Phase 1/2 Study of DNL593 for Frontotemporal Dementia (FTD-GRN)

  • Study Director: Lawren VandeVrede, MD, PhD
  • Sponsor: Denali Therapeutics Inc.
  • Status: Recruiting
  • Official Study Title: A Phase 1/2, Multicenter, Randomized, Placebo-Controlled, Double-Blind Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Single and Multiple Doses of DNL593 in Healthy Participants and Participants with Frontotemporal Dementia Followed by an Open-Label Extension
  • ClinicalTrials.gov Identifier: NCT05262023
  • Conditions Studied: Frontotemporal Dementia with granulin (GRN) mutation
  • Intervention:
    • DNL593 (Drug): Administered via intravenous infusion in single ascending doses for healthy volunteers, and multiple doses for participants with FTD.
    • Placebo (Drug): Administered via intravenous infusion in single ascending doses for healthy volunteers, and multiple doses for participants with FTD.
  • Phase: Phase 1/2
  • Duration of Participation:
    • Part A: Single-dose study for healthy volunteers.
    • Part B: Multiple-dose study for participants with FTD over 25 weeks.
    • Part C: Optional 18-month open-label extension (OLE) for participants who complete Part B.

Purpose of the Study

This study evaluates the safety, tolerability, pharmacokinetics (how the drug is absorbed, distributed, metabolized, and eliminated in the body), and pharmacodynamics (the drug’s effects on the body) of DNL593 in healthy participants and participants with frontotemporal dementia (FTD) due to a granulin (GRN) mutation.

For healthy participants, the study will assess single ascending doses of DNL593. For participants with FTD-GRN, the study will evaluate multiple doses of DNL593 over 25 weeks and its potential to slow disease progression. Those who complete this phase may continue into an optional open-label extension (OLE) period for an additional 18 months, where they will receive DNL593 and further monitoring.

Eligibility

Inclusion Criteria
  • Part A (Healthy Participants):
    • Women of non-childbearing potential (surgically sterilized or postmenopausal) or men aged 18–55 years.
    • Body mass index (BMI) between 18–32 kg/m².
    • Agreement to use two forms of contraception during the study when engaging in sex with a woman of childbearing potential.
  • Part B (Participants with FTD-GRN):
    • Women of non-childbearing potential (surgically sterilized or postmenopausal) or men aged 18–80 years. Women of childbearing potential may participate if using highly effective contraceptive methods.
    • BMI between 18–32 kg/m².
    • Diagnosis of frontotemporal dementia with confirmed granulin (GRN) mutation via genetic testing.
    • Clinical Dementia Rating® plus National Alzheimer’s Coordinating Center frontotemporal lobar degeneration global score ≥0.5.
    • Agreement to use highly effective contraception when engaging in sex with a woman of childbearing potential.
  • Part C (Open-Label Extension):
    • Completion of Part B without unresolved clinically significant adverse events (TEAEs).
Exclusion Criteria
  • Clinically significant neurologic, psychiatric, endocrine, pulmonary, cardiovascular, gastrointestinal, hepatic, renal, or allergic disease.
  • History of malignancy, except fully resected basal cell carcinoma or malignancies at low risk of recurrence.
  • History of stroke, cognitive impairment due to causes other than FTD, seizure within 5 years, or head trauma with loss of consciousness within 2 years before screening.
  • Positive serum pregnancy test, current lactation, or breastfeeding.

What to Expect

Testing: Participants will undergo neurological and physical examinations, MRIs, cognitive testing, neuropsychiatric assessments, telephone calls, blood and urine specimen collection, vital sign monitoring, and lumbar punctures.

The Frequency of Visits: Every 4 weeks during active study phases.

Materials Needed Before Evaluation: Participants must have a confirmed diagnosis of frontotemporal dementia with a granulin (GRN) mutation.

Costs: Study procedures are provided at no cost. Parking is validated at UCSF public garages for all study visits.

Contact Information

Coordinator: [email protected], 415.353.3585
Clinical Trials Nurse: Whitney Walker, MS, CNS, RN – [email protected], 415.353.7532