Study to Evaluate DNL747 in Subjects With Amyotrophic Lateral Sclerosis

NCT03757351 | Terminated Phase 1 FDA Drug

• 2 other identifiers: TDR16536DNLI-D-0003
• Study Type: interventional
• Target: 15
• Locations: 2 countries
• Sites: 3

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

Conditions

Amyotrophic Lateral Sclerosis

Outcome Measures

Primary Outcomes (3)

• 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 Outcomes (6)

• 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

Study Arms (3)

DNL747 First, Placebo Second

EXPERIMENTAL

Drug: DNL747; Drug: Placebo

Placebo First, DNL747 Second

EXPERIMENTAL

Drug: DNL747; Drug: Placebo

Open-Label Extension

EXPERIMENTAL

Conducted in the Netherlands only.

Drug: DNL747

Interventions

DNL747 DRUG

Repeating oral dose

DNL747 First, Placebo Second; Open-Label Extension; Placebo First, DNL747 Second

Placebo DRUG

Repeating oral dose

DNL747 First, Placebo Second; Placebo First, DNL747 Second

Eligibility Criteria

• Age: 21 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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
• 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
• 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)

Sponsors & Collaborators

• Sanofi: lead
• Denali Therapeutics Inc.: collaborator

Study Sites (3)

Bioclinica

Orlando, Florida, 32806, United States

Location

PRA Health Sciences

Salt Lake City, Utah, 84124, United States

Location

CHDR

Leiden, South Holland, 2333, Netherlands

Location

Related Publications (1)

• 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.

  PMID: 35649245 DERIVED

Related Links

• TDR16536 Plain Language Results Summary

MeSH Terms

Conditions

Amyotrophic Lateral Sclerosis

Condition Hierarchy (Ancestors)

Spinal Cord Diseases; Central Nervous System Diseases; Nervous System Diseases; Motor Neuron Disease; Neurodegenerative Diseases; TDP-43 Proteinopathies; Neuromuscular Diseases; Proteostasis Deficiencies; Metabolic Diseases; Nutritional and Metabolic Diseases

Study Officials

• Clinical Sciences & Operations

  Sanofi

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 27, 2018
• First Posted: November 28, 2018
• Study Start: December 14, 2018
• Primary Completion: June 18, 2020
• Study Completion: June 18, 2020
• Last Updated: September 22, 2025

Record last verified: 2025-09

Data Sharing

• IPD Sharing: Will share

Locations

NL (1); US (2)