Phase 2 Study for SAR443820 in Participants With Amyotrophic Lateral Sclerosis (ALS)

NCT05237284 | Terminated Phase 2 Results DMC FDA Drug

• 4 other identifiers: ACT16970U1111-1263-57662023-509442-36-002021-004156-42
• Study Type: interventional
• Target: 305
• Locations: 13 countries
• Sites: 63

Brief Summary

This was a parallel treatment, Phase 2, randomized, double-blind study to assess the efficacy, safety, tolerability, PK, and PD of twice daily (BID) oral SAR443820 compared with placebo in male and female participants, 18 to 80 years of age with ALS followed by an open-label, long-term extension period. Study ACT16970 consisted of 2 parts (A and B) as follows: Part A was a 24-week, double blind, placebo-controlled part, preceded by a screening period of up to 4 weeks before Day 1. On Day 1 of Part A, participants were randomized in a 2:1 ratio to the SAR443820 treatment arm or matching placebo arm as listed below:

• Treatment arm: SAR443820, BID
• Placebo arm: Placebo, BID Randomization was stratified by the geographic region of the study site, region of ALS onset (bulbar vs other areas), use of riluzole (yes vs no), use of edaravone (yes vs no) and use of the combination of sodium phenylbutyrate and taurursodiol (named Relyvrio in the United States of America \[USA\] and Albrioza in Canada) (yes vs no). Participants attended in-clinic study assessments at baseline (Day 1), Week 2, Week 4, Week 6, Week 8, Week 10, Week 12, Week 16, Week 20, Week 21, Week 22, Week 23, and Week 24. All ongoing participants at Week 24 rolled to open-label extension Part B. The Week 24 Visit was the end of Part A and the beginning of Part B. Part B was an open-label, long-term extension period that starts from Week 24 and continues up to Week 106. The objectives of Part B were to provide extended access to SAR443820 participants in Part A and to further evaluate the safety and efficacy of long-term SAR443820 treatment. The treatment assignment of participants at randomization in Part A remained blinded to Investigators, participants, and site personnel until the end of Part B. Every participant, except those who discontinued Investigational Medicinal Product (IMP) treatment permanently in Part A, received BID oral tablets of SAR443820 in Part B.

Conditions

Amyotrophic Lateral Sclerosis

Outcome Measures

Primary Outcomes (2)

• Part A: Change From Baseline to Week 24 in the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R) Total Score

  The ALSFRS-R is an instrument to evaluate the functional status of participants with ALS. It consists of 12 items across 4 sub-domains of bodily function: bulbar, fine motor, gross motor, and breathing. Each item was scored on an ordinal scale from 0 (total loss of function) to 4 (no loss of function). The total scores was the sum of the individual items score and it ranges from 0 to 48, with a higher score indicating better function. The analysis was performed using mixed-effect model with repeated measures (MMRM). Baseline was defined as the Day 1 pre-dose value.

  Baseline (Day 1, pre-dose) and Week 24

• Part B: Combined Assessment of the Function and Survival (CAFS) Score at Week 52

  The CAFS at Week 52 is a composite endpoint based on time to earlier occurrence of death or permanent assisted ventilation (\>22 hours a day for \>7 consecutive days) and change from baseline in ALSFRS-R score up to Week 52. ALSFRS-R is a rating scale where 12 functions are rated on 5-point scales (from 0 to 4) with a maximum score of 48 (sum of all 12 items), with a higher score indicating better function. Each participant's outcome was compared to every other participant's outcome by time to death or permanent assisted ventilation and change on ALSFRS-R if survived without permanent assisted ventilation, assigned a score which is sum of comparisons (+1 \[better\], 0 \[tie\], -1 \[worse\]), and summed scores were ranked, from 1 to 296 (modified ITT\[mITT\] population) lowest rank corresponds to participant who died first and highest rank to 1 with best ALSFRS-R outcome among those who survived. A higher rank is considered a better outcome.

