A treatment-emergent Adverse Events (TEAE) is any Adverse Events that newly appeared, increased in frequency or worsened in severity following initiation of study drug administration. A severity grade was defined by the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03. As per CTCAE, Grade 1 scales as Mild; Grade 2 scales as Moderate; Grade 3 scales as severe or medically significant but not immediately life threatening; Grade 4 scales as life-threatening consequences; and Grade 5 scales as death related to AE.

Safety Population includes all sentinel and randomized participants in the FAS who received at least one dose of vosoritide or placebo in this study.

Serious adverse event (SAE)

Safety Population: The Safety Population was a subset of the FAS who received at least one dose of vosoritide or placebo in the study.

Z-Scores were derived using age-sex specific reference data (means and SDS) for average stature children per the Centers for Disease Control and Prevention. A height Z score of 0 would indicate that the subject's height is equal to the mean height for the average stature population of the same sex and age. A positive height Z score indicates that the subjects height is above the mean height for the average stature population of the same sex and age, whilst a negative height Z score indicates that the subjects height is below the mean height for the average stature population of the same sex and age. To conclude if the height Z score increases then this means the height deficit has decreased.

standard deviation score (SDS).

The primary efficacy analysis population was the subset of randomized participants in the FAS.

FAS & FAS (randomized) population:The FAS (randomized) was a subset of the FAS, which included 64 participants who were randomized to study treatment (32 participants randomized to vosoritide & 32 participants randomized to placebo).

This is model-based analysis, it is true that the participants analyzed for placebo FAS & FAS (randomized) are the same, but participants analyzed for vosoritide arm FAS & FAS(randomized) are different, that's why the model-based results for placebo are different

As a general rule, standing height/sitting height was used if participants were aged >= 24 months at baseline. Body length/crown to rump was used if participants were aged < 24 months at baseline. If body length was not measured and standing height was available, standing height was used.

FAS (randomized) Population and FAS population.

This is model-based analysis, it is true that the participants analyzed for placebo FAS & FAS (randomized) are the same, but participants analyzed for vosoritide arm FAS & FAS (randomized) are different, that's why the model-based results for placebo are different.

AGV was derived over 12-month intervals starting from the baseline visit. Annualized growth velocity (AGV) = Standing Height at Date 2 - Standing Height at Date 1/Interval Length (Days) x 365.25.

Difference in LS means were obtained from an analysis of covariance model.

FAS (randomized) Population and FAS population.

This is model-based analysis, it is true that the participants analyzed for placebo FAS & FAS (randomized) are the same, but participants analyzed for vosoritide arm FAS & FAS (randomized) are different, that's why the model-based results for placebo are different.

Upper to Lower Body ratio=Sitting Height / (Standing Height - Sitting Height).

FAS (randomized) Population and FAS population.

This is model-based analysis, it is true that the participants analyzed for placebo FAS & FAS (randomized) are the same, but participants analyzed for vosoritide arm FAS & FAS (randomized) are different, that's why the model-based results for placebo are different.

Change from baseline in other growth measures (upper body length, head circumference, arm span, upper arm length, lower arm (Forearm) length, Lower Body Length, Upper Leg Length (Thigh), knee to heel length, and tibial length) at Week 52.

Participants aged <24 months, body length and crown to rump length take precedence over standing height and sitting height. Participants aged <24 months at baseline and >=24 months at Week 52, body length and crown to rump length take precedence.

FAS population.

Change from baseline was based on the participants with available measurements at both time points. Baseline is defined as Day 1 or screening if a Day 1 measurement is not available.

For Height: subjects aged < 24 months, body length takes precedence over standing height. Subjects aged < 24 months at baseline and >= 24 months at Week 52, body length takes precedence.

FAS population.

Change from baseline was based on the subjects with available measurements at both time points. Baseline is defined as Day 1 or screening if a Day 1 measurement is not available

Body Mass Index (BMI): For height used for BMI calculation, participants aged < 24 months, body length takes precedence over standing height. Participants aged < 24 months at baseline and >= 24 months at Week 52, body length takes precedence.

FAS population.

Change from baseline was based on the subjects with available measurements at both time points. Baseline is defined as Day 1 or screening if a Day 1 measurement is not available.

