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Clinical Trial Results:
A Phase 2 Randomized, Double-Blind, Placebo-Controlled Clinical Trial to Evaluate the Safety and Efficacy of BMN 111 in Infants and Young Children with Achondroplasia, Age 0 to < 60 Months

Summary
EudraCT number	2016-003826-18
Trial protocol	GB
Global end of trial date	26 Jan 2022

Results information
Results version number	v1(current)
This version publication date	28 Mar 2023
First version publication date	28 Mar 2023
Other versions
Summary report(s)	Secondary Endpoints_ITQOL Tables PK parameter Endpoints tables

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

BMN 111-206

ISRCTN number

US NCT number

NCT03583697

WHO universal trial number (UTN)

Sponsor organisation name

BioMarin Pharmaceutical Inc

Sponsor organisation address

105 Digital Drive, Novato, CA, United States, 94949

Public contact

Clinical Trials Information, BioMarin Pharmaceutical Inc., clinicaltrials@bmrn.com

Scientific contact

Clinical Trials Information, BioMarin Pharmaceutical Inc., clinicaltrials@bmrn.com

Is trial part of an agreed paediatric investigation plan (PIP)

Yes

EMA paediatric investigation plan number(s)

EMEA-002033-PIP01-16

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Yes

Analysis stage

Final

Date of interim/final analysis

26 Jan 2022

Is this the analysis of the primary completion data?

Yes

Primary completion date

26 Jan 2022

Global end of trial reached?

Yes

Global end of trial date

26 Jan 2022

Was the trial ended prematurely?

Main objective of the trial

The primary objectives of the study were to: - Evaluate the safety and tolerability of Vosoritide in children aged 0 to < 60 months with ACH - Evaluate the effect of Vosoritide on change from baseline in length/height Z-score

Protection of trial subjects

This clinical study was designed, implemented and reported in accordance with the protocol and also with the following: • European Clinical Trial Directive 2001/20/EC and Good Clinical Practice (GCP) Directive 2005/28/EC, for studies conducted within any European country • United States (US) Code of Federal Regulations (CFR) sections that address clinical research studies, and/or other national and local regulations, as applicable • International Council on Harmonisation, Harmonised Tripartite Guideline: Guideline for GCP E6 (ICH E6) • The ethical principles established by the Declaration of Helsinki

Background therapy

Evidence for comparator

Actual start date of recruitment

13 Jun 2018

Long term follow-up planned

Yes

Long term follow-up rationale

Safety, Efficacy

Long term follow-up duration

19 Years

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

United Kingdom: 8

Country: Number of subjects enrolled

United States: 41

Country: Number of subjects enrolled

Japan: 8

Country: Number of subjects enrolled

Australia: 18

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

This was a multi-center study conducted by 16 principal investigators at 16 study centers in four countries (United States, Australia, United Kingdom and Japan).

Screening details

A total of 75 participants (full analysis set [FAS]) were enrolled into the study, of which 11 participants were enrolled to receive vosoritide (sentinel participants). 64 participants were randomized to receive vosoritide or placebo (32 randomized for vosoritide and 32 for placebo), which constituted the FAS (randomized).

Period 1 title

Overall period

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Data analyst, Carer, Assessor

Blinding implementation details

Participants & site members were blinded to study treatment. The investigator and staff involved with the study also remained blinded to the treatment randomization code. In an emergency medical situation where participant management would be determined or significantly altered by knowing the treatment assignment, the investigator could be unblinded without prior written approval from the Medical Monitor.

Are arms mutually exclusive

Yes

Sentinel

Arm description

Cohort 1 Sentinel: Participants stratified by age >= 24 to < 60 months, received vosoritide 15 µg/kg/day (n=4) Cohort 2 Sentinel: Participants stratified by age >= 6 to < 24 months, received vosoritide 15 µg/kg/day & 30 µg/kg/day (n=4) Cohort 3 Sentinel: Participants stratified by age 0 to < 6 months, received vosoritide 30 µg/kg/day (n=3)

Arm type

Active comparator

Investigational medicinal product name

BMN 111

Investigational medicinal product code

Other name

Vosoritide

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Cohort 1 Sentinel participants received a 15 μg/kg vosoritide single daily subcutaneous injection for 52 weeks. Cohort 2 Sentinel participants Initially dosed with single daily subcutaneous injection of vosoritide 15 µg/kg/day and were adjusted to 30 µg/kg/day following the review of safety and PK data then adjusted to 15 µg/kg/day during the visit immediately preceding the 2-year birthday. Cohort 3 Sentinel participants received a 30 μg/kg vosoritide single daily subcutaneous injection for 52 weeks.

