A Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of DNL593 in Healthy Participants and Participants With Frontotemporal Dementia (FTD-GRN)
DNL593: Ascending single doses (for healthy participants) and multiple doses (for participants with FTD)
Placebo: Ascending single doses (for healthy participants) and multiple doses (for participants with FTD)
Study 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.
Eligibility
Sex
ALL
Min age
18 Years
Max age
80 Years
Healthy volunteers
Accepted
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, 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.
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
Primary outcome measure(s)
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
Trial sites (26)
Facility
City
Region
Status
University of California San Francisco
San Francisco
California
John Hopkins University
Baltimore
Maryland
Hospital of the University of Pennsylvania
Philadelphia
Pennsylvania
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
This page summarises publicly available registry data for informational purposes — not medical advice. Eligibility is determined by each study team; patients should discuss participation with their clinician.
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