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

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

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.

Study Overview

• Status: Completed
• Conditions: Healthy Volunteers
• Intervention / Treatment: Drug: DNL343; Drug: Placebo

Detailed Description

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.).

• Study Type: Interventional
• Enrollment (Actual): 96
• Phase: Phase 1

Contacts and Locations

Study Locations

• Netherlands
  • South Holland
    • Leiden, South Holland, Netherlands, 2333
      • Centre for Human Drug Research (CHDR)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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	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

Collaborators and Investigators

• Sponsor: Denali Therapeutics Inc.
• Investigators: Study Director: Richard Tsai, MD, Denali Therapeutics Inc.

Study record dates

Study Major Dates

• Study Start (Actual): February 20, 2020
• Primary Completion (Actual): August 3, 2021
• Study Completion (Actual): August 3, 2021

Study Registration Dates

• First Submitted: February 10, 2020
• First Submitted That Met QC Criteria: February 11, 2020
• First Posted (Actual): February 13, 2020

Study Record Updates

• Last Update Posted (Actual): February 7, 2022
• Last Update Submitted That Met QC Criteria: February 3, 2022
• Last Verified: February 1, 2022

More Information

Terms related to this study

• Other Study ID Numbers: DNLI-F-0001; 2019-004027-21 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No