Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Efficacy of SAR442501 in Pediatric Participants With Achondroplasia

Stage 1: Change From Baseline to Weeks 26 and 52 in Annualized Growth Velocity

The AGV was defined as follows: (Height at Date 2 - height at Date 1) divided by interval length in days x 365.25, where the interval length in days was calculated as (Date 2 - Date 1 +1) days. The post-treatment AGV was calculated from height measurements collected during the study. The baseline value was defined as the last available value before the first dose of study drug.

Time frame: Baseline (Day 1) and Weeks 26 and 52

Stage 1: Change From Baseline to Weeks 26 and 52 in Height Z-Score

Post-treatment AGV was calculated from height measurements collected during the study. AGV was calculated as: AGV (centimeter per year)= (Height at Date 2 - Height at Date 1) divided by interval length in days x 365.25, where interval length in days was calculated as (Date 2 - Date 1+1). Z scores were calculated using LMS methods (Box Cox power L, Median M and Variation S), where appropriate: If L≠ 0: Z= \[(AGV/M)\^L-1\]/(LxS); If L= 0: Z= ln(AGV/M)/S. A Z score of 0 represents the mean AGV of the reference population (ACH). For AGV Z scores in children with ACH: Higher Z scores represent better outcomes, meaning faster linear growth relative to age and sex matched reference populations. Lower Z scores represent worse outcomes, indicating slower growth compared to reference norms. Baseline value was defined as last available pre dose height measurement meeting statistical analysis plan specified time interval definitions.

Time frame: Baseline (Day 1) and Weeks 26 and 52

Stage 1: Change From Baseline to Weeks 26 and 52 in Upper to Lower Body Segment Ratio

The upper to lower body segment ratio was calculated by (standing height or total length - lower body segment length) divided by lower body segment length. The baseline value was defined as the last available value before the first dose of study drug.

Time frame: Baseline (Day 1) and Weeks 26 and 52

Stage 1: Change From Baseline to Weeks 26 and 52 in Upper to Lower Extremity Ratio

The upper to lower extremity ratio was calculated by (upper arm + forearm length) divided by (upper leg + lower leg length). The baseline value was defined as the last available value before the first dose of study drug.

Time frame: Baseline (Day 1) and Weeks 26 and 52

Stage 1: Change From Baseline to Weeks 26 and 52 in Sitting to Standing Height Ratio

The sitting to standing height ratio was calculated by sitting height divided by standing height, or crown to rump length divided by total length. The baseline value was defined as the last available value before the first dose of study drug.

Time frame: Baseline (Day 1) and Weeks 26 and 52

Stage 1: Change From Baseline to Weeks 26 and 52 in Arm Span to Height Ratio

The arm span to height ratio was calculated by arm span divided by standing height, or arm span divided by total length. The baseline value was defined as the last available value before the first dose of study drug.

Time frame: Baseline (Day 1) and Weeks 26 and 52

Stage 1: Change From Baseline to Weeks 26 and 52 in Upper Arm to Forearm Length Ratio

The upper arm to forearm length ratio was calculated by upper arm length divided by forearm length. The baseline value was defined as the last available value before the first dose of study drug.

Time frame: Baseline (Day 1) and Weeks 26 and 52

Stage 1: Change From Baseline to Weeks 26 and 52 in Upper Leg to Lower Leg Ratio

The upper leg to lower leg length ratio was calculated by upper leg length divided by lower leg length. The baseline value was defined as the last available value before the first dose of study drug.

Time frame: Baseline (Day 1) and Weeks 26 and 52

Stage 1: Change From Baseline to Weeks 26 and 52 in Head Circumference to Height Ratio

The head circumference to height ratio was calculated by head circumference divided by standing height, or head circumference divided by total length. The baseline value was defined as the last available value before the first dose of study drug.

Time frame: Baseline (Day 1) and Weeks 26 and 52

Stage 2: Change From Baseline to Week 52 in Brainstem, Skull, and Spine Morphometric and Volumetric Parameters

The magnetic resonance imaging was planned to be collected to measure foramen magnum and other brainstem, skull, and spine morphometric parameters in Stage 2 participants. The baseline value was defined as the last available value before the first dose of study drug.

Time frame: Baseline (Day 1) and Week 52

Stage 1: Change From Baseline to Weeks 26 and 52 in Social Score, Emotional Score, and School Functioning Score

The pediatric quality of life (PedsQL) Generic Core Scales assesses pediatric health related quality of life (HRQOL) across functioning domains. Items use a 5-point scale (0=Never to 4=Almost Always). Responses are reverse scored and linearly transformed to a 0-100 scale (0→100, 1→75, 2→50, 3→25, 4→0), where higher scores indicate better quality of life (fewer problems). Domain scores for Social, Emotional, and School Functioning are calculated from the transformed item scores. If more than 50% of items in a domain are missing, the domain score is not computed. If at least 50% are completed, the domain score equals the mean of the non missing transformed item scores. All domain scores range from 0 (almost always) to 100 (never), with higher scores indicate better HRQOL. Baseline was defined as the last available value prior to the first dose of study drug.

