Study to Evaluate DNL747 in Subjects With Amyotrophic Lateral Sclerosis

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple oral doses of DNL747 in subjects with Amyotrophic Lateral Sclerosis in a cross-over design

Official Title
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A Multicenter, Randomized, Placebo-Controlled, Double-Blind, Phase 1b Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of DNL747 in Subjects With Amyotrophic Lateral Sclerosis

Conditions
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Amyotrophic Lateral Sclerosis

Intervention / Treatment
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* Drug: DNL747
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria (Double-Blind Part): Women of non-childbearing potential and men, aged 21-80 years Willingness and ability to complete all aspects of the study; participant should be capable of completing assessments either alone or with help of a caregiver Diagnosis of laboratory-supported probable, probable, or definite (sporadic or familial) ALS according to the El Escorial World Federation of Neurology revised research diagnostic criteria Less than 3 years since symptom onset Forced vital capacity (FVC) >50% predicted measured within 30 days of screening If subject is taking approved ALS treatments (riluzole and/or edaravone), doses must be stable for ≥2 months prior to screening and subject is expected to stay on a stable regimen throughout the study Key Exclusion Criteria (Double-Blind Part): History of a clinically significant non-ALS neurologic disorder (other than frontal temporal lobe dementia), including, but not limited to, muscular dystrophy, spinal stenosis, peripheral neuropathy, inherited neuropathies, AD, Parkinson's disease, Lewy body dementia, vascular dementia, Huntington's disease, epilepsy, stroke, multiple sclerosis, brain tumor, or brain infection or abscess Unstable or poorly controlled comorbid disease process of any organ system currently requiring active treatment or likely to require treatment adjustment during the study Key Inclusion Criteria (Open-Label Extension): Successful completion of both periods of the the double-blind, crossover part of the study Continued diagnosis of laboratory-supported probable, probable, or definite (sporadic or familial) ALS according to the El Escorial World Federation of Neurology revised research diagnostic criteria Key Exclusion Criteria (Open-Label Extension): Presence of laboratory abnormalities, physical examination findings, or AEs determined to be clinically significant by the investigator from the double-blind part of the study that have not resolved by the final follow-up visit as part of the double-blind study period New diagnosis of clinically significant neurological disorder (other than frontal temporal lobe dementia)

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: DNL747 First, Placebo Second<br> | Drug: DNL747<br>* Repeating oral dose<br>Drug: Placebo<br>* Repeating oral dose<br>|
| Experimental: Placebo First, DNL747 Second<br> | Drug: DNL747<br>* Repeating oral dose<br>Drug: Placebo<br>* Repeating oral dose<br>|
| Experimental: Open-Label Extension<br>Conducted in the Netherlands only. | Drug: DNL747<br>* Repeating oral dose<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects with Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) |  | Randomization - Day 86 | 
| Number of Subjects with clinically significant neurological examination abnormalities |  | Randomization - Day 86 | 
| Number of Subjects with laboratory test abnormalities |  | Randomization - Day 86 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic measure of maximum observed plasma concentration (Cmax) of DNL747 |  | Randomization - Day 86 | 
| Pharmacokinetic measure of time to reach maximum observed plasma concentration (Tmax) of DNL747 |  | Randomization - Day 86 | 
| Pharmacokinetic measure of area under the plasma drug concentration-time curve (AUC) of DNL747 |  | Randomization - Day 86 | 
| Pharmacokinetic terminal disposition rate constant (λz) with the respective t1/2 of DNL747 |  | Randomization - Day 86 | 
| Pharmacokinetic measure of CSF concentrations of DNL747 |  | Randomization - Day 86 | 
| Pharmacodynamic measure of pS166 in PBMCs |  | Randomization - Day 86 |