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

NCT ID: NCT05262023

Last Updated: 2026-01-15

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 85 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2022-02-01
• Study Completion Date: 2028-11-30

Brief Summary

This is a Phase 1/2, multicenter, randomized, placebo-controlled, double-blind study to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of single and multiple doses of DNL593 in two parts followed by an optional open-label extension (OLE) period.

Part A will evaluate the safety, tolerability, PK, and PD of single doses of DNL593 in healthy male and healthy female participants of nonchildbearing potential. Part B will evaluate the safety, tolerability, PK, and PD of multiple doses of DNL593 in participants with frontotemporal dementia (FTD) over 25 weeks. Part B will be followed by Part C, an optional 18-month OLE period available for all participants who complete Part B.

Conditions

Frontotemporal Dementia

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

DNL593 (Healthy Participant)

Group Type: EXPERIMENTAL

DNL593

Intervention Type: DRUG

Ascending single doses (for healthy participants) and multiple doses (for participants with FTD)

Placebo (Healthy Participant)

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Ascending single doses (for healthy participants) and multiple doses (for participants with FTD)

DNL593 (Participants with FTD)

Group Type: EXPERIMENTAL

DNL593

Intervention Type: DRUG

Ascending single doses (for healthy participants) and multiple doses (for participants with FTD)

Placebo (Participants with FTD)

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Ascending single doses (for healthy participants) and multiple doses (for participants with FTD)

Interventions

DNL593

Ascending single doses (for healthy participants) and multiple doses (for participants with FTD)

Intervention Type: DRUG

Placebo

Ascending single doses (for healthy participants) and multiple doses (for participants with FTD)

Intervention Type: DRUG

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Takeda

INDUSTRY

Sponsor Role: collaborator

Denali Therapeutics Inc.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Amy Berger, MD

Role: STUDY_DIRECTOR

Denali Therapeutics Inc.

Locations

University of California San Francisco

San Francisco, California, United States

John Hopkins University

Baltimore, Maryland, United States

Hospital of the University of Pennsylvania

Philadelphia, Pennsylvania, United States

University of Antwerp

Antwerp, , Belgium

UZ Leuven

Leuven, , Belgium

L2IP - Instituto de Pesquisas Clinicas LTDA

Brasília, , Brazil

Faculdade de Medicina Da Universidade de São Paulo

São Paulo, , Brazil

Hospital Universitario San Ignacio

Bogotá, , Colombia

Grupo de Neurosicencias de la Universidad de Antioquia

Medellín, , Colombia

Fakultni nemocnice v Motole

Prague, , Czechia

CHU de Nantes

Nantes, , France

CHU Rouen

Rouen, , France

CHU Toulouse

Toulouse, , France

ASST degli Spedali Civili di Brescia

Brescia, , Italy

Azienda Ospedaliera Universitaria Careggi

Florence, , Italy

IRCCS Istituto Auxologico Italiano

Milan, , Italy

Azienda Ospedaliera Cardinale G Panico

Tricase, , Italy

Erasmus University Medical Center

Rotterdam, , Netherlands

Hospital de Braga

Braga, , Portugal

Campus Neurológico Sénior

Torres Vedras, , Portugal

Hospital Clinic de Barcelona

Barcelona, Barcelona, Spain

Hospital Universitario de Donostia

Donostia / San Sebastian, Guipúzcoa, Spain

Hospital Universitario Virgen del Rocio

Seville, Sevilla, Spain

Istanbul University Istanbul Medical Faculty

Istanbul, , Turkey (Türkiye)

Ondokuz Mayis University Hospital

Samsun, , Turkey (Türkiye)

Simbec Orion

Merthyr Tydfil, Wales, United Kingdom

Countries

United States; Belgium; Brazil; Colombia; Czechia; France; Italy; Netherlands; Portugal; Spain; Turkey (Türkiye); United Kingdom

Other Identifiers

2023-508697-28-00

Identifier Type: CTIS

Identifier Source: secondary_id

2021-005733-16

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

DNLI-H-0001

Identifier Type: -

Identifier Source: org_study_id