Time frame: Baseline (Day 1) and Weeks 26 and 52

Stage 1: Change From Baseline to Weeks 26 and 52 in Psychosocial Health Summary Score, Physical Health Summary Score, and Total Score

The PedsQL core scale was a brief, standardized, generic instrument that was used to measure HRQOL in various pediatric conditions. Psychosocial health summary scores were the meaning of item scores in emotional, social, and school functioning scales; and Physical health summary scores were the meaning of item scores in physical scale. Total score was the mean of all the item scores in all scales. Psychosocial and physical health summary scores and total scores each ranged from 0 (almost always) to 100 (never). Higher scores indicate better HRQOL. For participants aged 5 to 7, only parents completed the questionnaire. The baseline value was defined as the last available value before the first dose of study drug.

Time frame: Baseline (Day 1) and Weeks 26 and 52

Stage 1: Change From Baseline to Weeks 26 and 52 in Mobility Score

The screening tool for everyday mobility and symptoms (STEMS) was completed by clinicians for participants 5 years of age and older. The STEMS captures mobility, use of mobility aides, and impact of pain and/or fatigue at the end of the day across 3 environments: home, school/work and community. Mobility aides were recorded using numeric 5-point rating scale, score ranged from 1 to 5, where 1= independent on all surfaces including stairs, 2= use of sticks, 3= use of crutches, 4= use of wheeled walking device, and 5= use of wheelchair or mobility scooter. Lower score indicated the better outcome. The baseline value was defined as the last available value before the first dose of study drug.

Time frame: Baseline (Day 1) and Weeks 26 and 52

Stage 1: Change From Baseline to Weeks 26 and 52 in Participants Reported Symptoms

The STEMS was completed by clinicians for participants 5 years of age and older. The STEMS captures mobility, use of mobility aides, and impact of pain and/or fatigue at the end of the day across 3 environments: home, school/work and community. Participant reported symptoms were recorded using letters where A= no pain or fatigue, B1= pain only, B2= fatigue and C= pain and fatigue. This was completed for each of the 3 environments resulting in 3 scores, whereby the numeric rating reflects the use of mobility aides and the letter reflects the symptoms. The baseline value was defined as the last available value before the first dose of study drug. Only participants with a Baseline response of "A" were included in the "A to A," "A to B1," and "A to missing" categories at each time point. Similarly, only participants with a Baseline response of "B1" were included in the "B1 to A" and "B1 to missing" categories at each time point.

Time frame: Baseline (Day 1) and Weeks 26 and 52

Stage 1: Change From Baseline to Weeks 26 and 52 in General Fatigue, Sleep/Rest Fatigue and Cognitive Fatigue Scores and Total Score

The PedsQL Multidimensional Fatigue Scale measures fatigue across 3 subscales:General Fatigue, Sleep/Rest Fatigue and Cognitive Fatigue. Items are rated on a 5 point scale (0=Never to 4=Almost Always). Responses are reverse scored and linearly transformed to a 0-100 scale (0→100, 1→75, 2→50, 3→25, 4→0), with higher scores indicate less fatigue and better functioning. Subscale scores are calculated as mean of transformed item scores within each subscale. A Total Score was calculated as mean of all transformed items across subscales. If more than 50% of items are missing within a subscale or across total scale, corresponding score is not computed. If at least 50% are completed, scores are calculated as mean of non missing transformed items. All scores range from 0 (no pain) to 100 (severe pain), with higher scores indicate less fatigue. Baseline was defined as last available value prior to first dose of study drug. For participants aged 5-7 years, only parent proxy report was completed.

Time frame: Baseline (Day 1) and Weeks 26 and 52

Stage 1: Change From Baseline to Weeks 26 and 52 in Current Pain and Worst Pain Rating (PPQ) Score

The PedsQL PPQ assesses current pain and worst pain intensity in the last week using a visual analog scale as well as pain location using a body map. Current and worst pain were scored separately, and scoring was based on the line length to the nearest 0.5 centimeter (5 millimeter). The score ranged from 0 (no pain) to 100 (severe pain), where higher scores indicated greater levels of pain intensity. The PedsQL PPQ was only administered in participants ages 5 years of age and older using both self-report (ages 8 and older) and parent proxy report (ages 5 and older) forms in all countries. For participants aged 5 to 7, only parents completed the questionnaire. The baseline value was defined as the last available value before the first dose of study drug.

