Study to Evaluate DNL747 in Subjects With Amyotrophic Lateral Sclerosis

• ClinicalTrials.gov Identifier: NCT03757351
• Recruitment Status: Terminated
• First Posted: November 28, 2018
• Last Update Posted: May 12, 2022
• Sponsor: Sanofi
• Collaborator: Denali Therapeutics Inc.
• Information provided by (Responsible Party): Sanofi

Study Description

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

Condition or disease	Intervention/treatment	Phase
Amyotrophic Lateral Sclerosis	Drug: DNL747; Drug: Placebo	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 15 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: December 14, 2018
• Actual Primary Completion Date: June 18, 2020
• Actual Study Completion Date: June 18, 2020

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. Number of Subjects with Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Randomization - Day 86 ]
2. Number of Subjects with clinically significant neurological examination abnormalities [ Time Frame: Randomization - Day 86 ]
3. Number of Subjects with laboratory test abnormalities [ Time Frame: Randomization - Day 86 ]

Secondary Outcome Measures :

1. Pharmacokinetic measure of maximum observed plasma concentration (Cmax) of DNL747 [ Time Frame: Randomization - Day 86 ]
2. Pharmacokinetic measure of time to reach maximum observed plasma concentration (Tmax) of DNL747 [ Time Frame: Randomization - Day 86 ]
3. Pharmacokinetic measure of area under the plasma drug concentration-time curve (AUC) of DNL747 [ Time Frame: Randomization - Day 86 ]
4. Pharmacokinetic terminal disposition rate constant (λz) with the respective t1/2 of DNL747 [ Time Frame: Randomization - Day 86 ]
5. Pharmacokinetic measure of CSF concentrations of DNL747 [ Time Frame: Randomization - Day 86 ]
6. Pharmacodynamic measure of pS166 in PBMCs [ Time Frame: Randomization - Day 86 ]

Eligibility Criteria

• Ages Eligible for Study: 21 Years to 80 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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)

Contacts and Locations

Locations

United States, Florida

Bioclinica

Orlando, Florida, United States, 32806

United States, Utah

PRA Health Sciences

Salt Lake City, Utah, United States, 84124

Netherlands

CHDR

Leiden, South Holland, Netherlands, 2333

Sponsors and Collaborators

Sanofi

Denali Therapeutics Inc.

Investigators

• Study Director: Clinical Sciences & Operations; Sanofi

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Sanofi
• ClinicalTrials.gov Identifier: NCT03757351
• Other Study ID Numbers: TDR16536; DNLI-D-0003 ( Other Identifier: Denali Therapeutics Inc. )
• First Posted: November 28, 2018
• Last Update Posted: May 12, 2022
• Last Verified: March 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• 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

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Motor Neuron Disease; Amyotrophic Lateral Sclerosis; Sclerosis; Pathologic Processes; Neurodegenerative Diseases; Nervous System Diseases; Neuromuscular Diseases; Spinal Cord Diseases; Central Nervous System Diseases; TDP-43 Proteinopathies; Proteostasis Deficiencies; Metabolic Diseases