Clinical trial NCT05262023: A Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of DNL593 in Healthy Participants and Participants With Frontotemporal Dementia (FTD-GRN)
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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Frontotemporal Dementia
Keywords: FTD
FTD-GRN
granulin
Lead sponsor: Denali Therapeutics Inc.
Sponsor class: INDUSTRY
Collaborators: name: Takeda
First posted: 2022-03-02
Enrollment: 106
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility 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, 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 outcomes:
measure: Incidence, severity, and seriousness of treatment-emergent adverse events (TEAEs)
timeFrame: up to 18 months
measure: Incidence of treatment-emergent clinically significant abnormalities in safety laboratory values
timeFrame: up to 18 months
measure: Change from baseline in vital sign measurements: systolic and diastolic blood pressure
timeFrame: up to 18 months
measure: Change from baseline in vital sign measurements: heart rate
timeFrame: up to 18 months
measure: Change from baseline in vital sign measurements: respiratory rate
timeFrame: up to 18 months
measure: Change from baseline in vital sign measurements: body temperature
timeFrame: up to 18 months
measure: Change from baseline in electrocardiogram (ECG) results including PR, QRS, and QTcF intervals
timeFrame: up to 18 months
measure: Incidence of treatment-emergent clinically significant abnormalities in physical/neurological examination findings
timeFrame: up to 18 months
measure: Change from baseline in Columbia-Suicide Severity Rating Scale (C-SSRS; Parts B and C only)
timeFrame: up to 18 months
Secondary outcomes:
measure: PK Parameter: Maximum concentration (Cmax) of DNL593 in serum
timeFrame: up to 18 months
measure: PK Parameter: Time to reach maximum concentration (tmax) of DNL593 in serum
timeFrame: up to 18 months
measure: PK Parameter: Area under the concentration-time curve (AUC) from time zero to time of last measurable concentration (AUClast) of DNL593 in serum
timeFrame: up to 18 months
measure: PK Parameter: terminal elimination half-life (t1/2) of DNL593 in serum
timeFrame: up to 18 months
measure: PK Parameter: AUC from time zero to infinity (AUC∞) of DNL593 in serum (Part A only)
timeFrame: up to 84 days
measure: PK Parameter: Accumulation ratio of DNL593 in serum (Parts B and C only)
timeFrame: up to 18 months
measure: PK Parameter: Trough concentration of DNL593 in serum (Ctrough) (Parts B and C only)
timeFrame: up to 18 months
measure: PK Parameter: AUC from time 0 to the end of the dosing interval (AUCτ) of DNL593 in serum (Parts B and C only)
timeFrame: up to 18 months
measure: Concentration of DNL593 in cerebrospinal fluid (CSF)
timeFrame: up to 18 months
measure: DNL593 CSF:serum concentration ratio
timeFrame: up to 18 months
measure: Percentage change from baseline in plasma NfL
timeFrame: up to 18 months
Other outcomes:
Locations:
city: Philadelphia
country: United States
facility: Hospital of the University of Pennsylvania
state: Pennsylvania
city: Antwerp
country: Belgium
facility: University of Antwerp
city: Leuven
country: Belgium
facility: UZ Leuven
city: Brasília
country: Brazil
facility: L2IP - Instituto de Pesquisas Clinicas LTDA
city: Porto Alegre
country: Brazil
facility: Hospital de Clinicas de Porto Alegre (HCPA) - PPDS
city: São Paulo
country: Brazil
facility: Faculdade de Medicina Da Universidade de São Paulo
city: Bogotá
country: Colombia
facility: Hospital Universitario San Ignacio
city: Prague
country: Czechia
facility: Fakultni nemocnice v Motole
city: Nantes
country: France
facility: CHU de Nantes
city: Rouen
country: France
facility: CHU Rouen
city: Toulouse
country: France
facility: CHU Toulouse
city: Brescia
country: Italy
facility: ASST degli Spedali Civili di Brescia
city: Firenze
country: Italy
facility: Azienda Ospedaliera Universitaria Careggi
city: Milano
country: Italy
facility: IRCCS Istituto Auxologico Italiano
city: Tricase
country: Italy
facility: Azienda Ospedaliera Cardinale G Panico
city: Rotterdam
country: Netherlands
facility: Erasmus University Medical Center
city: Braga
country: Portugal
facility: Hospital de Braga
city: Matosinhos
country: Portugal
facility: Hospital Pedro Hispano
city: Torres Vedras
country: Portugal
facility: Campus Neurológico Sénior
city: Niš
country: Serbia
facility: University Clinical Center Nis
city: Donostia-San Sebastian
country: Spain
facility: Hospital Universitario de Donostia
state: Guipúzcoa
city: Barcelona
country: Spain
facility: Hospital Clinic de Barcelona
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocio
city: Ankara
country: Turkey
facility: Hacettepe University
city: Istanbul
country: Turkey
facility: Istanbul University Istanbul Medical Faculty
city: İzmir
country: Turkey
facility: Dokuz Eylul University Medical Faculty
city: Samsun
country: Turkey
facility: Ondokuz Mayis University Hospital
city: Merthyr Tydfil
country: United Kingdom
facility: Simbec Orion
state: Wales
Study officials:
affiliation: Denali Therapeutics Inc.
name: Amy Berger, MD
role: STUDY_DIRECTOR
References: