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: Active, not recruiting
• First Posted: March 2, 2022
• Last Update Posted: January 9, 2024
• Sponsor: Denali Therapeutics Inc.
• Collaborator: Takeda
• Information provided by (Responsible Party): Denali Therapeutics Inc.

Tracking Information

• First Submitted Date: February 1, 2022
• First Posted Date: March 2, 2022
• Last Update Posted Date: January 9, 2024
• Actual Study Start Date: February 1, 2022
• Estimated Primary Completion Date: November 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 26, 2022)

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

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: February 26, 2022)

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

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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

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 Provided
• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Frontotemporal Dementia

Intervention

• Drug: DNL593
  Ascending single doses (for healthy participants) and multiple doses (for participants with FTD)
• Drug: Placebo
  Ascending single doses (for healthy participants) and multiple doses (for participants with FTD)

Study Arms

• Experimental: DNL593 (Healthy Participant)
  Intervention: Drug: DNL593
• Placebo Comparator: Placebo (Healthy Participant)
  Intervention: Drug: Placebo
• Experimental: DNL593 (Participants with FTD)
  Intervention: Drug: DNL593
• Placebo Comparator: Placebo (Participants with FTD)
  Intervention: Drug: Placebo

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Estimated Enrollment (submitted: February 26, 2022): 106
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: November 2025
• Estimated Primary Completion Date: November 2025 (Final data collection date for primary outcome measure)

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, 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 80 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Belgium, Brazil, Colombia, Czechia, France, Italy, Netherlands, Portugal, Serbia, Spain, Turkey, United Kingdom

Administrative Information

• NCT Number: NCT05262023
• Other Study ID Numbers: DNLI-H-0001; 2021-005733-16 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• 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

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Denali Therapeutics Inc.
• Original Responsible Party: Same as current
• Current Study Sponsor: Denali Therapeutics Inc.
• Original Study Sponsor: Same as current
• Collaborators: Takeda

Investigators

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

• PRS Account: Denali Therapeutics Inc.
• Verification Date: January 2024