Trial Outcomes & Findings for Phase 2 Study for SAR443820 in Participants With Amyotrophic Lateral Sclerosis (ALS) (NCT NCT05237284)

Last Updated: 2025-03-21

Results Overview

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.

Recruitment status

TERMINATED

Study phase

PHASE2

Target enrollment

305 participants

Primary outcome timeframe

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

Results posted on

2025-03-21

Participant Flow

This study is double-blind followed by an open-label extension, 2 parts: Part (A and B) conducted at 63 investigational sites in 13 countries. A total of 397 participants were screened between 13 Apr 2022 and 17 July 2023, of which 92 were screen failures. Screen failures were due to not meeting the eligibility criteria.

The study consisted of a screening period (up to 4 weeks prior to randomization), treatment period (a 24-week double-blinded in Part A, an 80-week open-label in Part B), and a 2-week post-treatment follow up period, with a maximum total study duration of 110 weeks. The study was terminated as Part A did not meet the primary endpoint.

Participant milestones

Participant milestones
Measure	Part A: Placebo Participants received placebo matching to SAR443820 tablet orally twice a day (BID) for 24 weeks in Part A.	Part A: SAR443820 Participants received SAR443820 20 milligram (mg) tablet orally BID for 24 weeks in Part A.	Part B: Placebo/SAR443820 Participants who had received placebo matching to SAR443820 tablet in Part A, continued to receive SAR443820 20 mg tablet orally BID for 80 weeks during Part B.	Part B: SAR443820/SAR443820 Participants who had received SAR443820 tablet in Part A, continued to receive SAR443820 20 mg tablet orally BID for 80 weeks during Part B.
Part A (Double-blind Period: 24 Weeks) STARTED	102	203	0	0
Part A (Double-blind Period: 24 Weeks) Randomized and Treated	102	202	0	0
Part A (Double-blind Period: 24 Weeks) COMPLETED	88	167	0	0
Part A (Double-blind Period: 24 Weeks) NOT COMPLETED	14	36	0	0
Part B (Open-label Period: 80 Weeks) STARTED	0	0	88	167
Part B (Open-label Period: 80 Weeks) Treated	0	0	79	136
Part B (Open-label Period: 80 Weeks) COMPLETED	0	0	0	0
Part B (Open-label Period: 80 Weeks) NOT COMPLETED	0	0	88	167

Reasons for withdrawal

Reasons for withdrawal
Measure	Part A: Placebo Participants received placebo matching to SAR443820 tablet orally twice a day (BID) for 24 weeks in Part A.	Part A: SAR443820 Participants received SAR443820 20 milligram (mg) tablet orally BID for 24 weeks in Part A.	Part B: Placebo/SAR443820 Participants who had received placebo matching to SAR443820 tablet in Part A, continued to receive SAR443820 20 mg tablet orally BID for 80 weeks during Part B.	Part B: SAR443820/SAR443820 Participants who had received SAR443820 tablet in Part A, continued to receive SAR443820 20 mg tablet orally BID for 80 weeks during Part B.
Part A (Double-blind Period: 24 Weeks) Other	0	2	0	0
Part A (Double-blind Period: 24 Weeks) Withdrawal by Subject	8	13	0	0
Part A (Double-blind Period: 24 Weeks) Poor compliance to protocol	0	1	0	0
Part A (Double-blind Period: 24 Weeks) Adverse Event	6	20	0	0
Part B (Open-label Period: 80 Weeks) Other	0	0	0	3
Part B (Open-label Period: 80 Weeks) Study terminated by sponsor	0	0	64	126
Part B (Open-label Period: 80 Weeks) Withdrawal by Subject	0	0	11	21
Part B (Open-label Period: 80 Weeks) Poor compliance to protocol	0	0	0	1
Part B (Open-label Period: 80 Weeks) Adverse Event	0	0	13	16

Baseline Characteristics

Only participants with data collected at specified timepoints are reported.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Part A: Placebo n=102 Participants Participants received placebo matching to SAR443820 tablet orally BID for 24 weeks in Part A.	Part A: SAR443820 n=203 Participants Participants received SAR443820 20 mg tablet orally BID for 24 weeks in Part A.	Total n=305 Participants Total of all reporting groups
Age, Continuous	56.7 years STANDARD_DEVIATION 11.5 • n=102 Participants	57.0 years STANDARD_DEVIATION 11.6 • n=203 Participants	56.9 years STANDARD_DEVIATION 11.5 • n=305 Participants
Sex: Female, Male Female	38 Participants n=102 Participants	84 Participants n=203 Participants	122 Participants n=305 Participants
Sex: Female, Male Male	64 Participants n=102 Participants	119 Participants n=203 Participants	183 Participants n=305 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=102 Participants	0 Participants n=203 Participants	0 Participants n=305 Participants
Race (NIH/OMB) Asian	26 Participants n=102 Participants	52 Participants n=203 Participants	78 Participants n=305 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	1 Participants n=102 Participants	1 Participants n=203 Participants	2 Participants n=305 Participants
Race (NIH/OMB) Black or African American	1 Participants n=102 Participants	3 Participants n=203 Participants	4 Participants n=305 Participants
Race (NIH/OMB) White	69 Participants n=102 Participants	126 Participants n=203 Participants	195 Participants n=305 Participants
Race (NIH/OMB) More than one race	0 Participants n=102 Participants	0 Participants n=203 Participants	0 Participants n=305 Participants
Race (NIH/OMB) Unknown or Not Reported	5 Participants n=102 Participants	21 Participants n=203 Participants	26 Participants n=305 Participants
Baseline Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R) Total Score	36.23 score on a scale STANDARD_DEVIATION 5.00 • n=100 Participants • Only participants with data collected at specified timepoints are reported.	35.97 score on a scale STANDARD_DEVIATION 4.41 • n=199 Participants • Only participants with data collected at specified timepoints are reported.	36.06 score on a scale STANDARD_DEVIATION 4.61 • n=299 Participants • Only participants with data collected at specified timepoints are reported.