Time frame: Baseline (Day 1) and Weeks 26 and 52

Stage 2: Change From Baseline to Week 52 in Achievement of Gross Motor, Fine Motor, Communication, and Feeding Milestones

For Stage 2 participants, achievement of developmental milestones was planned to be assessed using the ACH developmental recording form. This form allows developmental milestones to be recorded and was not a formalized screening tool or assessment. The form measures the domains of gross motor function, fine motor function, communication and feeding via participant reports to the Investigator. The form depicts the cumulative percentage distributions for children with ACH for each item as well as norms for reference based on the Denver II test, where available. Data collected via this form was planned to be evaluated descriptively to explore the age at which participants in this study achieve developmental milestones. The baseline value was defined as the last available value before the first dose of study drug.

Time frame: Baseline (Day 1) and Week 52

Stage 1: Plasma Concentration of SAR442501

Blood samples are collected to determine plasma concentration of SAR442501.

Time frame: Pre-dose and 6, 24 and 72 hours post dose on Day 1; Pre-dose and 3, 6, 12, 24 and 72 hours post dose on Day 57

Stage 1: Maximum Observed Plasma Concentration (Cmax) of SAR442501

Blood samples are collected to determine Cmax of SAR442501. The Cmax of SAR442501 was calculated using non-compartmental method.

Time frame: Pre-dose and 3, 6, 12, 24 and 72 hours post dose on Day 57

Stage 1: Time to Reach the Maximum Concentration (Tmax) of SAR442501

Blood samples are collected to determine tmax of SAR442501. The tmax of SAR442501 was calculated using non-compartmental method.

Time frame: Pre-dose and 3, 6, 12, 24 and 72 hours post dose on Day 57

Stage 1: Area Under the Concentration Versus Time Curve From Time 0 to 72 Hours After Study Drug Administration (AUC0-tau) of SAR442501

Blood samples are collected to determine AUC0-tau of SAR442501. The AUC0-tau of SAR442501 was calculated using non-compartmental method.

Time frame: Pre-dose and 3, 6, 12, 24 and 72 hours post dose on Day 57

Stage 1: Minimum Plasma Concentration (Ctrough) of SAR442501

Blood samples are collected to determine Ctrough of SAR442501. The Ctrough of SAR442501 was calculated using non-compartmental method.

Time frame: Pre-dose on Days 8, 29, 57, 92, 183, 274, 365 and 449

Stage 1: Change From Baseline to Week 26 in Collagen X Biomarker (CXM) Level

Serum samples were collected to assess the change in CXM level with study drug. The CXM was also named PRO-C10 because the biomarker assay used was aimed to target the recognition of the C terminus of the NC1 domain of type X collagen. The baseline value was defined as the last available value before the first dose of study drug. Change from baseline in CXM level has been reported.

Time frame: Baseline (Day 1) and Week 26

Stage 1: Change From Baseline to Weeks 26 and 52 in Osteocalcin Level

Serum samples were collected to assess the change in osteocalcin level with study drug. The baseline value was defined as the last available value before the first dose of study drug.

Time frame: Baseline (Day 1) and Weeks 26 and 52

Stage 1: Change From Baseline to Weeks 26 and 52 in Bone-Specific Alkaline Phosphatase Level

Serum samples were collected to assess the change in bone-specific alkaline phosphatase level with study drug. The baseline value was defined as the last available value before the first dose of study drug.

Time frame: Baseline (Day 1) and Weeks 26 and 52

Stage 1: Change From Baseline to Weeks 26 and 52 in Procollagen Type 1 N-Terminal Propeptide (P1NP) Level

Serum samples were collected to assess the change in P1NP level with study drug. The baseline value was defined as the last available value before the first dose of study drug.

Time frame: Baseline (Day 1) and Weeks 26 and 52

Stage 1: Change From Baseline to Weeks 26 and 52 in Collagen-Type 1 C-Telopeptide (CTX) Level

Serum samples were collected to assess the change in CTX level with study drug. The baseline value was defined as the last available value before the first dose of study drug.

Time frame: Baseline (Day 1) and Weeks 26 and 52

Stage 1: Number of Participants With Anti-drug Antibodies (ADA) to SAR442501

Serum samples were collected to assess the antibodies to SAR442501. Samples were screened and then confirmed for antibodies binding to SAR442501 and the titer of confirmed positive samples were reported. Positive ADA refers to pre-existing ADA at the pre-dose assessment on Day 1.

Time frame: From the first dose of study drug administration (Day 1) up to early termination of the study, approximately 58 weeks (Stage 1: SAR442501 Dose A) and 46 weeks (Stage 1: SAR442501 Dose B)

Stage 2: Number of Participants With Change From Baseline to Weeks 26 and 52 in Neurological Examination Findings

A complete neurological examination included assessment of mental status, motor function and balance, sensory exam, newborn and infant reflexes, muscle stretch reflexes in the older children and evaluation of the cranial nerves. The baseline value was defined as the last available value before the first dose of study drug.

Time frame: Baseline (Day 1) and Weeks 26 and 52