The body mass index (BMI) Z-score represents the participant's BMI converted to an age and sex appropriate standard deviation score (SDS) by comparison with an average stature reference population. The weight Z-score of 0 represents the mean BMI for age and sex of the reference population. A positive BMI Z-score means BMI is above the mean BMI for the average stature population of the same sex and age and a negative BMI Z-Score means BMI is below the mean BMI for the average stature population of the same sex and age.

BMI Z-scores are derived only for participants aged 24 months or older, the change from baseline to Week 52 in BMI Z-score is summarized for Cohort 1 only as no participants in Cohort 2 or Cohort 3 were 24 months at baseline.

FAS population.

The weight Z-score represents the participant's weight converted to an age and sex appropriate standard deviation score (SDS) by comparison with an average stature reference population. The weight Z-score of 0 represents the mean weight for age and sex of the reference population. A positive weight Z-score means weight is above the mean weight for the average stature population of the same sex and age and a negative weight Z-Score means weight is below the mean weight for the average stature population of the same sex and age.

FAS population

Change from baseline was based on the subjects with available measurements at both time points. Baseline is defined as Day 1 or screening if a Day 1 measurement is not available

97(ITQOL) item full-length version was used. For each concept, item responses are scored, summed, & transformed on a scale from 0(worst health) to 100(best health).

FAS population.

Change from baseline was based on the subjects with available measurements at both time points. Baseline is defined as Day 1 or screening if a Day 1 assessment is not available.

97(ITQOL) item full-length version was used. For each concept, item responses are scored, summed, & transformed on a scale from 0(worst health) to 100(best health).

The number of subjects assessed in Cohort 3 Placebo is 0 as assessment was not done or overall score could not be derived because no more than half assessments were done at Screening/ baseline. Hence, Mean and Standard Deviation (SD) are not applicable.

Note: For each variable, there are different numbers of individual questions. The variable can only be derived if at least half of the questions were completed.

Full Analysis Set.

Change from baseline was based on the subjects with available measurements at both time points. Baseline is defined as Day 1 or screening if a Day 1 assessment is not available.

97(ITQOL) item full-length version was used. For each concept, item responses are scored, summed, & transformed on a scale from 0(worst health) to 100(best health). A higher score indicates better global behaviour.

The number of subjects assessed in Cohort 3 Placebo is 0 as assessment was not done or overall score could not be derived because no more than half assessments were done at Screening/ baseline. Hence, Mean and Standard Deviation (SD) are not applicable.

Note: For each variable, there are different numbers of individual questions. The variable can only be derived if at least half of the questions were completed.

FAS population.

Change from baseline was based on the subjects with available measurements at both time points. Baseline is defined as Day 1 or screening if a Day 1 assessment is not available.

97(ITQOL) item full-length version was used. For each concept, item responses are scored, summed, & transformed on a scale from 0(worst health) to 100(best health). A higher score indicates better global health perceptions.

The number of subjects assessed in Cohort 3 Placebo and Cohort 3 vosoritide are 0 as assessment was not done or overall score could not be derived because no more than half assessments were done at Screening/baseline. Hence, Mean and Standard Deviation (SD) are not applicable.

Note: For each variable, there are different numbers of individual questions. The variable can only be derived if at least half of the questions were completed.

FAS population.

Change from baseline was based on the subjects with available measurements at both time points. Baseline is defined as Day 1 or screening if a Day 1 assessment is not available.

97(ITQOL) item full-length version was used. For each concept, item responses are scored, summed, & transformed on a scale from 0(worst health) to 100(best health). A higher score indicates better global change in health.

The number of subjects assessed in Cohort 3 Placebo is 0 as assessment was not done or overall score could not be derived because no more than half assessments were done at Screening/ baseline. Hence, Mean and Standard Deviation (SD) are not applicable.

Note: For each variable, there are different numbers of individual questions. The variable can only be derived if at least half of the questions were completed.

FAS population.

Change from baseline was based on the subjects with available measurements at both time points. Baseline is defined as Day 1 or screening if a Day 1 assessment is not available.