PRIMARY outcome

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

Population: The Intent-to-treat (ITT) population consisted of all randomized participants. Only participants with data collected at Baseline and Week 24 are reported.

Outcome measures

Outcome measures
Measure	Part A: Placebo n=87 Participants Participants received placebo matching to SAR443820 tablet orally BID for 24 weeks in Part A.	Part A: SAR443820 n=169 Participants Participants received SAR443820 20 mg tablet orally BID for 24 weeks in Part A.	Part B: Placebo/SAR443820 Participants who had received placebo matching to SAR443820 tablet in Part A, continued to receive SAR443820 20 mg tablet orally BID for 80 weeks during Part B.	Part B: SAR443820/SAR443820 Participants who had received SAR443820 tablet in Part A, continued to receive SAR443820 20 mg tablet orally BID for 80 weeks during Part B.
Part A: Change From Baseline to Week 24 in the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R) Total Score	-5.9 score on a scale Standard Deviation 5.9	-6.1 score on a scale Standard Deviation 5.4	—	—

PRIMARY outcome

Timeframe: Week 52

Population: The mITT population consisted of all randomized participants who either died or had available baseline and at least 1 post-baseline ALSFRS-R assessment. All participants who had either early termination or who did not enter Part B, were also included in Week 52 analysis.

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.

Outcome measures

Outcome measures
Measure	Part A: Placebo n=100 Participants Participants received placebo matching to SAR443820 tablet orally BID for 24 weeks in Part A.	Part A: SAR443820 n=196 Participants Participants received SAR443820 20 mg tablet orally BID for 24 weeks in Part A.	Part B: Placebo/SAR443820 Participants who had received placebo matching to SAR443820 tablet in Part A, continued to receive SAR443820 20 mg tablet orally BID for 80 weeks during Part B.	Part B: SAR443820/SAR443820 Participants who had received SAR443820 tablet in Part A, continued to receive SAR443820 20 mg tablet orally BID for 80 weeks during Part B.
Part B: Combined Assessment of the Function and Survival (CAFS) Score at Week 52	154.89 score on a scale Standard Deviation 92.16	145.24 score on a scale Standard Deviation 82.09	—	—

SECONDARY outcome

Timeframe: Week 24

The CAFS at Week 24 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 24. 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 (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.

Outcome measures

Outcome measures
Measure	Part A: Placebo n=100 Participants Participants received placebo matching to SAR443820 tablet orally BID for 24 weeks in Part A.	Part A: SAR443820 n=196 Participants Participants received SAR443820 20 mg tablet orally BID for 24 weeks in Part A.	Part B: Placebo/SAR443820 Participants who had received placebo matching to SAR443820 tablet in Part A, continued to receive SAR443820 20 mg tablet orally BID for 80 weeks during Part B.	Part B: SAR443820/SAR443820 Participants who had received SAR443820 tablet in Part A, continued to receive SAR443820 20 mg tablet orally BID for 80 weeks during Part B.
Part A: Combined Assessment of the Function and Survival Score at Week 24	151.19 score on a scale Standard Deviation 90.71	147.13 score on a scale Standard Deviation 83.06	—	—

SECONDARY outcome

Timeframe: Weeks 76 and 104

Population: The mITT population consisted of all randomized participants who either died or had available baseline and at least 1 post-baseline ALSFRS-R assessment. Only participants with data collected at specified timepoints are reported. The study was terminated prematurely since the Part A did not meet the primary endpoint. The data for Week 104 was not collected. All participants who had either early termination or who did not enter Part B, were also included in Week 76 analysis.

The CAFS at Weeks 76 and 106 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 Weeks 76 and 104. 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 (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.

Outcome measures

Outcome measures
Measure	Part A: Placebo n=100 Participants Participants received placebo matching to SAR443820 tablet orally BID for 24 weeks in Part A.	Part A: SAR443820 n=196 Participants Participants received SAR443820 20 mg tablet orally BID for 24 weeks in Part A.	Part B: Placebo/SAR443820 Participants who had received placebo matching to SAR443820 tablet in Part A, continued to receive SAR443820 20 mg tablet orally BID for 80 weeks during Part B.	Part B: SAR443820/SAR443820 Participants who had received SAR443820 tablet in Part A, continued to receive SAR443820 20 mg tablet orally BID for 80 weeks during Part B.
Combined Assessment of the Function and Survival Score at Weeks 76 and 104 Week 76	155.54 score on a scale Standard Deviation 92.17	144.91 score on a scale Standard Deviation 82.04	—	—

SECONDARY outcome

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

Population: The ITT population consisted of all randomized participants. Only participants with data collected at specified timepoints are reported. The study was terminated prematurely since the Part A did not meet the primary endpoint. The data for Week 104 was not collected.