Randomized Vosoritide

Arm description

Cohort 1: Vosoritide 15 µg/kg/day (n=15) Cohort 2: Vosoritide 15 µg/kg/day & 30 µg/kg/day (n=8) Cohort 3: Vosoritide 30 µg/kg/day (n=9)

Arm type

Experimental

Investigational medicinal product name

BMN 111

Investigational medicinal product code

Other name

Vosoritide

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Cohort 1: Participants received a vosoritide 15 μg/kg daily subcutaneous injection for 52 weeks. Cohort 2: Participants received vosoritide 15 μg/kg to 30 μg/kg daily subcutaneous injection for 52 weeks. Cohort 3: Participants received vosoritide 30 μg/kg daily subcutaneous injection for 52 weeks.

Randomized Placebo

Arm description

Cohort 1: Placebo (n=16) Cohort 2: Placebo (n=8) Cohort 3: Placebo (n=8)

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Participants received a placebo single daily subcutaneous injection for 52 weeks.

Number of subjects in period 1	Sentinel	Randomized Vosoritide	Randomized Placebo
Started	11	32	32
Completed	11	31	31
Not completed	0	1	1
Consent withdrawn by subject	-	-	1
AE of sudden infant death syndrome, not related	-	1	-

Baseline characteristics

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Reporting group title

Sentinel

Reporting group description

Reporting group title

Randomized Vosoritide

Reporting group description

Cohort 1: Vosoritide 15 µg/kg/day (n=15) Cohort 2: Vosoritide 15 µg/kg/day & 30 µg/kg/day (n=8) Cohort 3: Vosoritide 30 µg/kg/day (n=9)

Reporting group title

Randomized Placebo

Reporting group description

Cohort 1: Placebo (n=16) Cohort 2: Placebo (n=8) Cohort 3: Placebo (n=8)

Reporting group values	Sentinel	Randomized Vosoritide	Randomized Placebo	Total
Number of subjects	11	32	32	75
Age categorical
Units: Subjects
Age continuous
Age at Screening, months Full analysis population (FAS).
Units: months
arithmetic mean (standard deviation)	23.4 ± 21.0	23.0 ± 16.9	26.5 ± 19.3	-
Gender categorical
Full analysis population (FAS).
Units: Subjects
Female	3	15	19	37
Male	8	17	13	38
Race
Full analysis population (FAS).
Units: Subjects
White	8	21	25	54
Asian-Other	1	6	2	9
Asian-Japanese	0	4	4	8
Multiple	2	1	0	3
Native Hawaiian or Other Pacific Islander	0	0	1	1
Ethnicity
Full analysis population (FAS).
Units: Subjects
Not Hispanic or Latino	11	29	29	69
Hispanic or Latino	0	3	3	6
Age continuous
Age on Day 1, months. Full analysis population (FAS).
Units: Months
arithmetic mean (standard deviation)	24.71 ± 20.79	24.39 ± 16.83	27.82 ± 19.25	-
Weight
Full analysis population (FAS).
Units: Kg
arithmetic mean (standard deviation)	10.12 ± 3.70	10.20 ± 3.83	10.55 ± 4.31	-
Weight Z-Score
Full analysis population (FAS).
Units: Z-Score
arithmetic mean (standard deviation)	-1.41 ± 0.73	-1.49 ± 1.26	-1.59 ± 1.44	-
BMI
Body Mass Index (BMI) Full analysis population (FAS).
Units: kg/m^2
arithmetic mean (standard deviation)	20.06 ± 1.87	19.48 ± 2.45	20.14 ± 2.39	-
BMI Z-Score
Baseline is defined as Day 1 or screening if a Day 1 assessment is not available. 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. 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. BMI Z-Scores were derived only for participants aged 24 months or older. BMI Z-Score: (n=Sentinel 4, Vosoritide 15, Placebo 16)
Units: Z-Score
arithmetic mean (standard deviation)	2.79 ± 0.98	2.52 ± 1.15	2.77 ± 0.75	-

End points

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Reporting group title

Sentinel

Reporting group description

Reporting group title

Randomized Vosoritide

Reporting group description

Cohort 1: Vosoritide 15 µg/kg/day (n=15) Cohort 2: Vosoritide 15 µg/kg/day & 30 µg/kg/day (n=8) Cohort 3: Vosoritide 30 µg/kg/day (n=9)

