A Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of DNL343 in Healthy Volunteers

Study Overview
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Brief Summary
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This is a Phase 1 study carried out at a single site in 88 healthy male subjects and healthy female subjects of non childbearing potential to investigate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of DNL343.

Detailed Description
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This clinical trial information was submitted voluntarily under the applicable law and, therefore, certain submission deadlines may not apply. (That is, clinical trial information for this applicable clinical trial was submitted under section 402(j)(4)(A) of the Public Health Service Act and 42 CFR 11.60 and is not subject to the deadlines established by sections 402(j)(2) and (3) of the Public Health Service Act or 42 CFR 11.24 and 11.44.).

Official Title
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A Phase 1, Single-Center, Randomized, Placebo-Controlled, Double-Blind Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of DNL343 In Healthy Volunteers

Conditions
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Healthy Volunteers

Intervention / Treatment
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* Drug: DNL343
* 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 18-50 years, inclusive BMI 18-32 kg/m², inclusive, and body weight of at least 50 kg Key Exclusion Criteria: History of clinically significant neurologic, psychiatric, endocrine, pulmonary, cardiovascular, gastrointestinal, hepatic, pancreatic, renal, metabolic, hematologic, immunologic, or allergic disease, or other major disorders

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: DNL343<br>Cohort A: Single-ascending dose; Cohort B: Multiple-ascending doses | Drug: DNL343<br>* Single and repeating oral dose(s)<br>|
| Placebo Comparator: Placebo<br>Cohort A: Single-ascending dose; Cohort B: Multiple-ascending doses | Drug: Placebo<br>* Single and repeating oral dose(s)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence and severity of treatment-emergent adverse events (TEAEs) including serious adverse events (SAEs), and discontinuations due to TEAEs |  | Up to 20 days | 
| PK parameter: The area under the concentration-time curve from time zero extrapolated to infinity (AUC0-∞) of DNL343 in plasma |  | Up to 20 days | 
| PK parameter: The area under the concentration-time curve from zero to 12 or 24 hours for twice daily (BID) or once daily (QD) dosing, respectively (AUC0-τ) of DNL343 in plasma |  | Up to 20 days | 
| PK parameter: Maximum observed concentration (Cmax) of DNL343 in plasma |  | Up to 20 days | 
| PK parameter: Area under the concentration-time curve from time zero to the time of last quantifiable concentration (AUC[0-last]) of DNL343 in plasma |  | Up to 20 days | 
| PK parameter: Time to maximum observed concentration (Tmax) of DNL343 in plasma |  | Up to 20 days | 
| PK parameter: Apparent terminal elimination rate constant (λz) with the respective t½ of DNL343 in plasma |  | Up to 20 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PK parameter: The amount of DNL343 excreted in urine from time zero to 48 hours postdose (Ae48) |  | Up to 20 days | 
| PK parameter: Estimation of renal clearance (CLR) |  | Up to 20 days | 
| PK parameter: Concentration of DNL343 in cerebrospinal fluid (CSF) |  | Up to 20 days | 
| The PD of DNL343 in blood as measured by percent reduction of integrated stress response (ISR) protein levels measured by enzyme-linked immunosorbent assay (ELISA) |  | Up to 20 days | 
| The PD of DNL343 in blood as measured by percent reduction in ISR gene expression levels measured by quantitative polymerase chain reaction (qPCR) |  | Up to 20 days |