Outcome measures

Outcome measures
Measure	Part A: Placebo n=23 Participants Participants received placebo matching to SAR443820 tablet orally BID for 24 weeks in Part A.	Part A: SAR443820 n=53 Participants Participants received SAR443820 20 mg tablet orally BID for 24 weeks in Part A.	Part B: Placebo/SAR443820 Participants who had received placebo matching to SAR443820 tablet in Part A, continued to receive SAR443820 20 mg tablet orally BID for 80 weeks during Part B.	Part B: SAR443820/SAR443820 Participants who had received SAR443820 tablet in Part A, continued to receive SAR443820 20 mg tablet orally BID for 80 weeks during Part B.
Part B:Change From Baseline to Weeks 52, 76, and 104 in the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R) Total Score Week 52	-11.9 score on a scale Standard Deviation 7.8	-12.1 score on a scale Standard Deviation 8.0	—	—
Part B:Change From Baseline to Weeks 52, 76, and 104 in the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R) Total Score Week 76	-12.0 score on a scale Standard Deviation 10.1	-13.3 score on a scale Standard Deviation 9.0	—	—

SECONDARY outcome

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

The ALSAQ-5 is a patient-reported outcome that consists of 5 items derived from the ALSAQ-40. The 5 items closely resemble those of the 5-dimension scores of the ALSAQ-40: eating and drinking; communication; activities of daily living/independence; physical mobility; and emotional functioning. Each item was scored on a 5-point Likert scale ranging from 0 (never) to 4 (always or cannot do at all) according to the frequency of a particular problem. The total scores was the sum of the individual items score and it ranges from 0 to 20, with higher scores indicative of greater physical and emotional limitations. Baseline was defined as the Day 1 pre-dose value.

Outcome measures

Outcome measures
Measure	Part A: Placebo n=65 Participants Participants received placebo matching to SAR443820 tablet orally BID for 24 weeks in Part A.	Part A: SAR443820 n=120 Participants Participants received SAR443820 20 mg tablet orally BID for 24 weeks in Part A.	Part B: Placebo/SAR443820 n=16 Participants Participants who had received placebo matching to SAR443820 tablet in Part A, continued to receive SAR443820 20 mg tablet orally BID for 80 weeks during Part B.	Part B: SAR443820/SAR443820 n=34 Participants Participants who had received SAR443820 tablet in Part A, continued to receive SAR443820 20 mg tablet orally BID for 80 weeks during Part B.
Parts A and B: Change From Baseline to Weeks 24, 52, 76, and 104 in Amyotrophic Lateral Sclerosis Assessment Questionnaire 5 Items (ALSAQ-5) Week 24	2.1 score on a scale Standard Deviation 3.1	2.4 score on a scale Standard Deviation 3.1	—	—
Parts A and B: Change From Baseline to Weeks 24, 52, 76, and 104 in Amyotrophic Lateral Sclerosis Assessment Questionnaire 5 Items (ALSAQ-5) Week 52	—	—	4.1 score on a scale Standard Deviation 4.2	4.4 score on a scale Standard Deviation 3.5
Parts A and B: Change From Baseline to Weeks 24, 52, 76, and 104 in Amyotrophic Lateral Sclerosis Assessment Questionnaire 5 Items (ALSAQ-5) Week 76	—	—	5.0 score on a scale Standard Deviation 3.5	5.8 score on a scale Standard Deviation 5.3

SECONDARY outcome

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

SVC is the maximum volume of air that can be slowly exhaled after slow, maximal inhalation. SVC is measured in participants while they are in an upright position at least 3 trials per assessment or up to 5 trials when the highest and second highest of the first 3 measurements differ by 10% or more. Baseline was defined as the Day 1 pre-dose value.

Outcome measures

Outcome measures
Measure	Part A: Placebo n=80 Participants Participants received placebo matching to SAR443820 tablet orally BID for 24 weeks in Part A.	Part A: SAR443820 n=141 Participants Participants received SAR443820 20 mg tablet orally BID for 24 weeks in Part A.	Part B: Placebo/SAR443820 n=14 Participants Participants who had received placebo matching to SAR443820 tablet in Part A, continued to receive SAR443820 20 mg tablet orally BID for 80 weeks during Part B.	Part B: SAR443820/SAR443820 n=34 Participants Participants who had received SAR443820 tablet in Part A, continued to receive SAR443820 20 mg tablet orally BID for 80 weeks during Part B.
Parts A and B: Change From Baseline to Weeks 24, 52, 76, and 104 in Percent Predicted Slow Vital Capacity (SVC) Week 24	-13.43 percentage of predicted volume Standard Deviation 14.66	-11.24 percentage of predicted volume Standard Deviation 13.35	—	—
Parts A and B: Change From Baseline to Weeks 24, 52, 76, and 104 in Percent Predicted Slow Vital Capacity (SVC) Week 52	—	—	-22.44 percentage of predicted volume Standard Deviation 16.35	-18.29 percentage of predicted volume Standard Deviation 15.75
Parts A and B: Change From Baseline to Weeks 24, 52, 76, and 104 in Percent Predicted Slow Vital Capacity (SVC) Week 76	—	—	-31.30 percentage of predicted volume Standard Deviation 30.72	-22.68 percentage of predicted volume Standard Deviation 15.93

SECONDARY outcome

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

Population: The ITT population consisted of all randomized participants. Only participants with data collected at specified timepoints are reported.

Serum blood samples were collected at indicated time points to measure changes in NfL, a marker of neuronal injury. Baseline was defined as the Day 1 pre-dose value.

Outcome measures

Outcome measures
Measure	Part A: Placebo n=89 Participants Participants received placebo matching to SAR443820 tablet orally BID for 24 weeks in Part A.	Part A: SAR443820 n=159 Participants Participants received SAR443820 20 mg tablet orally BID for 24 weeks in Part A.	Part B: Placebo/SAR443820 n=21 Participants Participants who had received placebo matching to SAR443820 tablet in Part A, continued to receive SAR443820 20 mg tablet orally BID for 80 weeks during Part B.	Part B: SAR443820/SAR443820 n=45 Participants Participants who had received SAR443820 tablet in Part A, continued to receive SAR443820 20 mg tablet orally BID for 80 weeks during Part B.
Parts A and B: Change From Baseline to Weeks 24 and 52 in Serum Neurofilament Light Chain (NfL) Week 52	—	—	0.925 picograms per milliliter (pg/mL) Geometric Coefficient of Variation -709.957	0.887 picograms per milliliter (pg/mL) Geometric Coefficient of Variation -1488.592
Parts A and B: Change From Baseline to Weeks 24 and 52 in Serum Neurofilament Light Chain (NfL) Week 24	1.016 picograms per milliliter (pg/mL) Geometric Coefficient of Variation 5853.645	0.996 picograms per milliliter (pg/mL) Geometric Coefficient of Variation 6136.969	—	—

SECONDARY outcome

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

Population: The ITT population consisted of all randomized participants. Only participants with data collected at Baseline and Week 24 are reported.

