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

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

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 Overview

• Status: Active, not recruiting
• Conditions: Frontotemporal Dementia
• Intervention / Treatment: Drug: DNL593; Drug: Placebo

• Study Type: Interventional
• Enrollment (Estimated): 106
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Clinical Trials at Denali Therapeutics; Phone Number: Email:; Email: clinical-trials@dnli.com

Study Locations

• Belgium
  • Leuven, Belgium
    • UZ Leuven
• Brazil
  • Brasília, Brazil
    • L2IP - Instituto de Pesquisas Clinicas LTDA
  • Porto Alegre, Brazil
    • Hospital de Clinicas de Porto Alegre (HCPA) - PPDS
  • São Paulo, Brazil
    • Faculdade de Medicina da Universidade de Sao Paulo
• Colombia
  • Bogotá, Colombia
    • Hospital Universitario San Ignacio
• Czechia
  • Prague, Czechia
    • Fakultni nemocnice v Motole
• France
  • Nantes, France
    • CHU de Nantes
  • Rouen, France
    • CHU Rouen
  • Toulouse, France
    • CHU Toulouse
• Italy
  • Brescia, Italy
    • ASST degli Spedali Civili di Brescia
  • Firenze, Italy
    • Azienda Ospedaliera Universitaria Careggi
  • Milano, Italy
    • IRCCS Istituto Auxologico Italiano
  • Tricase, Italy
    • Azienda Ospedaliera Cardinale G Panico
• Netherlands
  • Rotterdam, Netherlands
    • Erasmus University Medical Center
• Portugal
  • Braga, Portugal
    • Hospital de Braga
  • Matosinhos, Portugal
    • Hospital Pedro Hispano
  • Torres Vedras, Portugal
    • Campus Neurologico Senior
• Serbia
  • Niš, Serbia
    • University Clinical Center Nis
• Spain
  • Barcelona, Spain, 8036
    • Hospital Clinic de Barcelona
  • Madrid, Spain, 28046
    • Hospital Universitario La Paz
  • Sevilla, Spain, 41013
    • Hospital Universitario Virgen del Rocio
  • Guipúzcoa
    • Donostia-San Sebastian, Guipúzcoa, Spain, 20014
      • Hospital Universitario de Donostia
• Turkey
  • Ankara, Turkey
    • Hacettepe University
  • Istanbul, Turkey
    • Istanbul University Istanbul Medical Faculty
  • Samsun, Turkey
    • Ondokuz Mayis University Hospital
  • İzmir, Turkey
    • Dokuz Eylul University Medical Faculty
• United Kingdom
  • Wales
    • Merthyr Tydfil, Wales, United Kingdom, CF48 4DR
      • Simbec Orion

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo (Healthy Participant)	Drug: Placebo; Ascending single doses (for healthy participants) and multiple doses (for participants with FTD)
Experimental: DNL593 (Healthy Participant)	Drug: DNL593; Ascending single doses (for healthy participants) and multiple doses (for participants with FTD)
Experimental: DNL593 (Participants with FTD)	Drug: DNL593; Ascending single doses (for healthy participants) and multiple doses (for participants with FTD)
Placebo Comparator: Placebo (Participants with FTD)	Drug: Placebo; Ascending single doses (for healthy participants) and multiple doses (for participants with FTD)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
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

Secondary Outcome Measures

Outcome Measure	Time Frame
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
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

Collaborators and Investigators

• Sponsor: Denali Therapeutics Inc.
• Collaborators: Takeda
• Investigators: Study Director: Amy Berger, MD, Denali Therapeutics Inc.

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2022
• Primary Completion (Estimated): November 1, 2025
• Study Completion (Estimated): November 1, 2025

Study Registration Dates

• First Submitted: February 1, 2022
• First Submitted That Met QC Criteria: February 26, 2022
• First Posted (Actual): March 2, 2022

Study Record Updates

• Last Update Posted (Actual): January 9, 2024
• Last Update Submitted That Met QC Criteria: January 8, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: FTD; FTD-GRN; granulin
• Additional Relevant MeSH Terms: Mental Disorders; Metabolic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurologic Manifestations; Neurobehavioral Manifestations; Neurocognitive Disorders; Neurodegenerative Diseases; TDP-43 Proteinopathies; Proteostasis Deficiencies; Language Disorders; Communication Disorders; Speech Disorders; Frontotemporal Lobar Degeneration; Aphasia; Dementia; Frontotemporal Dementia; Aphasia, Primary Progressive; Pick Disease of the Brain
• Other Study ID Numbers: DNLI-H-0001; 2021-005733-16 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No