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

NCT05262023 | Active Not Recruiting Phase 1 DMC FDA Drug

• 3 other identifiers: DNLI-H-00012023-508697-28-002021-005733-16
• Study Type: interventional
• Target: 85
• Locations: 12 countries
• Sites: 26

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

Keywords

FTD; FTD-GRN; granulin

Outcome Measures

Primary Outcomes (9)

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

  up to 18 months

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

  up to 18 months

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

  up to 18 months

• Change from baseline in vital sign measurements: heart rate

  up to 18 months

• Change from baseline in vital sign measurements: respiratory rate

  up to 18 months

• Change from baseline in vital sign measurements: body temperature

  up to 18 months

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

  up to 18 months

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

  up to 18 months

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

  up to 18 months

Secondary Outcomes (11)

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

  up to 18 months

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

  up to 18 months

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

  up to 18 months

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

  up to 18 months

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

  up to 84 days

Study Arms (4)

DNL593 (Healthy Participant)

EXPERIMENTAL

Drug: DNL593

Placebo (Healthy Participant)

PLACEBO COMPARATOR

Drug: Placebo

DNL593 (Participants with FTD)

EXPERIMENTAL

Drug: DNL593

Placebo (Participants with FTD)

PLACEBO COMPARATOR

Drug: Placebo

Interventions

DNL593 DRUG

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

DNL593 (Healthy Participant); DNL593 (Participants with FTD)

Placebo DRUG

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

Placebo (Healthy Participant); Placebo (Participants with FTD)

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Takeda: collaborator
• Denali Therapeutics Inc.: lead

Study Sites (26)

University of California San Francisco

San Francisco, California, 94143, United States

Location

John Hopkins University

Baltimore, Maryland, 21218, United States

Location

Hospital of the University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

Location

University of Antwerp

Antwerp, Belgium

Location

UZ Leuven

Leuven, Belgium

Location

L2IP - Instituto de Pesquisas Clinicas LTDA

Brasília, Brazil

Location

Faculdade de Medicina Da Universidade de São Paulo

São Paulo, Brazil

Location

Hospital Universitario San Ignacio

Bogotá, Colombia

Location

Grupo de Neurosicencias de la Universidad de Antioquia

Medellín, Colombia

Location

Fakultni nemocnice v Motole

Prague, Czechia

Location

CHU de Nantes

Nantes, France

Location

CHU Rouen

Rouen, France

Location

CHU Toulouse

Toulouse, France

Location

ASST degli Spedali Civili di Brescia

Brescia, Italy

Location

Azienda Ospedaliera Universitaria Careggi

Florence, Italy

Location

IRCCS Istituto Auxologico Italiano

Milan, Italy

Location

Azienda Ospedaliera Cardinale G Panico

Tricase, Italy

Location

Erasmus University Medical Center

Rotterdam, Netherlands

Location

Hospital de Braga

Braga, Portugal

Location

Campus Neurológico Sénior

Torres Vedras, Portugal

Location

Hospital Clinic de Barcelona

Barcelona, Barcelona, 8036, Spain

Location

Hospital Universitario de Donostia

Donostia / San Sebastian, Guipúzcoa, 20014, Spain

Location

Hospital Universitario Virgen del Rocio

Seville, Sevilla, 41013, Spain

Location

Istanbul University Istanbul Medical Faculty

Istanbul, Turkey (Türkiye)

Location

Ondokuz Mayis University Hospital

Samsun, Turkey (Türkiye)

Location

Simbec Orion

Merthyr Tydfil, Wales, CF48 4DR, United Kingdom

Location

MeSH Terms

Conditions

Frontotemporal Dementia

Condition Hierarchy (Ancestors)

Frontotemporal Lobar Degeneration; Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; TDP-43 Proteinopathies; Neurodegenerative Diseases; Proteostasis Deficiencies; Metabolic Diseases; Nutritional and Metabolic Diseases; Neurocognitive Disorders; Mental Disorders

Study Officials

• Amy Berger, MD

  Denali Therapeutics Inc.

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 1, 2022
• First Posted: March 2, 2022
• Study Start: February 1, 2022
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): November 1, 2028
• Last Updated: January 15, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (3); IT (4); FR (3); CO (2); BR (2); NL (1); PT (2); ES (3); TU (2); BE (2); GB (1); CZ (1)