The muscles measured in the study included upper limb and lower-limb muscle groups. Bilateral hand grip were measured using a grip dynamometer and all other muscles were measured using a handheld dynamometer (HHD). Nine upper and lower extremity muscles or muscle groups were examined: shoulder flexion, elbow flexion, wrist extension, first dorsal interosseous contraction, hip flexion, knee extension, and ankle dorsiflexion. Each group was measured at least twice bilaterally and the average of the 2 highest measurements were analyzed. Individual muscles are standardized into the corresponding Z-scores using data from standard sample of healthy participants. A Z-score of 0 in a muscle measurement is equal to the mean of that measurement from the standard sample. Negative numbers indicate decreased muscle strength. For analysis, individual Z-scores were averaged to produce a total megascore including all available muscle groups. Baseline was defined as the Day 1 pre-dose value.

Outcome measures

Outcome measures
Measure	Part A: Placebo n=75 Participants Participants received placebo matching to SAR443820 tablet orally BID for 24 weeks in Part A.	Part A: SAR443820 n=128 Participants Participants received SAR443820 20 mg tablet orally BID for 24 weeks in Part A.	Part B: Placebo/SAR443820 Participants who had received placebo matching to SAR443820 tablet in Part A, continued to receive SAR443820 20 mg tablet orally BID for 80 weeks during Part B.	Part B: SAR443820/SAR443820 Participants who had received SAR443820 tablet in Part A, continued to receive SAR443820 20 mg tablet orally BID for 80 weeks during Part B.
Part A: Change From Baseline to Week 24 in Muscle Strength	-0.498 score on a scale Standard Deviation 0.960	-0.495 score on a scale Standard Deviation 0.704	—	—

SECONDARY outcome

Timeframe: Baseline (Day 1, pre-dose) up to early termination of study, approximately 84 weeks

Population: The ITT population consisted of all randomized participants. Only participants with data collected at specified timepoints are reported.

The survival endpoint was defined as the time to death or permanent assisted ventilation (\>22 hours a day for \>7 consecutive days), whichever comes first. Baseline was defined as the Day 1 pre-dose value.

Outcome measures

Outcome measures
Measure	Part A: Placebo n=17 Participants Participants received placebo matching to SAR443820 tablet orally BID for 24 weeks in Part A.	Part A: SAR443820 n=31 Participants Participants received SAR443820 20 mg tablet orally BID for 24 weeks in Part A.	Part B: Placebo/SAR443820 Participants who had received placebo matching to SAR443820 tablet in Part A, continued to receive SAR443820 20 mg tablet orally BID for 80 weeks during Part B.	Part B: SAR443820/SAR443820 Participants who had received SAR443820 tablet in Part A, continued to receive SAR443820 20 mg tablet orally BID for 80 weeks during Part B.
Part B: Time From Baseline to Occurrence of Either Death or Permanent Assisted Ventilation	31.90 weeks Standard Deviation 16.71	31.54 weeks Standard Deviation 18.82	—	—

SECONDARY outcome

Timeframe: Baseline (Day 1, pre-dose) up to early termination of study, approximately 84 weeks

Population: The ITT population consisted of all randomized participants. Only participants with data collected at specified timepoints are reported.

Time to the occurrence of death from baseline due to any reason has been reported. Baseline was defined as the Day 1 pre-dose value.

Outcome measures

Outcome measures
Measure	Part A: Placebo n=14 Participants Participants received placebo matching to SAR443820 tablet orally BID for 24 weeks in Part A.	Part A: SAR443820 n=23 Participants Participants received SAR443820 20 mg tablet orally BID for 24 weeks in Part A.	Part B: Placebo/SAR443820 Participants who had received placebo matching to SAR443820 tablet in Part A, continued to receive SAR443820 20 mg tablet orally BID for 80 weeks during Part B.	Part B: SAR443820/SAR443820 Participants who had received SAR443820 tablet in Part A, continued to receive SAR443820 20 mg tablet orally BID for 80 weeks during Part B.
Part B: Time From Baseline to the Occurrence of Death	38.30 weeks Standard Deviation 16.45	29.93 weeks Standard Deviation 17.13	—	—

SECONDARY outcome

Timeframe: From first dose of SAR443820 up to 14 days after last dose of SAR443820 administration in Part B, approximately 82 weeks for Parts A+B combined Arm (SAR443820/SAR443820), approximately 58 weeks for Part B Arm (Placebo/SAR443820)

Population: The safety population consisted of all randomized participants who received at least 1 dose (including partial dose) of SAR443820. All participants from safety population and treated with SAR443820 are included in Part B arm and participants from safety population are included in Parts A+B arm. The combined safety analysis for TEAE provided the accurate summary of all TEAE in both treatment groups after the initiation of SAR443820.

An adverse event (AE) was any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. TEAEs were defined as the AEs that developed, worsened or became serious during the treatment-emergent period (defined as time from first administration of study treatment (Day 1) to last administration of study treatment + 14 days). Serious adverse events (SAE): Any AE that at any dose: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, was a medically important event. All TEAE occurring after SAR443820 initiation are provided for both randomized treatment arms in this endpoint.

