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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
85
Ascending single doses (for healthy participants) and multiple doses (for participants with FTD)
Ascending single doses (for healthy participants) and multiple doses (for participants with FTD)
University of California San Francisco
San Francisco, California, United States
John Hopkins University
Baltimore, Maryland, United States
Hospital of the University of Pennsylvania
Philadelphia, Pennsylvania, United States
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
Medellín, Colombia
Fakultni nemocnice v Motole
Prague, Czechia
...and 16 more locations
Incidence, severity, and seriousness of treatment-emergent adverse events (TEAEs)
Time frame: up to 18 months
Incidence of treatment-emergent clinically significant abnormalities in safety laboratory values
Time frame: up to 18 months
Change from baseline in vital sign measurements: systolic and diastolic blood pressure
Time frame: up to 18 months
Change from baseline in vital sign measurements: heart rate
Time frame: up to 18 months
Change from baseline in vital sign measurements: respiratory rate
Time frame: up to 18 months
Change from baseline in vital sign measurements: body temperature
Time frame: up to 18 months
Change from baseline in electrocardiogram (ECG) results including PR, QRS, and QTcF intervals
Time frame: up to 18 months
Incidence of treatment-emergent clinically significant abnormalities in physical/neurological examination findings
Time frame: up to 18 months
Change from baseline in Columbia-Suicide Severity Rating Scale (C-SSRS; Parts B and C only)
Time frame: up to 18 months
PK Parameter: Maximum concentration (Cmax) of DNL593 in serum
Time frame: up to 18 months
PK Parameter: Time to reach maximum concentration (tmax) of DNL593 in serum
Time frame: 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
Time frame: up to 18 months
PK Parameter: terminal elimination half-life (t1/2) of DNL593 in serum
Time frame: up to 18 months
PK Parameter: AUC from time zero to infinity (AUC∞) of DNL593 in serum (Part A only)
Time frame: up to 84 days
PK Parameter: Accumulation ratio of DNL593 in serum (Parts B and C only)
Time frame: up to 18 months
PK Parameter: Trough concentration of DNL593 in serum (Ctrough) (Parts B and C only)
Time frame: up to 18 months
PK Parameter: AUC from time 0 to the end of the dosing interval (AUCτ) of DNL593 in serum (Parts B and C only)
Time frame: up to 18 months
Concentration of DNL593 in cerebrospinal fluid (CSF)
Time frame: up to 18 months
DNL593 CSF:serum concentration ratio
Time frame: up to 18 months
Percentage change from baseline in plasma NfL
Time frame: up to 18 months
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