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

Denali Therapeutics

Status and phase: Active, not recruiting; Phase 2; Phase 1

Conditions: Frontotemporal Dementia

Treatments: Drug: DNL593; Drug: Placebo

Study type: Interventional

Funder types: Industry

Identifiers

NCT05262023

2021-005733-16 (EudraCT Number)

DNLI-H-0001

Details and patient eligibility

About

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.

Enrollment: 106 estimated patients

Sex: All

Ages: 18 to 80 years old

Volunteers: Accepts Healthy Volunteers

Inclusion and exclusion 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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Double Blind

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106 participants in 4 patient groups, including a placebo group

DNL593 (Healthy Participant)

Experimental group

Treatment:

Drug: DNL593

Placebo (Healthy Participant)

Placebo Comparator group

Treatment:

Drug: Placebo

DNL593 (Participants with FTD)

Experimental group

Treatment:

Drug: DNL593

Placebo (Participants with FTD)

Placebo Comparator group

Treatment:

Drug: Placebo