Outcome measures

Outcome measures
Measure	Part A: Placebo n=79 Participants Participants received placebo matching to SAR443820 tablet orally BID for 24 weeks in Part A.	Part A: SAR443820 n=202 Participants Participants received SAR443820 20 mg tablet orally BID for 24 weeks in Part A.	Part B: Placebo/SAR443820 Participants who had received placebo matching to SAR443820 tablet in Part A, continued to receive SAR443820 20 mg tablet orally BID for 80 weeks during Part B.	Part B: SAR443820/SAR443820 Participants who had received SAR443820 tablet in Part A, continued to receive SAR443820 20 mg tablet orally BID for 80 weeks during Part B.
Parts B and A+B: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) After SAR443820 Initiation TEAEs	51 Participants	183 Participants	—	—
Parts B and A+B: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) After SAR443820 Initiation TESAEs	13 Participants	53 Participants	—	—

SECONDARY outcome

Timeframe: Part A: Day 1: 0.25- 1 hour and 1-3 hours post-dose; Weeks 2 and 8: pre-dose; Week 8: 0.25-3 hours post-dose; Part B: Week 28: pre-dose

Population: Pharmacokinetic (PK) population consisted of all randomized participants who received at least 1 dose of SAR443820 and had at least 1 PK assessment with adequate documentation of dosing and sampling. It was prespecified (statistical analysis plan) that participants will be analyzed according to actual intervention received. In Part B, all participants received SAR443820, so data were combined. Only participants who received SAR443820 with data collected at specified timepoints are reported.

Plasma samples were collected at specified timepoints to determine plasma concentrations of SAR443820.

Outcome measures

Outcome measures
Measure	Part A: Placebo n=911 Samples Participants received placebo matching to SAR443820 tablet orally BID for 24 weeks in Part A.	Part A: SAR443820 n=127 Samples Participants received SAR443820 20 mg tablet orally BID for 24 weeks in Part A.	Part B: Placebo/SAR443820 Participants who had received placebo matching to SAR443820 tablet in Part A, continued to receive SAR443820 20 mg tablet orally BID for 80 weeks during Part B.	Part B: SAR443820/SAR443820 Participants who had received SAR443820 tablet in Part A, continued to receive SAR443820 20 mg tablet orally BID for 80 weeks during Part B.
Parts A and B: Plasma Concentration of SAR443820 Day 1: 0.25- 1 hours post-dose	181.500 nanogram (ng)/mL Standard Deviation 169.940	—	—	—
Parts A and B: Plasma Concentration of SAR443820 Day 1: 1-3 hours post-dose	250.188 nanogram (ng)/mL Standard Deviation 95.867	—	—	—
Parts A and B: Plasma Concentration of SAR443820 Week 2: pre-dose	165.833 nanogram (ng)/mL Standard Deviation 91.355	—	—	—
Parts A and B: Plasma Concentration of SAR443820 Week 8: pre-dose	165.089 nanogram (ng)/mL Standard Deviation 92.686	—	—	—
Parts A and B: Plasma Concentration of SAR443820 Week 8: 0.25- 3 hours post-dose	365.488 nanogram (ng)/mL Standard Deviation 198.609	—	—	—
Parts A and B: Plasma Concentration of SAR443820 Week 28: pre-dose	—	171.865 nanogram (ng)/mL Standard Deviation 104.304	—	—

