A Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of DNL593 in Healthy Participants and Participants with Frontotemporal Dementia (FTD-GRN)
- Conditions
- Frontotemporal Dementia
- Interventions
- Drug: PlaceboDrug: DNL593
- Registration Number
- NCT05262023
- Lead Sponsor
- Denali Therapeutics Inc.
- Brief 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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 106
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
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Placebo (Healthy Participant) Placebo - DNL593 (Participants with FTD) DNL593 - DNL593 (Healthy Participant) DNL593 - Placebo (Participants with FTD) Placebo -
- Primary Outcome Measures
Name Time Method Change from baseline in electrocardiogram (ECG) results including PR, QRS, and QTcF intervals up to 18 months Change from baseline in vital sign measurements: body temperature up to 18 months 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: respiratory rate up to 18 months Incidence of treatment-emergent clinically significant abnormalities in physical/neurological examination findings up to 18 months Change from baseline in vital sign measurements: heart rate up to 18 months Change from baseline in Columbia-Suicide Severity Rating Scale (C-SSRS; Parts B and C only) up to 18 months
- Secondary Outcome Measures
Name Time Method PK Parameter: AUC from time 0 to the end of the dosing interval (AUCτ) of DNL593 in serum (Parts B and C only) up to 18 months Concentration of DNL593 in cerebrospinal fluid (CSF) up to 18 months DNL593 CSF:serum concentration ratio up to 18 months Percentage change from baseline in plasma NfL up to 18 months PK Parameter: Maximum concentration (Cmax) of DNL593 in serum up to 18 months PK Parameter: Time to reach maximum concentration (tmax) of DNL593 in serum 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 up to 18 months PK Parameter: terminal elimination half-life (t1/2) of DNL593 in serum up to 18 months PK Parameter: AUC from time zero to infinity (AUC∞) of DNL593 in serum (Part A only) up to 84 days PK Parameter: Accumulation ratio of DNL593 in serum (Parts B and C only) up to 18 months PK Parameter: Trough concentration of DNL593 in serum (Ctrough) (Parts B and C only) up to 18 months
Trial Locations
- Locations (29)
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
Hospital de Clinicas de Porto Alegre (HCPA) - PPDS
🇧🇷Porto Alegre, Brazil
Faculdade de Medicina Da Universidade de São Paulo
🇧🇷São Paulo, Brazil
Hospital Universitario San Ignacio
🇨🇴Bogotá, Colombia
Fakultni nemocnice v Motole
🇨🇿Prague, Czechia
CHU de Nantes
🇫🇷Nantes, France
CHU Rouen
🇫🇷Rouen, France
CHU Toulouse
🇫🇷Toulouse, France
ASST degli Spedali Civili di Brescia
🇮🇹Brescia, Italy
Azienda Ospedaliera Universitaria Careggi
🇮🇹Firenze, Italy
IRCCS Istituto Auxologico Italiano
🇮🇹Milano, Italy
Azienda Ospedaliera Cardinale G Panico
🇮🇹Tricase, Italy
Erasmus University Medical Center
🇳🇱Rotterdam, Netherlands
Hospital de Braga
🇵🇹Braga, Portugal
Hospital Pedro Hispano
🇵🇹Matosinhos, Portugal
Campus Neurológico Sénior
🇵🇹Torres Vedras, Portugal
University Clinical Center Nis
🇷🇸Niš, Serbia
Hospital Universitario de Donostia
🇪🇸Donostia-San Sebastian, Guipúzcoa, Spain
Hospital Clinic de Barcelona
🇪🇸Barcelona, Spain
Hospital Universitario La Paz
🇪🇸Madrid, Spain
Hospital Universitario Virgen del Rocio
🇪🇸Sevilla, Spain
Hacettepe University
🇹🇷Ankara, Turkey
Istanbul University Istanbul Medical Faculty
🇹🇷Istanbul, Turkey
Dokuz Eylul University Medical Faculty
🇹🇷İzmir, Turkey
Ondokuz Mayis University Hospital
🇹🇷Samsun, Turkey
Simbec Orion
🇬🇧Merthyr Tydfil, Wales, United Kingdom