities, agrees to provide information at clinic visits that require input for scale completion, assists the participant with compliance for at-home study treatment administration, and signs the necessary consent form (note: the caregiver is not required to stay in the unit) Approved AD treatments (acetylcholinesterase inhibitors ± memantine) and other prescription medications must be stable for ≥1 month prior to screening and anticipated to be stable over the duration of the study Key Exclusion Criteria: Clinical history within 2 years of the screening visit or current evidence of any neurological or neurodegenerative disorder other than AD that is associated with transient or sustained alterations in cognition Magnetic resonance imaging (MRI) at screening (or within 1 year of screening visit) consistent with any neurological or neurodegenerative disorder other than AD that is associated with transient or sustained alterations in cognition

Ages Eligible for Study
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Minimum Age: 55 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: DNL747 First, Placebo Second<br>Subjects will receive DNL747 for 29 days for the first period and then will switch to placebo for 29 days for the second period. There will be a 14-day washout period between the 2 treatment periods. | Drug: DNL747<br>* DNL747<br>Drug: Placebo<br>* Placebo<br>|
| Experimental: Placebo First, DNL747 Second<br>Subjects will receive placebo for 29 days for the first period and then will switch to DNL747 for 29 days for the second period. There will be a 14-day washout period between the 2 treatment periods. | Drug: DNL747<br>* DNL747<br>Drug: Placebo<br>* Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects with Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) |  | Randomization - Day 86 | 
| Number of Subjects with clinically significant neurological examination abnormalities |  | Randomization - Day 86 | 
| Number of Subjects with laboratory test abnormalities |  | Randomization - Day 86 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic measure of maximum observed plasma concentration (Cmax) of DNL747 |  | Randomization - Day 86 | 
| Pharmacokinetic measure of time to reach maximum observed plasma concentration (Tmax) of DNL747 |  | Randomization - Day 86 | 
| Pharmacokinetic measure of area under the plasma drug concentration-time curve (AUC) of DNL747 |  | Randomization - Day 86 | 
| Pharmacokinetic terminal disposition rate constant (λz) with the respective t1/2 of DNL747 |  | Randomization - Day 86 | 
| Pharmacokinetic measure of CSF concentrations of DNL747 |  | Randomization - Day 86 | 
| Pharmacodynamic measure of pS166 in PBMCs |  | Randomization - Day 86 |