Adverse Events

Part A: Placebo

Serious events: 17 serious events

Other events: 56 other events

Deaths: 5 deaths

Part A: SAR443820

Serious events: 34 serious events

Other events: 116 other events

Deaths: 11 deaths

Part B: Placebo/SAR443820

Serious events: 17 serious events

Other events: 29 other events

Deaths: 9 deaths

Part B: SAR443820/SAR443820

Serious events: 26 serious events

Other events: 43 other events

Deaths: 12 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Part A: Placebo n=102 participants at risk Participants received placebo matching to SAR443820 tablet orally BID for 24 weeks in Part A.	Part A: SAR443820 n=202 participants at risk Participants received SAR443820 20 mg tablet orally BID for 24 weeks in Part A.	Part B: Placebo/SAR443820 n=79 participants at risk Participants who had received placebo matching to SAR443820 tablet in Part A, continued to receive SAR443820 20 mg tablet orally BID for 80 weeks during Part B.	Part B: SAR443820/SAR443820 n=136 participants at risk Participants who had received SAR443820 tablet in Part A, continued to receive SAR443820 20 mg tablet orally BID for 80 weeks during Part B.
Infections and infestations Covid-19	8.8% 9/102 • Number of events 9 • Adverse events were collected from first dose of study treatment (Day 1) up to 14 days after last dose of study treatment administration, up to 26 weeks for Part A, and 58 weeks for Part B. All-cause mortality (death) was assessed from signing of the informed consent form to study termination, approximately 99 weeks. Analysis was performed on safety population.	9.9% 20/202 • Number of events 20 • Adverse events were collected from first dose of study treatment (Day 1) up to 14 days after last dose of study treatment administration, up to 26 weeks for Part A, and 58 weeks for Part B. All-cause mortality (death) was assessed from signing of the informed consent form to study termination, approximately 99 weeks. Analysis was performed on safety population.	3.8% 3/79 • Number of events 3 • Adverse events were collected from first dose of study treatment (Day 1) up to 14 days after last dose of study treatment administration, up to 26 weeks for Part A, and 58 weeks for Part B. All-cause mortality (death) was assessed from signing of the informed consent form to study termination, approximately 99 weeks. Analysis was performed on safety population.	2.2% 3/136 • Number of events 3 • Adverse events were collected from first dose of study treatment (Day 1) up to 14 days after last dose of study treatment administration, up to 26 weeks for Part A, and 58 weeks for Part B. All-cause mortality (death) was assessed from signing of the informed consent form to study termination, approximately 99 weeks. Analysis was performed on safety population.
Infections and infestations Nasopharyngitis	3.9% 4/102 • Number of events 6 • Adverse events were collected from first dose of study treatment (Day 1) up to 14 days after last dose of study treatment administration, up to 26 weeks for Part A, and 58 weeks for Part B. All-cause mortality (death) was assessed from signing of the informed consent form to study termination, approximately 99 weeks. Analysis was performed on safety population.	4.0% 8/202 • Number of events 8 • Adverse events were collected from first dose of study treatment (Day 1) up to 14 days after last dose of study treatment administration, up to 26 weeks for Part A, and 58 weeks for Part B. All-cause mortality (death) was assessed from signing of the informed consent form to study termination, approximately 99 weeks. Analysis was performed on safety population.	6.3% 5/79 • Number of events 6 • Adverse events were collected from first dose of study treatment (Day 1) up to 14 days after last dose of study treatment administration, up to 26 weeks for Part A, and 58 weeks for Part B. All-cause mortality (death) was assessed from signing of the informed consent form to study termination, approximately 99 weeks. Analysis was performed on safety population.	2.9% 4/136 • Number of events 4 • Adverse events were collected from first dose of study treatment (Day 1) up to 14 days after last dose of study treatment administration, up to 26 weeks for Part A, and 58 weeks for Part B. All-cause mortality (death) was assessed from signing of the informed consent form to study termination, approximately 99 weeks. Analysis was performed on safety population.
Nervous system disorders Dizziness	2.0% 2/102 • Number of events 2 • Adverse events were collected from first dose of study treatment (Day 1) up to 14 days after last dose of study treatment administration, up to 26 weeks for Part A, and 58 weeks for Part B. All-cause mortality (death) was assessed from signing of the informed consent form to study termination, approximately 99 weeks. Analysis was performed on safety population.	5.9% 12/202 • Number of events 13 • Adverse events were collected from first dose of study treatment (Day 1) up to 14 days after last dose of study treatment administration, up to 26 weeks for Part A, and 58 weeks for Part B. All-cause mortality (death) was assessed from signing of the informed consent form to study termination, approximately 99 weeks. Analysis was performed on safety population.	1.3% 1/79 • Number of events 1 • Adverse events were collected from first dose of study treatment (Day 1) up to 14 days after last dose of study treatment administration, up to 26 weeks for Part A, and 58 weeks for Part B. All-cause mortality (death) was assessed from signing of the informed consent form to study termination, approximately 99 weeks. Analysis was performed on safety population.	1.5% 2/136 • Number of events 2 • Adverse events were collected from first dose of study treatment (Day 1) up to 14 days after last dose of study treatment administration, up to 26 weeks for Part A, and 58 weeks for Part B. All-cause mortality (death) was assessed from signing of the informed consent form to study termination, approximately 99 weeks. Analysis was performed on safety population.
Nervous system disorders Headache	8.8% 9/102 • Number of events 10 • Adverse events were collected from first dose of study treatment (Day 1) up to 14 days after last dose of study treatment administration, up to 26 weeks for Part A, and 58 weeks for Part B. All-cause mortality (death) was assessed from signing of the informed consent form to study termination, approximately 99 weeks. Analysis was performed on safety population.	12.4% 25/202 • Number of events 28 • Adverse events were collected from first dose of study treatment (Day 1) up to 14 days after last dose of study treatment administration, up to 26 weeks for Part A, and 58 weeks for Part B. All-cause mortality (death) was assessed from signing of the informed consent form to study termination, approximately 99 weeks. Analysis was performed on safety population.	3.8% 3/79 • Number of events 3 • Adverse events were collected from first dose of study treatment (Day 1) up to 14 days after last dose of study treatment administration, up to 26 weeks for Part A, and 58 weeks for Part B. All-cause mortality (death) was assessed from signing of the informed consent form to study termination, approximately 99 weeks. Analysis was performed on safety population.	1.5% 2/136 • Number of events 2 • Adverse events were collected from first dose of study treatment (Day 1) up to 14 days after last dose of study treatment administration, up to 26 weeks for Part A, and 58 weeks for Part B. All-cause mortality (death) was assessed from signing of the informed consent form to study termination, approximately 99 weeks. Analysis was performed on safety population.