  Week 52

Secondary Outcomes (11)

• Part A: Combined Assessment of the Function and Survival Score at Week 24

  Week 24

• Combined Assessment of the Function and Survival Score at Weeks 76 and 104

  Weeks 76 and 104

• Part B:Change From Baseline to Weeks 52, 76, and 104 in the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R) Total Score

  Baseline (Day 1, pre-dose) and Weeks 52, 76 and 104

• Parts A and B: Change From Baseline to Weeks 24, 52, 76, and 104 in Amyotrophic Lateral Sclerosis Assessment Questionnaire 5 Items (ALSAQ-5)

  Baseline (Day 1, pre-dose) and Part A: Week 24, Part B: Weeks 52, 76 and 104

• Parts A and B: Change From Baseline to Weeks 24, 52, 76, and 104 in Percent Predicted Slow Vital Capacity (SVC)

  Baseline (Day 1, pre-dose) and Part A: Week 24, Part B: Weeks 52, 76 and 104

Study Arms (2)

SAR443820

EXPERIMENTAL

twice daily (BID) oral SAR443820

Drug: SAR443820

Placebo

PLACEBO COMPARATOR

twice daily (BID) oral placebo

Drug: Placebo

Interventions

SAR443820 DRUG

Tablet oral

SAR443820

Placebo DRUG

Tablet

Placebo

Eligibility Criteria

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

You may qualify if:

• Diagnosis of possible, clinically probable ALS, clinically probable laboratory supported ALS, or clinically definite ALS according to the revised version of the El Escorial World Federation of Neurology criteria
• Time since onset of first symptom of ALS ≤2 years.
• Slow Vital Capacity (SVC) ≥60% of the predicted value.
• Had to be able to swallow the study tablets at the screening visit.
• Either not currently receiving riluzole or on a stable dose of riluzole for at least 4 weeks before the screening visit. Participants receiving riluzole were expected to remain on the same dose throughout the duration of the study.
• Either not currently receiving edaravone or on the approved standard schedule of edaravone treatment. Participants receiving edaravone had to have completed at least 1 cycle of treatment before the screening visit and were expected to continue edaravone treatment throughout the duration of the study.
• Either not currently receiving the combination of sodium phenylbutyrate and taurursodiol or on the approved standard schedule of the combination of sodium phenylbutyrate and taurursodiol treatment for at least 4 weeks before the screening visit. Participants receiving the combination of sodium phenylbutyrate and taurursodiol were expected to remain on the approved standard schedule throughout the duration of the study.
• Participants with a body weight no less than 45 kg and body mass index no less than 18 kg/m2 at the screening visit
• Female participants with childbearing potential were eligible to participate if they were not pregnant or breastfeeding and agreed to use adequate contraceptive method during study intervention period and for at least 32 days after the last dose of study drug.
• Male participants had to agree to use highly effective contraceptive method during the study period and for at least 92 days following their last dose of the study drug. Male participants were not donate sperms for the duration of study and 92 days after last dose of study drug.

You may not qualify if:

• A history of seizure (History of febrile seizure during childhood was allowed).
• Having central IV lines, such as a peripherally inserted central catheter (PICC XE ' PICC ' \\f Abbreviation \\t 'peripherally inserted central catheter' ) or midline or portacath lines.
• With significant cognitive impairment, psychiatric disease, other neurodegenerative disorder (eg, Parkinson disease or AD), substance abuse other causes of neuromuscular weakness, or any other condition that would make the participants unsuitable for participating in the study or could interfere with assessment or completing the study in the opinion of the Investigator.
• History of recent serious infection (eg, pneumonia, septicemia) within 4 weeks of the screening visit; infection requiring hospitalization or treatment with IV antibiotics, antivirals, or antifungals within 4 weeks of screening; or chronic bacterial infection (such as tuberculosis) deemed unacceptable as per the Investigator's judgment.
• With active herpes zoster infection within 2 months prior to the screening visit.
• A documented history of attempted suicide within 6 months prior to the screening visit, present with suicidal ideation of category 4 or 5 on the Columbia Suicide Severity Rating Scale (CSSRS) , or in the Investigator's judgment are at risk for a suicide attempt.
• History of unstable or severe cardiac, pulmonary, oncological, hepatic, or renal disease or another medically significant illness other than ALS precluding their safe participation in this study.
• Participants who were pregnant or were currently breastfeeding.
• A known history of allergy to any ingredients of SAR443820.
• Currently or previously treated with any strong or moderate CYP3A4 inhibitors or strong CYP3A4 inducers within the specified washout period before the screening visit.
• Received a live vaccine within 14 days before the screening visit.
• Participants with concurrent participation in any other interventional clinical study or who had received treatment with another investigational drug (eg sodium phenylbutyrate or taurursodiol ) within 4 weeks or 5 halflives of the investigational agent before the screening visit, whichever is longer.
• Participants who had received stem cell or gene therapy for ALS at any time in the past.
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \>3.0 × upper limit of normal (ULN)
• Bilirubin \>1.5 × ULN unless the participant had documented Gilbert syndrome (isolated bilirubin \>1.5 × ULN was acceptable if bilirubin was fractionated and direct bilirubin is \<35%)

