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

A Phase 2, Multicenter, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy and Safety of SAR443820 in Adult Participants With Amyotrophic Lateral Sclerosis, Followed by an Open-label Extension

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.

The study duration included an up to 4-week screening period, 24-week double-blind treatment period in Part A, 80-week open-label treatment period in Part B and 2-week post-treatment follow-up period, with a maximum total study duration of 110 weeks.

Inclusion Criteria:

• 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.

Exclusion Criteria:

• 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%)
• Serum albumin <3.5 g/dL
• Estimated glomerular filtration rate <60 mL/min/1.73 m2 (Modification of Diet in Renal Disease [MDRD])

The above information was not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.