Respiratory, thoracic and mediastinal disorders Cough	8.8% 9/102 • Number of events 10 • Adverse events were collected from first dose of study treatment (Day 1) up to 14 days after last dose of study treatment administration, up to 26 weeks for Part A, and 58 weeks for Part B. All-cause mortality (death) was assessed from signing of the informed consent form to study termination, approximately 99 weeks. Analysis was performed on safety population.	3.0% 6/202 • Number of events 6 • Adverse events were collected from first dose of study treatment (Day 1) up to 14 days after last dose of study treatment administration, up to 26 weeks for Part A, and 58 weeks for Part B. All-cause mortality (death) was assessed from signing of the informed consent form to study termination, approximately 99 weeks. Analysis was performed on safety population.	2.5% 2/79 • Number of events 2 • Adverse events were collected from first dose of study treatment (Day 1) up to 14 days after last dose of study treatment administration, up to 26 weeks for Part A, and 58 weeks for Part B. All-cause mortality (death) was assessed from signing of the informed consent form to study termination, approximately 99 weeks. Analysis was performed on safety population.	0.74% 1/136 • Number of events 1 • Adverse events were collected from first dose of study treatment (Day 1) up to 14 days after last dose of study treatment administration, up to 26 weeks for Part A, and 58 weeks for Part B. All-cause mortality (death) was assessed from signing of the informed consent form to study termination, approximately 99 weeks. Analysis was performed on safety population.
Gastrointestinal disorders Constipation	9.8% 10/102 • Number of events 10 • Adverse events were collected from first dose of study treatment (Day 1) up to 14 days after last dose of study treatment administration, up to 26 weeks for Part A, and 58 weeks for Part B. All-cause mortality (death) was assessed from signing of the informed consent form to study termination, approximately 99 weeks. Analysis was performed on safety population.	6.9% 14/202 • Number of events 15 • Adverse events were collected from first dose of study treatment (Day 1) up to 14 days after last dose of study treatment administration, up to 26 weeks for Part A, and 58 weeks for Part B. All-cause mortality (death) was assessed from signing of the informed consent form to study termination, approximately 99 weeks. Analysis was performed on safety population.	7.6% 6/79 • Number of events 6 • Adverse events were collected from first dose of study treatment (Day 1) up to 14 days after last dose of study treatment administration, up to 26 weeks for Part A, and 58 weeks for Part B. All-cause mortality (death) was assessed from signing of the informed consent form to study termination, approximately 99 weeks. Analysis was performed on safety population.	5.1% 7/136 • Number of events 7 • Adverse events were collected from first dose of study treatment (Day 1) up to 14 days after last dose of study treatment administration, up to 26 weeks for Part A, and 58 weeks for Part B. All-cause mortality (death) was assessed from signing of the informed consent form to study termination, approximately 99 weeks. Analysis was performed on safety population.
Gastrointestinal disorders Diarrhoea	6.9% 7/102 • Number of events 10 • Adverse events were collected from first dose of study treatment (Day 1) up to 14 days after last dose of study treatment administration, up to 26 weeks for Part A, and 58 weeks for Part B. All-cause mortality (death) was assessed from signing of the informed consent form to study termination, approximately 99 weeks. Analysis was performed on safety population.	6.4% 13/202 • Number of events 16 • Adverse events were collected from first dose of study treatment (Day 1) up to 14 days after last dose of study treatment administration, up to 26 weeks for Part A, and 58 weeks for Part B. All-cause mortality (death) was assessed from signing of the informed consent form to study termination, approximately 99 weeks. Analysis was performed on safety population.	1.3% 1/79 • Number of events 1 • Adverse events were collected from first dose of study treatment (Day 1) up to 14 days after last dose of study treatment administration, up to 26 weeks for Part A, and 58 weeks for Part B. All-cause mortality (death) was assessed from signing of the informed consent form to study termination, approximately 99 weeks. Analysis was performed on safety population.	5.9% 8/136 • Number of events 9 • Adverse events were collected from first dose of study treatment (Day 1) up to 14 days after last dose of study treatment administration, up to 26 weeks for Part A, and 58 weeks for Part B. All-cause mortality (death) was assessed from signing of the informed consent form to study termination, approximately 99 weeks. Analysis was performed on safety population.
Gastrointestinal disorders Nausea	6.9% 7/102 • Number of events 7 • Adverse events were collected from first dose of study treatment (Day 1) up to 14 days after last dose of study treatment administration, up to 26 weeks for Part A, and 58 weeks for Part B. All-cause mortality (death) was assessed from signing of the informed consent form to study termination, approximately 99 weeks. Analysis was performed on safety population.	3.0% 6/202 • Number of events 7 • Adverse events were collected from first dose of study treatment (Day 1) up to 14 days after last dose of study treatment administration, up to 26 weeks for Part A, and 58 weeks for Part B. All-cause mortality (death) was assessed from signing of the informed consent form to study termination, approximately 99 weeks. Analysis was performed on safety population.	3.8% 3/79 • Number of events 3 • Adverse events were collected from first dose of study treatment (Day 1) up to 14 days after last dose of study treatment administration, up to 26 weeks for Part A, and 58 weeks for Part B. All-cause mortality (death) was assessed from signing of the informed consent form to study termination, approximately 99 weeks. Analysis was performed on safety population.	2.2% 3/136 • Number of events 3 • Adverse events were collected from first dose of study treatment (Day 1) up to 14 days after last dose of study treatment administration, up to 26 weeks for Part A, and 58 weeks for Part B. All-cause mortality (death) was assessed from signing of the informed consent form to study termination, approximately 99 weeks. Analysis was performed on safety population.