The Pediatric Functional Independence Measure-II (WeeFIM®-II) is designed to measure functional independence of children between the ages of 6 months & 18 yrs who have physical or general developmental limitations. The WeeFIM-II is comprised of 3 domains that are rated by clinicians based on information obtained from parents/caregivers (self-care [score range 8 to 56], mobility [score range 8 to 35], & cognition [score range 8 to 35]) & provides a total score between 18 (worst) & 126 (Best). Higher score reflects higher level of independence.

Performance of a child on each of individual items within WeeFIM is assigned to one of seven levels on an ordinal scale that represent function from complete & modified independence (levels 7 & 6) without a helping person to modified & complete dependence (levels 5 to 1) with a helping person.

Functional Independence Measure (Wee-FIM-II) is only validated in children ages 6 months to 18 yrs. Therefore results for Cohort 3 is not summarized.

FAS population

Change from baseline was based on the subjects with available measurements at both time points. Baseline is defined as Day 1 or screening if a Day 1 assessment is not available.

BSID-III is performance-based clinician-reported outcome assessment for use in children from 1 to 42 months (1 month to 3.5 years). individually administered by the trained clinician to the participant/child

Scales include Cognitive subscale, Receptive and Expressive subscales, and Gross and Fine Motor subscales. The two language scales make up a composite Language Scale score and the Gross and Fine Motor subscales yield a composite Motor Scale score. In addition, there is a Social-Emotional Scale and Adaptive Behavior Scale, which is a questionnaire read and completed by parent or caregiver. Scores range from 0 to 2, and indicate mastery (2), emerging (1) or zero (not present)

Each (sub)scale yields a total raw score, standardized according to the participant's chronological age (scaled scores)

FAS population

Change from baseline was based on the subjects with available measurements at both time points. Baseline is defined as Day 1 or screening if a Day 1 assessment is not available.

The CBCL is used as a screening tool for emotional or behavioral problems, measuring initial behavior severity, tracking changes in behavioral problems over the course of treatment, and treatment planning. The CBCL 1.5-5 years old consists of 100 questions, scored on a three-point Likert scale (0=Not True (as far as you know), 1= Somewhat or Sometimes True, 2=Very True or Often True). The scores for each individual question within a domain are summed to give a domain score. The CBCL uses a normative sample to create standard scores, which are scaled so that 50 is average with a standard deviation of 10, where higher scores indicate more emotional or behavioral issues.

CBCL was waived for children < 18 months old. Therefore results for Cohort 3 is not summarized.

Safety population

Change from baseline was based on the subjects with available measurements at both time points. Baseline is defined as Day 1 or screening if a Day 1 assessment is not available.

Safety population

Change from baseline was based on the subjects with available measurements at both time points. Baseline is defined as Day 1 or screening if a Day 1 assessment is not available.

Safety population

Change from baseline was based on the subjects with available measurements at both time points. Baseline is defined as Day 1 or screening if a Day 1 assessment is not available

Safety Population

Change from baseline was based on the subjects with available measurements at both time points. Baseline is defined as Day 1 or screening if a Day 1 assessment is not available.

Safety population

Change from baseline was based on the subjects with available measurements at both time points. Baseline is defined as Day 1 or screening if a Day 1 assessment is not available.

Safety population

Change from baseline was based on the subjects with available measurements at both time points. Baseline is defined as Day 1 or screening if a Day 1 assessment is not available.

Safety population

Change from baseline was based on the subjects with available measurements at both time points. Baseline is defined as Day 1 or screening if a Day 1 assessment is not available.

Baseline is defined as Day 1 or screening if a Day 1 assessment is not available.

Safety population

Change from baseline was based on subjects with available measurements at both time points. Overall no. of participants analyzed (N) is greater than no. analyzed for Placebo, as different participants missed for different variables (Ex:1 subject missed sagittal width L1,L2,L3, 1 subject missed sagittal width L5 & 1 subject missed sagittal width L4 & L5. Therefore, n for sagittal width L1,L2,L3,L4 & L5 are 26,26,26,26,25 respectively but the overall number of subjects is 27)

Safety population

Change from baseline was based on the subjects with available measurements at both time points. Baseline is defined as Day 1 or screening if a Day 1 assessment is not available.

Percentages were calculated using the total number of subjects in the safety population (N for each treatment group) as the denominator.

All increases are comparing results at Week 52 relative to the baseline assessment.

