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

Frontotemporal Dementia Clinical Trial

Official title:

A Phase 1/2, Multicenter, Randomized, Placebo-Controlled, Double Blind Single Dose and Multiple Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of DNL593 in Healthy Participants and Participants With Frontotemporal Dementia Followed by an Open-Label Extension

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT05262023
• Other study ID #: DNLI-H-0001
• Secondary ID: 2021-005733-16
• Status: Active, not recruiting
• Phase: Phase 1/Phase 2
• Start date: February 1, 2022
• Est. completion date: November 2025

Study information

• Verified date: January 2024
• Source: Denali Therapeutics Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 106
• Est. completion date: November 2025
• Est. primary completion date: November 2025
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

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

Related Conditions & MeSH terms

• Aphasia, Primary Progressive
• Dementia
• Frontotemporal Dementia
• Pick Disease of the Brain

Intervention

Drug:
• 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)

Locations

Country	Name	City	State
Belgium	UZ Leuven	Leuven
Brazil	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
Colombia	Hospital Universitario San Ignacio	Bogotá
Czechia	Fakultni nemocnice v Motole	Prague
France	CHU de Nantes	Nantes
France	CHU Rouen	Rouen
France	CHU Toulouse	Toulouse
Italy	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
Netherlands	Erasmus University Medical Center	Rotterdam
Portugal	Hospital de Braga	Braga
Portugal	Hospital Pedro Hispano	Matosinhos
Portugal	Campus Neurológico Sénior	Torres Vedras
Serbia	University Clinical Center Nis	Niš
Spain	Hospital Clinic de Barcelona	Barcelona
Spain	Hospital Universitario de Donostia	Donostia-San Sebastian	Guipúzcoa
Spain	Hospital Universitario La Paz	Madrid
Spain	Hospital Universitario Virgen del Rocio	Sevilla
Turkey	Hacettepe University	Ankara
Turkey	Istanbul University Istanbul Medical Faculty	Istanbul
Turkey	Dokuz Eylul University Medical Faculty	Izmir
Turkey	Ondokuz Mayis University Hospital	Samsun
United Kingdom	Simbec Orion	Merthyr Tydfil	Wales

Sponsors (2)

Lead Sponsor	Collaborator
Denali Therapeutics Inc.	Takeda

Countries where clinical trial is conducted

Belgium,  Brazil,  Colombia,  Czechia,  France,  Italy,  Netherlands,  Portugal,  Serbia,  Spain,  Turkey,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Incidence, severity, and seriousness of treatment-emergent adverse events (TEAEs)		up to 18 months
Primary	Incidence of treatment-emergent clinically significant abnormalities in safety laboratory values		up to 18 months
Primary	Change from baseline in vital sign measurements: systolic and diastolic blood pressure		up to 18 months
Primary	Change from baseline in vital sign measurements: heart rate		up to 18 months
Primary	Change from baseline in vital sign measurements: respiratory rate		up to 18 months
Primary	Change from baseline in vital sign measurements: body temperature		up to 18 months
Primary	Change from baseline in electrocardiogram (ECG) results including PR, QRS, and QTcF intervals		up to 18 months
Primary	Incidence of treatment-emergent clinically significant abnormalities in physical/neurological examination findings		up to 18 months
Primary	Change from baseline in Columbia-Suicide Severity Rating Scale (C-SSRS; Parts B and C only)		up to 18 months
Secondary	PK Parameter: Maximum concentration (Cmax) of DNL593 in serum		up to 18 months
Secondary	PK Parameter: Time to reach maximum concentration (tmax) of DNL593 in serum		up to 18 months
Secondary	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
Secondary	PK Parameter: terminal elimination half-life (t1/2) of DNL593 in serum		up to 18 months
Secondary	PK Parameter: AUC from time zero to infinity (AUC8) of DNL593 in serum (Part A only)		up to 84 days
Secondary	PK Parameter: Accumulation ratio of DNL593 in serum (Parts B and C only)		up to 18 months
Secondary	PK Parameter: Trough concentration of DNL593 in serum (Ctrough) (Parts B and C only)		up to 18 months
Secondary	PK Parameter: AUC from time 0 to the end of the dosing interval (AUCt) of DNL593 in serum (Parts B and C only)		up to 18 months
Secondary	Concentration of DNL593 in cerebrospinal fluid (CSF)		up to 18 months
Secondary	DNL593 CSF:serum concentration ratio		up to 18 months