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

• Status: Recruiting
• Trial end date: 2025-11-01
• Target enrollment: 0
• Participant gender: All

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.

• Phase: Phase 1/Phase 2
• Accepts Healthy Volunteers?: Accepts Healthy Volunteers

Details

• Lead Sponsor: Denali Therapeutics Inc.
• Collaborator: Takeda

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, both the male participant and his female partner must use highly effective contraception

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.

Key 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