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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Frontotemporal Dementia

Intervention / Treatment
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* Drug: DNL593
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: DNL593 (Healthy Participant)<br> | Drug: DNL593<br>* Ascending single doses (for healthy participants) and multiple doses (for participants with FTD)<br>|
| Placebo Comparator: Placebo (Healthy Participant)<br> | Drug: Placebo<br>* Ascending single doses (for healthy participants) and multiple doses (for participants with FTD)<br>|
| Experimental: DNL593 (Participants with FTD)<br> | Drug: DNL593<br>* Ascending single doses (for healthy participants) and multiple doses (for participants with FTD)<br>|
| Placebo Comparator: Placebo (Participants with FTD)<br> | Drug: Placebo<br>* Ascending single doses (for healthy participants) and multiple doses (for participants with FTD)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | 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 | Measure Description | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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FTD, FTD-GRN, granulin