Sponsors & Collaborators

• Sanofi: lead

Study Sites (63)

UC San Diego Health Site Number : 8400022

La Jolla, California, 92121, United States

Location

USC Site Number : 8400008

Los Angeles, California, 90033, United States

Location

University of California Irvine Site Number : 8400012

Orange, California, 92868, United States

Location

California Pacific Medical Center Site Number : 8400015

San Francisco, California, 94115, United States

Location

University of Colorado Site Number : 8400025

Aurora, Colorado, 80045, United States

Location

Georgetown University Medical Center Site Number : 8400020

Washington D.C., District of Columbia, 20007, United States

Location

Mayo Clinic Site Number : 8400029

Jacksonville, Florida, 32224, United States

Location

AdventHealth Medical Group - Neurology at Winter Park Site Number : 8400006

Winter Park, Florida, 32789, United States

Location

Northwestern Medical Group, Department of Neurology Site Number : 8400003

Chicago, Illinois, 60611, United States

Location

Johns Hopkins University Site Number : 8400028

Baltimore, Maryland, 21287, United States

Location

Massachusetts General Hospital Site Number : 8400001

Boston, Massachusetts, 02114, United States

Location

Mount Sinai - Union Square Site Number : 8400002

New York, New York, 10003, United States

Location

Penn State Milton S. Hershey Medical Center Site Number : 8400004

Hershey, Pennsylvania, 17033, United States

Location

University of Pennsylvania Site Number : 8400021

Philadelphia, Pennsylvania, 19104, United States

Location

Thomas Jefferson University Hospital Site Number : 8400014

Philadelphia, Pennsylvania, 19107, United States

Location

University of Utah Site Number : 8400009

Salt Lake City, Utah, 84132, United States

Location

Froedtert Hospital & Medical College of Wisconsin Site Number : 8400010

Milwaukee, Wisconsin, 53226, United States

Location

Investigational Site Number : 0560001

Leuven, 3000, Belgium

Location

Investigational Site Number : 1240004

Edmonton, Alberta, T6G 2C8, Canada

Location

Investigational Site Number : 1240007

Hamilton, Ontario, L8N 3Z5, Canada

Location

Investigational Site Number : 1240006

London, Ontario, N6A 5A5, Canada

Location

Investigational Site Number : 1240008

Toronto, Ontario, M4N 3M5, Canada

Location

Investigational Site Number : 1240002

Montreal, Quebec, H3A 2B4, Canada

Location

Investigational Site Number : 1240001

Québec, G1J 1Z4, Canada

Location

Investigational Site Number : 1560001

Beijing, 100191, China

Location

Investigational Site Number : 1560003

Chengdu, 610041, China

Location

Investigational Site Number : 1560005

Guangzhou, 510515, China

Location

Investigational Site Number : 1560002

Hangzhou, 310009, China

Location

Investigational Site Number : 1560004

Wuhan, 430030, China

Location

Investigational Site Number : 1560006

Xi'an, 710061, China

Location

Investigational Site Number : 2500007

Caen, 14033, France

Location

Investigational Site Number : 2500006

Lille, 59037, France

Location

Investigational Site Number : 2500002

Marseille, 13385, France

Location

Investigational Site Number : 2500003

Montpellier, 34295, France

Location

Investigational Site Number : 2500004

Tours, 37044, France

Location

Investigational Site Number : 2500005

Vandœuvre-lès-Nancy, 54511, France

Location

Investigational Site Number : 2760004

Berlin, 13353, Germany