Safety population

Change from baseline was based on the subjects with available measurements at both time points. Baseline is defined as Day 1 or screening if a Day 1 assessment is not available.

Safety population

Change from baseline and percent change from baseline are based on the subjects with available measurements at both time points. Baseline is defined as Day 1 or screening if a Day 1 assessment is not available.

Safety Population

Change from baseline and percent change from baseline are based on the subjects with available measurements at both time points. Baseline is defined as Day 1 or screening if a Day 1 assessment is not available

Safety population

Change from baseline and percent change from baseline are based on the subjects with available measurements at both time points. Baseline is defined as Day 1 or screening if a Day 1 assessment is not available.

Safety Population.

Change from baseline and percent change from baseline are based on the subjects with available measurements at both time points. Baseline is defined as Day 1 or screening if a Day 1 assessment is not available.

Safety population.

Change from baseline and percent change from baseline are based on the subjects with available measurements at both time points. Baseline is defined as Day 1 or screening if a Day 1 assessment is not available.

Safety Population.

Change from baseline and percent change from baseline are based on the subjects with available measurements at both time points. Baseline is defined as Day 1 or screening if a Day 1 assessment is not available.

Safety population

Change from baseline was based on the subjects with available measurements at both time points. Baseline is defined as Day 1 or screening if a Day 1 assessment is not available.

Safety population

Change from baseline was based on the subjects with available measurements at both time points. Baseline is defined as Day 1 or screening if a Day 1 assessment is not available.

Safety population

Change from baseline was based on the subjects with available measurements at both time points. Baseline is defined as Day 1 or screening if a Day 1 assessment is not available.

Safety population

Change from baseline was based on the subjects with available measurements at both time points. Baseline is defined as Day 1 or screening if a Day 1 assessment is not available.

Safety population

Change from baseline was based on the subjects with available measurements at both time points. Baseline is defined as Day 1 or screening if a Day 1 assessment is not available.

Safety population

Change from baseline was based on the subjects with available measurements at both time points. Baseline is defined as Day 1 or screening if a Day 1 assessment is not available.

Hologic - Discovery Horizon Whole Body BMD Z-Score.

Change in whole body bone mineral density (BMD) Z-score from baseline at 52 weeks indicates whether there has been a positive or negative change in BMD using a z-score generated by converting the participants BMD to an age and sex appropriate standard deviation score (SDS) by comparison with an average stature reference population. A whole body BMD Z-score <-2 SD can indicate low bone density in children. The Whole Body BMD (bone mineral density) z-score compares the BMD to the average bone density of people of the same age, and sex as a comparator. A Z-score less than 0 means that the participant has a lower BMD than people in the same age and sex group, and could indicate a risk of osteopenia or osteoporosis.

Safety population

Change from baseline was based on the subjects with available measurements at both time points. Baseline is defined as Day 1 or screening if a Day 1 assessment is not available.

Hologic - Discovery Horizon Lumbar Spine BMD Z-Score

Change in lumbar spine bone mineral density (BMD) Z-score from baseline at 52 weeks indicates whether there has been a positive or negative change in BMD using a z-score generated by converting the participants lumbar spine BMD to an age and sex appropriate standard deviation score (SDS) by comparison with an average stature reference population. A BMD Z-score <-2 SD can indicate low bone density in the lumbar spine in children. The Lumbar Spine BMD (bone mineral density) z-score compares the BMD in the lumbar spine to the average spinal bone density of people of the same age, and sex as a comparator. A Z-score less than 0 means that the participant has a lower BMD than people in the same age and sex group, and could indicate a risk of osteopenia or osteoporosis of the spine.

Safety population

Change from baseline was based on the subjects with available measurements at both time points. Baseline is defined as Day 1 or screening if a Day 1 assessment is not available.

Number of participants with Incidence of Antibody Positivity at Scheduled Visits for : total antibody (TAb), Neutralizing antibodies (NAb), atrial natriuretic peptide (ANP), B-type Natriuretic Peptide (BNP) & C-type natriuretic peptide (CNP).

TAb Titer Positive, NAb Titer Positive, ANP Reactivity Positive, BNP Reactivity Positive & CNP Reactivity Positive.

Day 1 is the baseline assessment result taken prior to first dose of study drug.

Ever Positive = the number of participants with at least one positive sample result.

