A Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of DNL201 in Healthy Volunteers

Study Overview
=================
Brief Summary
-----------------
This is a Phase 1, randomized, double-blind, placebo-controlled, single- and multiple-ascending oral dose study conducted in three parts.

Official Title
-----------------
A First-In-Human Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Single and Multiple Ascending Oral Doses of DNL201 in Healthy Subjects

Conditions
-----------------
Healthy Volunteers

Intervention / Treatment
-----------------
* Drug: DNL201
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Key Inclusion Criteria: Body mass index 18.5 to 35.0 kg/m², inclusive, and body weight of at least 50.0 kg at screening In good health, determined by no clinically significant findings from medical history, physical examination, and vital sign measurements Women of non-childbearing potential and men using contraceptive measures Key Exclusion Criteria: History of clinically significant hematological, renal, pancreatic, gastrointestinal, hepatic, cardiovascular, metabolic, endocrine, immunological, allergic disease, or other major disorders History of asthma, chronic obstructive pulmonary disease, or emphysema Clinically significant neurologic disorder History of stomach or intestinal surgery or resection History of malignancy

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: DNL201<br>Part 1: Single-ascending dose cohorts; Part 2: Multiple-ascending dose cohorts (10 days); Part 3: Additional multiple-dose cohort (10 days) | Drug: DNL201<br>* Oral dose(s)<br>|
| Placebo Comparator: Placebo<br>Part 1: Single-ascending dose cohorts; Part 2: Multiple-ascending dose cohorts (10 days); Part 3: Additional multiple-dose cohort (10 days) | Drug: Placebo<br>* Oral dose(s)<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of treatment-emergent adverse events (TEAEs) including serious adverse events (SAEs), and discontinuations due to TEAEs |  | Up to 20 days | 
| PK parameter: Maximum observed concentration (Cmax) of DNL201 in plasma |  | Up to 10 days | 
| PK parameter: Time to maximum observed concentration (Tmax) of DNL201 in plasma |  | Up to 10 days | 
| PK parameter: The area under the concentration-time curve from time zero extrapolated to infinity (AUC0-∞) of DNL201 in plasma (single dosing only) |  | Up to 10 days | 
| PK parameter: Area under the concentration-time curve from time zero to the time of last quantifiable concentration (AUC[0-last]) of DNL201 in plasma |  | Up to 10 days | 
| PK parameter: The area under the concentration-time curve over a dosing interval (AUC0-τ) of DNL201 in plasma (multiple dosing only) |  | Up to 10 days | 
| PK parameter: Apparent terminal elimination half-life (t1/2) of DNL201 in plasma |  | Up to 10 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Concentration of DNL201 in cerebrospinal fluid (CSF) (following selected single and multiple doses) |  | Up to 10 days | 
| The pharmacodynamics of DNL201 in whole blood as measured by the percent change from baseline in pS935 |  | Up to 10 days |