Reporting group title

Randomized Placebo

Reporting group description

Cohort 1: Placebo (n=16) Cohort 2: Placebo (n=8) Cohort 3: Placebo (n=8)

Subject analysis set title

Cohort 1: Placebo

Subject analysis set type

Full analysis

Subject analysis set description

Cohort 1 included participants stratified by age >=24 to <36 months and >=36 to <60 months. The Full Analysis Set (FAS) was defined according to the intent-to-treat principle and included all enrolled sentinel and randomized participants with a signed informed consent

Subject analysis set title

Cohort 1: Vosoritide

Subject analysis set type

Full analysis

Subject analysis set description

Cohort 1 included participants stratified by age >=24 to <36 months and >=36 to <60 months. Vosoritide 15 μg/kg/day The Full Analysis Set (FAS) was defined according to the intent-to-treat principle and included all enrolled sentinel and randomized participants with a signed informed consent.

Subject analysis set title

Cohort 2: Placebo

Subject analysis set type

Full analysis

Subject analysis set description

Cohort 2 included participants stratified by age >=6 to <15 months and >=15 months to <24 months). The Full Analysis Set (FAS) was defined according to the intent-to-treat principle and included all enrolled sentinel and randomized participants with a signed informed consent

Subject analysis set title

Cohort 2: Vosoritide

Subject analysis set type

Full analysis

Subject analysis set description

Cohort 2 included participants stratified by age >=6 to <15 months and >=15 months to <24 months). Vosoritide 15 μg/kg/day & 30 μg/kg/day The Full Analysis Set (FAS) was defined according to the intent-to-treat principle and included all enrolled sentinel and randomized participants with a signed informed consent

Subject analysis set title

Cohort 3: Placebo

Subject analysis set type

Full analysis

Subject analysis set description

Cohort 3 included participants stratified by age 0 to < 6 months. The Full Analysis Set (FAS) was defined according to the intent-to-treat principle and included all enrolled sentinel and randomized participants with a signed informed consent

Subject analysis set title

Cohort 3: Vosoritide

Subject analysis set type

Full analysis

Subject analysis set description

Cohort 3 included participants stratified by age 0 to < 6 months. Vosoritide 30 μg/kg/day The Full Analysis Set (FAS) was defined according to the intent-to-treat principle and included all enrolled sentinel and randomized participants with a signed informed consent

Subject analysis set title

All Vosoritide

Subject analysis set type

Full analysis

Subject analysis set description

The Full Analysis Set (FAS) was defined according to the intent-to-treat principle and included all enrolled sentinel and randomized participants with a signed informed consent.

Subject analysis set title

Placebo

Subject analysis set type

Full analysis

Subject analysis set description

The Full Analysis Set (FAS) was defined according to the intent-to-treat principle and included all enrolled sentinel and randomized participants with a signed informed consent.

Primary: Number of participants with adverse events (AEs) by severity grade and study drug treatment-emergent adverse events (TEAEs)

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End point title

Number of participants with adverse events (AEs) by severity grade and study drug treatment-emergent adverse events (TEAEs) ^[1]

End point description

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)

End point type

Primary

End point timeframe

Up to Week 56 (Safety Follow-Up +/-7d)

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive data was analyzed for this endpoint.

End point values	Sentinel	Randomized Vosoritide	Randomized Placebo
Number of subjects analysed	11	32	32
Units: Numbers
Participants with any AE	11	32	32
Participants with any SAE	0	3	6
Participants with any treatment-related AE	8	29	17
Participants with any treatment-related SAEs	0	0	0
Participants with any AE of CTCAE grade >=3	0	2	3
Participants who died	0	1	0

No statistical analyses for this end point

Primary: Change from baseline in height Z-score at Week 52

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End point title

Change from baseline in height Z-score at Week 52 ^[2]

End point description

Standing Height/body length was converted to an age-and sex-appropriate standard deviation score (SDS), also referred to as a Z-score, by comparison with reference data available for average stature children from the Centers for Disease Control and Prevention(CDC). The primary efficacy analysis population was the subset of randomized participants in the FAS. The Full Analysis Set (FAS) was defined according to the intent-to-treat principle and included all enrolled sentinel and randomized participants with a signed informed consent. FAS Randomized population includes randomized vosoritide (32 participants) and randomized placebo (32 participants). FAS analysis population includes All vosoritide (43 participants) and Placebo (32 participants).

End point type

Primary

End point timeframe

Baseline to Week 52

Notes
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Statistical analysis for FAS (All Vosoritide and Placebo) includes Sentinel participants.

