This is 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 consists of 2 parts (A and B) as follows: Part A is 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 will be 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 will be 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 will attend 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 will rollover to open-label extension Part B. The Week 24 Visit is the end of Part A and the beginning of Part B. Part B is an open-label, long-term extension period that starts from Week 24 and continues up to Week 106. The objectives of Part B are 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 will remain blinded to Investigators, participants, and site personnel until the end of Part B. Every participant, except those who discontinue Investigational Medicinal Product (IMP) treatment permanently in Part A, will receive BID oral tablets of SAR443820 in Part B.
The study duration includes 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.
- 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 are 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 must have completed at least 1
cycle of treatment before the screening visit and are 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 are 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 are eligible to participate if they
are not pregnant or breastfeeding and agree to use adequate contraceptive method
during study intervention period and for at least 32 days after the last dose of study
drug.
- Male participants must 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 must 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 is 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 are pregnant or are 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 have 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 have 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 has documented Gilbert syndrome (isolated
bilirubin >1.5 × ULN is acceptable if bilirubin is 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 is not intended to contain all considerations relevant to a patient's
potential participation in a clinical trial.