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

• ClinicalTrials.gov Identifier: NCT04268784
• Recruitment Status: Completed
• First Posted: February 13, 2020
• Last Update Posted: February 7, 2022
• Sponsor: Denali Therapeutics Inc.
• Information provided by (Responsible Party): Denali Therapeutics Inc.

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Healthy Volunteers	Drug: DNL343; Drug: Placebo	Phase 1

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 96 participants
• Allocation: Randomized
• Intervention Model: Sequential Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Phase 1, Single-Center, Randomized, Placebo-Controlled, Double-Blind Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of DNL343 In Healthy Volunteers
• Actual Study Start Date: February 20, 2020
• Actual Primary Completion Date: August 3, 2021
• Actual Study Completion Date: August 3, 2021

Arms and Interventions

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)

Outcome Measures

Primary Outcome Measures :

1. Incidence and severity of treatment-emergent adverse events (TEAEs) including serious adverse events (SAEs), and discontinuations due to TEAEs [ Time Frame: Up to 20 days ]
2. PK parameter: The area under the concentration-time curve from time zero extrapolated to infinity (AUC0-∞) of DNL343 in plasma [ Time Frame: Up to 20 days ]
3. 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 [ Time Frame: Up to 20 days ]
4. PK parameter: Maximum observed concentration (Cmax) of DNL343 in plasma [ Time Frame: Up to 20 days ]
5. 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 [ Time Frame: Up to 20 days ]
6. PK parameter: Time to maximum observed concentration (Tmax) of DNL343 in plasma [ Time Frame: Up to 20 days ]
7. PK parameter: Apparent terminal elimination rate constant (λz) with the respective t½ of DNL343 in plasma [ Time Frame: Up to 20 days ]

Secondary Outcome Measures :

1. PK parameter: The amount of DNL343 excreted in urine from time zero to 48 hours postdose (Ae48) [ Time Frame: Up to 20 days ]
2. PK parameter: Estimation of renal clearance (CLR) [ Time Frame: Up to 20 days ]
3. PK parameter: Concentration of DNL343 in cerebrospinal fluid (CSF) [ Time Frame: Up to 20 days ]
4. 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) [ Time Frame: Up to 20 days ]
5. The PD of DNL343 in blood as measured by percent reduction in ISR gene expression levels measured by quantitative polymerase chain reaction (qPCR) [ Time Frame: Up to 20 days ]

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Locations

Netherlands

Centre for Human Drug Research (CHDR)

Leiden, South Holland, Netherlands, 2333

Sponsors and Collaborators

Denali Therapeutics Inc.

Investigators

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

More Information

• Responsible Party: Denali Therapeutics Inc.
• ClinicalTrials.gov Identifier: NCT04268784
• Other Study ID Numbers: DNLI-F-0001; 2019-004027-21 ( EudraCT Number )
• First Posted: February 13, 2020
• Last Update Posted: February 7, 2022
• Last Verified: February 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• 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