Location

Investigational Site Number : 2760003

Dresden, 01307, Germany

Location

Investigational Site Number : 2760008

Haag in OB, 83527, Germany

Location

Investigational Site Number : 2760005

Hanover, 30625, Germany

Location

Investigational Site Number : 2760002

Lübeck, 23538, Germany

Location

Investigational Site Number : 2760001

Ulm, 89081, Germany

Location

Investigational Site Number : 2760009

Würzburg, 97074, Germany

Location

Investigational Site Number : 3800001

Milan, 20132, Italy

Location

Investigational Site Number : 3800004

Milan, 20138, Italy

Location

Investigational Site Number : 3800002

Torino, 10126, Italy

Location

Investigational Site Number : 3920003

Nagoya, Aichi-ken, 466-8560, Japan

Location

Investigational Site Number : 3920004

Ichikawa-shi, Chiba, 272-0827, Japan

Location

Investigational Site Number : 3920006

Tokushima, Tokushima, 770-8503, Japan

Location

Investigational Site Number : 3920005

Fuchu-shi, Tokyo, 183-0042, Japan

Location

Investigational Site Number : 3920001

Ōta-ku, Tokyo, 143-8541, Japan

Location

Investigational Site Number : 3920002

Koshi-shi, 861-1196, Japan

Location

Investigational Site Number : 5280001

Utrecht, 3584 CX, Netherlands

Location

Investigational Site Number : 6160001

Krakow, 31-503, Poland

Location

Investigational Site Number : 6160002

Ksawerów, 95-054, Poland

Location

Investigational Site Number : 7240005

Barcelona, Barcelona [Barcelona], 08035, Spain

Location

Investigational Site Number : 7240002

L'Hospitalet de Llobregat, Barcelona [Barcelona], 08907, Spain

Location

Investigational Site Number : 7240003

Madrid, 28029, Spain

Location

Investigational Site Number : 7240001

Valencia, 46026, Spain

Location

Investigational Site Number : 7520002

Stockholm, 113 61, Sweden

Location

Investigational Site Number : 7520001

Umeå, SE-901 85 Umea, Sweden

Location

Investigational Site Number : 8260002

Plymouth, Devon, PL6 8DH, United Kingdom

Location

Investigational Site Number : 8260003

Stoke-on-Trent, Staffordshire, ST46QG, United Kingdom

Location

Related Publications (1)

• Hincelin-Mery A, Nicolas X, Cantalloube C, Pomponio R, Lewanczyk P, Benamor M, Ofengeim D, Krupka E, Hsiao-Nakamoto J, Eastenson A, Atassi N. Safety, pharmacokinetics, and target engagement of a brain penetrant RIPK1 inhibitor, SAR443820 (DNL788), in healthy adult participants. Clin Transl Sci. 2024 Jan;17(1):e13690. doi: 10.1111/cts.13690. Epub 2023 Dec 11.

  PMID: 38010108 DERIVED

Related Links

• ACT16970 (Himalaya study)-Amyotrophic Lateral Sclerosis website

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

Limitations and Caveats

The study was terminated prematurely since the Part A did not meet the primary endpoint.

Results Point of Contact

• Title: Trial Transparency Team
• Organization: Sanofi aventis recherche & développement

Contact-US@sanofi.com

800-633-1610

Study Officials

• Clinical Sciences & Operations

  Sanofi

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 2, 2022
• First Posted: February 14, 2022
• Study Start: April 13, 2022
• Primary Completion: March 7, 2024
• Study Completion: March 7, 2024
• Last Updated: March 21, 2025
• Results First Posted: March 21, 2025

Record last verified: 2025-03

Data Sharing

• IPD Sharing: Will share

Locations

FR (6); BE (1); DE (7); NL (1); US (17); SE (2); PL (2); CA (6); JP (6); CN (6); IT (3); ES (4); GB (2)