Study to Evaluate DNL747 in Subjects With Amyotrophic Lateral Sclerosis

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

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

Study Overview

• Status: Terminated
• Conditions: Amyotrophic Lateral Sclerosis
• Intervention / Treatment: Drug: DNL747; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 15
• Phase: Phase 1

Contacts and Locations

Study Locations

• Netherlands
  • South Holland
    • Leiden, South Holland, Netherlands, 2333
      • CHDR
• United States
  • Florida
    • Orlando, Florida, United States, 32806
      • Bioclinica
  • Utah
    • Salt Lake City, Utah, United States, 84124
      • PRA Health Sciences

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 80 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: DOUBLE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: DNL747 First, Placebo Second	Drug: DNL747; Repeating oral dose; Drug: Placebo; Repeating oral dose
EXPERIMENTAL: Placebo First, DNL747 Second	Drug: DNL747; Repeating oral dose; Drug: Placebo; Repeating oral dose
EXPERIMENTAL: Open-Label Extension; Conducted in the Netherlands only.	Drug: DNL747; Repeating oral dose

What is the study measuring?

Primary Outcome Measures

Outcome 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 Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: Sanofi
• Collaborators: Denali Therapeutics Inc.

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (ACTUAL): December 14, 2018
• Primary Completion (ACTUAL): June 18, 2020
• Study Completion (ACTUAL): June 18, 2020

Study Registration Dates

• First Submitted: November 27, 2018
• First Submitted That Met QC Criteria: November 27, 2018
• First Posted (ACTUAL): November 28, 2018

Study Record Updates

• Last Update Posted (ACTUAL): May 12, 2022
• Last Update Submitted That Met QC Criteria: May 11, 2022
• Last Verified: March 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Metabolic Diseases; Central Nervous System Diseases; Nervous System Diseases; Neuromuscular Diseases; Neurodegenerative Diseases; Spinal Cord Diseases; TDP-43 Proteinopathies; Proteostasis Deficiencies; Sclerosis; Motor Neuron Disease; Amyotrophic Lateral Sclerosis
• Other Study ID Numbers: TDR16536; DNLI-D-0003 (OTHER: Denali Therapeutics Inc.)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: https://vivli.org

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No