FAS population

Safety population

Change from baseline and percent change from baseline are based on the subjects with available measurements at both time points. Baseline is the last measurement prior to the initiation of study drug.

Safety Population

Change from baseline and percent change from baseline are based on the subjects with available measurements at both time points. Baseline is the last measurement prior to the initiation of study drug.

Safety population. Change from baseline and percent change from baseline are based on the subjects with available measurements at both time points. Baseline is the last measurement prior to the initiation of study drug.

Laboratory results up to 30 days after study drug discontinuation were included.

Baseline is the last measurement prior to the initiation of study drug.

Safety Population.

Change from baseline was based on subjects with available measurements at both timepoints.Overall no. of participants analyzed(N) is greater than no. analyzed for All Vosoritide, as different participants missed for different timepoints(Ex:1 of 42 participants who were part of CNP Col X BM:Baseline was not present in 42 participants who participated in CNP Col X BM:Day 8.Therefore, n for CNP Col X BM:Baseline & CNP Col X BM:Day 8 are 42 however, overall no of subjects,N=43)

Sleep-testing device was used to assess presence & severity of sleep-disordered breathing by measurement of blood oxygen(O2)saturation,pulse rate,& airflow during overnight monitoring

Episodes(Epi) of sleep apnea variables summarized as: Number(No.)of epi of apnea/hr(AI);No.of epi of hypopnea/hr(HI);No.of epi of obstructive apnea hypopneas/hr(AHI);No.of epi of obstructive apneas/hr(Obstructive Apnea Index);No.of epi of central apneas/hr(CAI);No.of desaturations/hr >=3%

AHI is a marker of obstructive sleep apnea (OSA), scored as No.of apnea or hypopnea epi/hr, with AHI <=1/hr normal, 1< AHI<=5 mild,5< AHI <=10 moderate,& AHI>10/hr severe OSA. CAI reflects cervical cord compression at cervical-medullary junction, & is No. of epi of a pause in ventilation with no associated respiratory effort, with> 5 epi/hr abnormal.O2 desaturation index measures average No. of desaturation epi/hr, defined as decrease in O2 saturation of >=3% for at least 10sec, with(<8/hr normal & >=8/hr abnormal

FAS population

Change from baseline was based on the subjects with available measurements at both time points. Baseline is defined as Day 1 or screening if a Day 1 measurement is not available.

Vosoritide concentrations at 5-, 15- and 30-minute post-dose for one participant on Day 1 were not available, hence PK parameters for this participant were excluded from summary statistics.

PK parameters for another participant on Day 1 obtained from extrapolation. AUC0-∞ excluded from summary statistics. PK parameters are not available for this participant at Week 13 due to unsuccessful venipuncture, and Week 26 as post-dose PK samples were not collected.

Pharmacokinetics (PK) Population includes all sentinel and randomized participants in the safety population who have at least one evaluable PK concentration.

PK Population

PK Population

PK Population

PK Population

Vosoritide concentrations at 5-, 15- and 30-minute post-dose for one participant on Day 1 were not available, hence PK parameters for this participant were excluded from summary statistics.

PK parameters for another participant on Day 1 obtained from extrapolation. AUC0-∞, CL/F, V/F and t1/2 excluded from summary statistics. PK parameters are not available for this participant at Week 13 due to unsuccessful venipuncture, and Week 26 as post-dose PK samples were not collected.

PK Population

Vosoritide concentrations at 5-, 15- and 30-minute post-dose for one participant on Day 1 were not available, hence PK parameters for this participant were excluded from summary statistics.

PK parameters for another participant on Day 1 obtained from extrapolation. V/F excluded from summary statistics. PK parameters are not available for this participant at Week 13 due to unsuccessful venipuncture, and Week 26 as post-dose PK samples were not collected.

PK Population

Vosoritide concentrations at 5-, 15- and 30-minute post-dose for one participant on Day 1 were not available, hence PK parameters for this participant were excluded from summary statistics.

PK parameters for another participant on Day 1 obtained from extrapolation. AUC0-∞, CL/F, V/F and t1/2 excluded from summary statistics. PK parameters are not available for this participant at Week 13 due to unsuccessful venipuncture, and Week 26 as post-dose PK samples were not collected.

PK Population