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

• ClinicalTrials.gov Identifier: NCT05262023
• Recruitment Status: Recruiting
• First Posted: March 2, 2022
• Last Update Posted: March 6, 2023
• Sponsor: Denali Therapeutics Inc.
• Collaborator: Takeda
• Information provided by (Responsible Party): Denali Therapeutics Inc.

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Frontotemporal Dementia	Drug: DNL593; Drug: Placebo	Phase 1; Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 106 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: February 1, 2022
• Estimated Primary Completion Date: November 2025
• Estimated Study Completion Date: November 2025

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. Incidence, severity, and seriousness of treatment-emergent adverse events (TEAEs) [ Time Frame: up to 18 months ]
2. Incidence of treatment-emergent clinically significant abnormalities in safety laboratory values [ Time Frame: up to 18 months ]
3. Change from baseline in vital sign measurements: systolic and diastolic blood pressure [ Time Frame: up to 18 months ]
4. Change from baseline in vital sign measurements: heart rate [ Time Frame: up to 18 months ]
5. Change from baseline in vital sign measurements: respiratory rate [ Time Frame: up to 18 months ]
6. Change from baseline in vital sign measurements: body temperature [ Time Frame: up to 18 months ]
7. Change from baseline in electrocardiogram (ECG) results including PR, QRS, and QTcF intervals [ Time Frame: up to 18 months ]
8. Incidence of treatment-emergent clinically significant abnormalities in physical/neurological examination findings [ Time Frame: up to 18 months ]
9. Change from baseline in Columbia-Suicide Severity Rating Scale (C-SSRS; Parts B and C only) [ Time Frame: up to 18 months ]

Secondary Outcome Measures :

1. PK Parameter: Maximum concentration (Cmax) of DNL593 in serum [ Time Frame: up to 18 months ]
2. PK Parameter: Time to reach maximum concentration (tmax) of DNL593 in serum [ Time Frame: up to 18 months ]
3. 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 ]
4. PK Parameter: terminal elimination half-life (t1/2) of DNL593 in serum [ Time Frame: up to 18 months ]
5. PK Parameter: AUC from time zero to infinity (AUC∞) of DNL593 in serum (Part A only) [ Time Frame: up to 84 days ]
6. PK Parameter: Accumulation ratio of DNL593 in serum (Parts B and C only) [ Time Frame: up to 18 months ]
7. PK Parameter: Trough concentration of DNL593 in serum (Ctrough) (Parts B and C only) [ Time Frame: up to 18 months ]
8. 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 ]
9. Concentration of DNL593 in cerebrospinal fluid (CSF) [ Time Frame: up to 18 months ]
10. DNL593 CSF:serum concentration ratio [ Time Frame: up to 18 months ]

Eligibility Criteria

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

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, 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

Contacts and Locations

Contacts

Contact: Clinical Trials at Denali Therapeutics; clinical-trials@dnli.com

Locations

Netherlands

Erasmus University Medical Center; Recruiting

Rotterdam, Netherlands

Spain

Hospital Universitario de Donostia; Recruiting

Donostia-San Sebastian, Guipúzcoa, Spain, 20014

Hospital Clinic de Barcelona; Recruiting

Barcelona, Spain, 8036

Hospital Universitario La Paz; Recruiting

Madrid, Spain, 28046

Hospital Universitario Virgen del Rocio; Recruiting

Sevilla, Spain, 41013

Turkey

Istanbul University Istanbul Medical Faculty; Recruiting

Istanbul, Turkey

Ondokuz Mayis University Hospital; Recruiting

Samsun, Turkey

United Kingdom

Simbec Orion; Recruiting

Merthyr Tydfil, Wales, United Kingdom, CF48 4DR

Contact: Study Coordinator Email: Enrolmentservices@simbecorion.com

Sponsors and Collaborators

Denali Therapeutics Inc.

Takeda

Investigators

• Study Director: Amy Berger, MD; Denali Therapeutics Inc.

More Information

• Responsible Party: Denali Therapeutics Inc.
• ClinicalTrials.gov Identifier: NCT05262023
• Other Study ID Numbers: DNLI-H-0001; 2021-005733-16 ( EudraCT Number )
• First Posted: March 2, 2022
• Last Update Posted: March 6, 2023
• Last Verified: March 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• 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

Keywords provided by Denali Therapeutics Inc.:

FTD; FTD-GRN; granulin

Additional relevant MeSH terms:

Dementia; Frontotemporal Dementia; Aphasia, Primary Progressive; Pick Disease of the Brain; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Mental Disorders; Neurodegenerative Diseases; Frontotemporal Lobar Degeneration; TDP-43 Proteinopathies; Proteostasis Deficiencies; Metabolic Diseases; Aphasia; Speech Disorders; Language Disorders; Communication Disorders; Neurobehavioral Manifestations; Neurologic Manifestations