Frontotemporal Dementia
Conditions
Keywords
FTD, FTD-GRN, granulin
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.
Interventions
DRUGDNL593
Ascending single doses (for healthy participants) and multiple doses (for participants with FTD)
DRUGPlacebo
Ascending single doses (for healthy participants) and multiple doses (for participants with FTD)
Sponsors
Takeda
Denali Therapeutics Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
Yes
Inclusion 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
Design outcomes
Primary
| 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
| Measure | Time frame |
|---|---|
| DNL593 CSF:serum concentration ratio | up to 18 months |
| PK Parameter: Maximum concentration (Cmax) of DNL593 in serum | up to 18 months |
| Percentage change from baseline in plasma NfL | 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 |
Countries
Belgium, Brazil, Colombia, Czechia, France, Italy, Netherlands, Portugal, Spain, Turkey (Türkiye), United Kingdom, United States
Outcome results
None listed