Amyotrophic Lateral Sclerosis
Conditions
Brief summary
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
Interventions
DRUGDNL747
Repeating oral dose
DRUGPlacebo
Repeating oral dose
Sponsors
Denali Therapeutics Inc.
Sanofi
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
21 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
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
Design outcomes
Primary
| Measure | 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
| Measure | Time frame |
|---|---|
| Pharmacokinetic terminal disposition rate constant (λz) with the respective t1/2 of DNL747 | Randomization - Day 86 |
| Pharmacokinetic measure of maximum observed plasma concentration (Cmax) of DNL747 | Randomization - Day 86 |
| Pharmacodynamic measure of pS166 in PBMCs | Randomization - Day 86 |
| Pharmacokinetic measure of CSF concentrations 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 |
Countries
Netherlands, United States
Outcome results
None listed