Clinical trial NCT03757351: Study to Evaluate DNL747 in Subjects With Amyotrophic Lateral Sclerosis
Official title: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Amyotrophic Lateral Sclerosis
Lead sponsor: Sanofi
Sponsor class: INDUSTRY
Collaborators: name: Denali Therapeutics Inc.
First posted: 2018-11-28
Enrollment: 15
Sex: ALL
Minimum age (years): 21
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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


Eligibility 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 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)

Primary outcomes:
measure: Number of Subjects with Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: Randomization - Day 86
measure: Number of Subjects with clinically significant neurological examination abnormalities
timeFrame: Randomization - Day 86
measure: Number of Subjects with laboratory test abnormalities
timeFrame: Randomization - Day 86
Secondary outcomes:
measure: Pharmacokinetic measure of maximum observed plasma concentration (Cmax) of DNL747
timeFrame: Randomization - Day 86
measure: Pharmacokinetic measure of time to reach maximum observed plasma concentration (Tmax) of DNL747
timeFrame: Randomization - Day 86
measure: Pharmacokinetic measure of area under the plasma drug concentration-time curve (AUC) of DNL747
timeFrame: Randomization - Day 86
measure: Pharmacokinetic terminal disposition rate constant (λz) with the respective t1/2 of DNL747
timeFrame: Randomization - Day 86
measure: Pharmacokinetic measure of CSF concentrations of DNL747
timeFrame: Randomization - Day 86
measure: Pharmacodynamic measure of pS166 in PBMCs
timeFrame: Randomization - Day 86
Other outcomes:
Locations:
city: Orlando
country: United States
facility: Bioclinica
state: Florida
city: Salt Lake City
country: United States
facility: PRA Health Sciences
state: Utah
city: Leiden
country: Netherlands
facility: CHDR
state: South Holland
Study officials:
affiliation: Sanofi
name: Clinical Sciences & Operations
role: STUDY_DIRECTOR
References:
citation: Vissers MFJM, Heuberger JAAC, Groeneveld GJ, Oude Nijhuis J, De Deyn PP, Hadi S, Harris J, Tsai RM, Cruz-Herranz A, Huang F, Tong V, Erickson R, Zhu Y, Scearce-Levie K, Hsiao-Nakamoto J, Tang X, Chang M, Fox BM, Estrada AA, Pomponio RJ, Alonso-Alonso M, Zilberstein M, Atassi N, Troyer MD, Ho C. Safety, pharmacokinetics and target engagement of novel RIPK1 inhibitor SAR443060 (DNL747) for neurodegenerative disorders: Randomized, placebo-controlled, double-blind phase I/Ib studies in healthy subjects and patients. Clin Transl Sci. 2022 Aug;15(8):2010-2023. doi: 10.1111/cts.13317. Epub 2022 Jun 1.