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Active not recruitingPhase 1 / PHASE2

A Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of DNL593 in Healthy Participants and Participants With Frontotemporal Dementia (FTD-GRN)

A Phase 1/2, Multicenter, Randomized, Placebo-Controlled, Double Blind Single Dose and Multiple Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of DNL593 in Healthy Participants and Participants With Frontotemporal Dementia Followed by an Open-Label Extension

Lead sponsor

Denali Therapeutics Inc.

Asset

DNL593

Listed sites

Recruiting sites

Enrollment

actual

Study population

Frontotemporal dementia

Key I/E criterion

•GRN mutation required

Primary endpoints

•Incidence, severity, and seriousness of treatment-emergent adverse events•Treatment-emergent clinically significant abnormalities in safety laboratory•Vital sign measurements

Footprint

Where this trial recruits

Site locations as reported to ClinicalTrials.gov. Site count is not enrollment count; per-site enrollment is not available from source.

Identifiers

Registered as

Eudract number2021-005733-16

Ctis2023-508697-28-00

Org study IDDNLI-H-0001

NCT IDNCT05262023

Timeline

Milestones

Study start2022-02-01actual

Study first posted2022-03-02actual

Last update posted2026-01-15actual

Primary completion2026-12estimated (month precision)

Study completion2028-11estimated (month precision)

Assets

Drug assets

DNL593

Study populations

Who this study enrolls

Frontotemporal dementia

Eligibility

Who can enroll

Minimum age18 Years

Maximum age80 Years

SexAll

Healthy volunteersAccepted

Inclusion criteria

Key Inclusion Criteria:

Part A:

•Women of non-childbearing potential (surgically sterilized or post menopausal) or men, aged ≥18 to ≤ 55 years

•BMI of ≥ 18 to ≤ 32 kg/m²

•When engaging in sex with a woman of child bearing potential, two forms of birth control are required

Part B:

•Women of non-childbearing potential (surgically sterilized or post menopausal) or men, aged ≥18 to ≤ 80 years. Women who are of childbearing potential but on highly effective, low user dependent contraceptive methods will be allowed.

•BMI of ≥ 18 to ≤ 32 kg/m²

•Have a Clinical Dementia Rating® plus National Alzheimer's Coordinating Center frontotemporal lobar degeneration global score ≥ 0.5

•Have confirmed granulin (GRN) mutation via genetic testing or historical records available for review by investigator

•When engaging in sex with a woman of child bearing potential, both the male participant and his female partner must use highly effective contraception

Part C:

•All participants who completed Part B of this trial are eligible for an 18-month OLE if the participant has no unresolved clinically significant TEAEs, where continued dosing may represent a risk to participant safety

Exclusion criteria

•Have any history of clinically significant neurologic, psychiatric, endocrine, pulmonary, cardiovascular, gastrointestinal, hepatic, pancreatic, renal, metabolic, hematologic, immunologic, or allergic disease, or other major disorders

•Have a history of malignancy, except fully resected basal cell carcinoma or other malignancies at low risk of recurrence

•Have a clinically significant history of stroke, cognitive impairment due to causes other than FTD, seizure within 5 years of screening, or head trauma with loss of consciousness within 2 years of screening

•Have a positive serum pregnancy test or are currently lactating or breastfeeding

Endpoints (20)

What's being measured

Protocol endpoints and posted registry outcome measures, grouped into outcome categories. Composite endpoints show their component event types. Standard codes (LOINC, SNOMED CT) are shown where available.

Coverage by outcome category

Safety / tolerability / PK

Other (unclassified)

Fluid / digital biomarkers

Neurodegeneration biomarkers

1 endpoint

Secondary/protocol endpoint

Percentage change from baseline in plasma NfL

Time frame:up to 18 months

Neurofilament light (NfL)

percent change from baseline, improvement

Fluid / digital biomarkers

2 endpoints

Secondary/protocol endpoint

Concentration of DNL593 in cerebrospinal fluid (CSF)

Time frame:up to 18 months

concentration, descriptive

Secondary/protocol endpoint

DNL593 CSF:serum concentration ratio

Time frame:up to 18 months

concentration, descriptive

Safety / tolerability / PK

13 endpoints

Primary/protocol endpoint

Incidence, severity, and seriousness of treatment-emergent adverse events (TEAEs)

Time frame:up to 18 months

event count, event

Primary/protocol endpoint

Incidence of treatment-emergent clinically significant abnormalities in safety laboratory values

Time frame:up to 18 months

event count, event

Primary/protocol endpoint

Change from baseline in vital sign measurements: systolic and diastolic blood pressure

Time frame:up to 18 months

change from baseline, event

Primary/protocol endpoint

Change from baseline in vital sign measurements: heart rate

Time frame:up to 18 months

change from baseline, event

Primary/protocol endpoint

Change from baseline in vital sign measurements: respiratory rate

Time frame:up to 18 months

change from baseline, event

Primary/protocol endpoint

Change from baseline in vital sign measurements: body temperature

Time frame:up to 18 months

change from baseline, event

Primary/protocol endpoint

Change from baseline in electrocardiogram (ECG) results including PR, QRS, and QTcF intervals

Time frame:up to 18 months

change from baseline, event

Secondary/protocol endpoint

PK Parameter: Maximum concentration (Cmax) of DNL593 in serum

Time frame:up to 18 months

concentration, descriptive

Secondary/protocol endpoint

PK Parameter: Time to reach maximum concentration (tmax) of DNL593 in serum

Time frame:up to 18 months

time to event, event

Secondary/protocol endpoint

PK Parameter: Area under the concentration-time curve (AUC) from time zero to time of last measurable concentration (AUClast) of DNL593 in serum

Time frame:up to 18 months

concentration, descriptive

Secondary/protocol endpoint

PK Parameter: terminal elimination half-life (t1/2) of DNL593 in serum

Time frame:up to 18 months

concentration, descriptive

Secondary/protocol endpoint

PK Parameter: AUC from time zero to infinity (AUC∞) of DNL593 in serum (Part A only)

Time frame:up to 84 days

concentration, descriptive

Secondary/protocol endpoint

PK Parameter: AUC from time 0 to the end of the dosing interval (AUCτ) of DNL593 in serum (Parts B and C only)

Time frame:up to 18 months

concentration, descriptive

Other (unclassified)

4 endpoints

Primary/protocol endpoint/low confidence

Incidence of treatment-emergent clinically significant abnormalities in physical/neurological examination findings

Time frame:up to 18 months

event count, event

Primary/protocol endpoint/low confidence

Change from baseline in Columbia-Suicide Severity Rating Scale (C-SSRS; Parts B and C only)

Time frame:up to 18 months

change from baseline, improvement

Secondary/protocol endpoint/low confidence

PK Parameter: Accumulation ratio of DNL593 in serum (Parts B and C only)

Time frame:up to 18 months

ratio, descriptive

Secondary/protocol endpoint/low confidence

PK Parameter: Trough concentration of DNL593 in serum (Ctrough) (Parts B and C only)

Time frame:up to 18 months

concentration, descriptive

Provenance

Sources

Trial identity, design, statusClinicalTrials.gov API v2

Snapshot dateJuly 21, 2026

Endpoint classificationDelfa ADRD endpoint taxonomy

Results tableno registry results posted yet

Trial facts come from public ClinicalTrials.gov records. Endpoint categories are Delfa's classification of those records, not a ClinicalTrials.gov field. All figures reflect the July 21, 2026 snapshot.