Gastrointestinal disorders Salivary Hypersecretion	5.9% 6/102 • Number of events 6 • Adverse events were collected from first dose of study treatment (Day 1) up to 14 days after last dose of study treatment administration, up to 26 weeks for Part A, and 58 weeks for Part B. All-cause mortality (death) was assessed from signing of the informed consent form to study termination, approximately 99 weeks. Analysis was performed on safety population.	2.0% 4/202 • Number of events 4 • Adverse events were collected from first dose of study treatment (Day 1) up to 14 days after last dose of study treatment administration, up to 26 weeks for Part A, and 58 weeks for Part B. All-cause mortality (death) was assessed from signing of the informed consent form to study termination, approximately 99 weeks. Analysis was performed on safety population.	1.3% 1/79 • Number of events 1 • Adverse events were collected from first dose of study treatment (Day 1) up to 14 days after last dose of study treatment administration, up to 26 weeks for Part A, and 58 weeks for Part B. All-cause mortality (death) was assessed from signing of the informed consent form to study termination, approximately 99 weeks. Analysis was performed on safety population.	2.2% 3/136 • Number of events 3 • Adverse events were collected from first dose of study treatment (Day 1) up to 14 days after last dose of study treatment administration, up to 26 weeks for Part A, and 58 weeks for Part B. All-cause mortality (death) was assessed from signing of the informed consent form to study termination, approximately 99 weeks. Analysis was performed on safety population.
Musculoskeletal and connective tissue disorders Arthralgia	4.9% 5/102 • Number of events 7 • Adverse events were collected from first dose of study treatment (Day 1) up to 14 days after last dose of study treatment administration, up to 26 weeks for Part A, and 58 weeks for Part B. All-cause mortality (death) was assessed from signing of the informed consent form to study termination, approximately 99 weeks. Analysis was performed on safety population.	5.4% 11/202 • Number of events 12 • Adverse events were collected from first dose of study treatment (Day 1) up to 14 days after last dose of study treatment administration, up to 26 weeks for Part A, and 58 weeks for Part B. All-cause mortality (death) was assessed from signing of the informed consent form to study termination, approximately 99 weeks. Analysis was performed on safety population.	1.3% 1/79 • Number of events 1 • Adverse events were collected from first dose of study treatment (Day 1) up to 14 days after last dose of study treatment administration, up to 26 weeks for Part A, and 58 weeks for Part B. All-cause mortality (death) was assessed from signing of the informed consent form to study termination, approximately 99 weeks. Analysis was performed on safety population.	0.74% 1/136 • Number of events 1 • Adverse events were collected from first dose of study treatment (Day 1) up to 14 days after last dose of study treatment administration, up to 26 weeks for Part A, and 58 weeks for Part B. All-cause mortality (death) was assessed from signing of the informed consent form to study termination, approximately 99 weeks. Analysis was performed on safety population.
Investigations Hepatic Enzyme Increased	2.0% 2/102 • Number of events 2 • Adverse events were collected from first dose of study treatment (Day 1) up to 14 days after last dose of study treatment administration, up to 26 weeks for Part A, and 58 weeks for Part B. All-cause mortality (death) was assessed from signing of the informed consent form to study termination, approximately 99 weeks. Analysis was performed on safety population.	14.9% 30/202 • Number of events 32 • Adverse events were collected from first dose of study treatment (Day 1) up to 14 days after last dose of study treatment administration, up to 26 weeks for Part A, and 58 weeks for Part B. All-cause mortality (death) was assessed from signing of the informed consent form to study termination, approximately 99 weeks. Analysis was performed on safety population.	12.7% 10/79 • Number of events 11 • Adverse events were collected from first dose of study treatment (Day 1) up to 14 days after last dose of study treatment administration, up to 26 weeks for Part A, and 58 weeks for Part B. All-cause mortality (death) was assessed from signing of the informed consent form to study termination, approximately 99 weeks. Analysis was performed on safety population.	5.1% 7/136 • Number of events 7 • Adverse events were collected from first dose of study treatment (Day 1) up to 14 days after last dose of study treatment administration, up to 26 weeks for Part A, and 58 weeks for Part B. All-cause mortality (death) was assessed from signing of the informed consent form to study termination, approximately 99 weeks. Analysis was performed on safety population.
Injury, poisoning and procedural complications Contusion	8.8% 9/102 • Number of events 13 • Adverse events were collected from first dose of study treatment (Day 1) up to 14 days after last dose of study treatment administration, up to 26 weeks for Part A, and 58 weeks for Part B. All-cause mortality (death) was assessed from signing of the informed consent form to study termination, approximately 99 weeks. Analysis was performed on safety population.	5.4% 11/202 • Number of events 17 • Adverse events were collected from first dose of study treatment (Day 1) up to 14 days after last dose of study treatment administration, up to 26 weeks for Part A, and 58 weeks for Part B. All-cause mortality (death) was assessed from signing of the informed consent form to study termination, approximately 99 weeks. Analysis was performed on safety population.	2.5% 2/79 • Number of events 5 • Adverse events were collected from first dose of study treatment (Day 1) up to 14 days after last dose of study treatment administration, up to 26 weeks for Part A, and 58 weeks for Part B. All-cause mortality (death) was assessed from signing of the informed consent form to study termination, approximately 99 weeks. Analysis was performed on safety population.	2.2% 3/136 • Number of events 3 • Adverse events were collected from first dose of study treatment (Day 1) up to 14 days after last dose of study treatment administration, up to 26 weeks for Part A, and 58 weeks for Part B. All-cause mortality (death) was assessed from signing of the informed consent form to study termination, approximately 99 weeks. Analysis was performed on safety population.
Injury, poisoning and procedural complications Fall	21.6% 22/102 • Number of events 40 • Adverse events were collected from first dose of study treatment (Day 1) up to 14 days after last dose of study treatment administration, up to 26 weeks for Part A, and 58 weeks for Part B. All-cause mortality (death) was assessed from signing of the informed consent form to study termination, approximately 99 weeks. Analysis was performed on safety population.	21.8% 44/202 • Number of events 91 • Adverse events were collected from first dose of study treatment (Day 1) up to 14 days after last dose of study treatment administration, up to 26 weeks for Part A, and 58 weeks for Part B. All-cause mortality (death) was assessed from signing of the informed consent form to study termination, approximately 99 weeks. Analysis was performed on safety population.	12.7% 10/79 • Number of events 13 • Adverse events were collected from first dose of study treatment (Day 1) up to 14 days after last dose of study treatment administration, up to 26 weeks for Part A, and 58 weeks for Part B. All-cause mortality (death) was assessed from signing of the informed consent form to study termination, approximately 99 weeks. Analysis was performed on safety population.	8.1% 11/136 • Number of events 12 • Adverse events were collected from first dose of study treatment (Day 1) up to 14 days after last dose of study treatment administration, up to 26 weeks for Part A, and 58 weeks for Part B. All-cause mortality (death) was assessed from signing of the informed consent form to study termination, approximately 99 weeks. Analysis was performed on safety population.

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