End point values	Randomized Vosoritide	Randomized Placebo	All Vosoritide	Placebo
Number of subjects analysed	32	32	43	32
Units: Z-score
least squares mean (confidence interval 95%)	-0.06 (-0.26 to 0.15)	-0.31 (-0.48 to -0.13)	0.01 (-0.15 to 0.17)	-0.30 (-0.47 to -0.13)

Height Z-Score-Placebo Vs Vosoritide(FAS Random)

Statistical analysis description

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

Comparison groups

Randomized Vosoritide v Randomized Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[3]

Method

Parameter type

Mean difference (final values)

Point estimate

0.25

Confidence interval

level

95%

sides

2-sided

lower limit

-0.02

upper limit

0.53

Notes
[3] - Covariance model

Height Z-Score - Placebo Vs Vosoritide (FAS)

Statistical analysis description

Comparison groups

All Vosoritide v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[4]

Method

Parameter type

Mean difference (final values)

Point estimate

0.3

Confidence interval

level

95%

sides

2-sided

lower limit

0.07

upper limit

0.54

Notes
[4] - Covariance model

Secondary: Change from baseline in height at Week 52

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End point title

Change from baseline in height at Week 52 ^[5]

End point description

FAS Randomized population includes randomized vosoritide (32 participants) and randomized placebo (32 participants). FAS analysis population includes All vosoritide (43 participants) and Placebo (32 participants).

End point type

Secondary

End point timeframe

Baseline to Week 52

Notes
[5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Statistical analysis for FAS (All Vosoritide and Placebo) includes Sentinel participants.

End point values	Randomized Vosoritide	Randomized Placebo	All Vosoritide	Placebo
Number of subjects analysed	32	32	43	32
Units: cm
least squares mean (confidence interval 95%)	8.15 (7.55 to 8.75)	7.38 (6.87 to 7.89)	8.41 (7.93 to 8.89)	7.45 (6.95 to 7.95)

Height-Placebo Vs Vosoritide(FAS Randomized)

Statistical analysis description

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

Comparison groups

Randomized Vosoritide v Randomized Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[6]

Method

Parameter type

Mean difference (final values)

Point estimate

0.77

Confidence interval

level

95%

sides

2-sided

lower limit

-0.02

upper limit

1.56

Notes
[6] - Covariance model.

Height - Placebo Vs Vosoritide (FAS)

Statistical analysis description

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

Comparison groups

All Vosoritide v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[7]

Method

Parameter type

Mean difference (final values)

Point estimate

0.96

Confidence interval

level

95%

sides

2-sided

lower limit

0.26

upper limit

1.66

Notes
[7] - Covariance model.

Secondary: Change from baseline in annualized growth velocity (AGV) at Week 52

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End point title

Change from baseline in annualized growth velocity (AGV) at Week 52 ^[8]

End point description

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 Lenght (Days) x 365.25. FAS Randomized population includes randomized vosoritide (32 participants) and randomized placebo (32 participants). FAS analysis population includes All vosoritide (43 participants) and Placebo (32 participants).

End point type

Secondary

End point timeframe

Baseline to Week 52

Notes
[8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Statistical analysis for FAS (All Vosoritide and Placebo) includes Sentinel participants.

End point values	Randomized Vosoritide	Randomized Placebo	All Vosoritide	Placebo
Number of subjects analysed	32	32	43	32
Units: cm/year
least squares mean (confidence interval 95%)	-2.17 (-2.76 to -1.58)	-2.95 (-3.45 to -2.45)	-2.41 (-2.88 to -1.94)	-3.32 (-3.81 to -2.84)

AGV - Placebo Vs Vosoritide(FAS Randomized)

Statistical analysis description

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

Comparison groups

Randomized Vosoritide v Randomized Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[9]

Method

Parameter type

Mean difference (final values)

Point estimate

0.78

Confidence interval

level

95%

sides

2-sided

lower limit

0.02

upper limit

1.54

Notes
[9] - Covariance model.

AGV - Placebo Vs Vosoritide (FAS)

Statistical analysis description

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

Comparison groups

All Vosoritide v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Mean difference (final values)

Point estimate

0.92

Confidence interval

level

95%

sides

2-sided

lower limit

0.24

upper limit

1.59

Secondary: Change from baseline in upper to lower body segment ratio at Week 52

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End point title

Change from baseline in upper to lower body segment ratio at Week 52 ^[10]

End point description

Upper to Lower Body ratio=Sitting Height / (Standing Height – Sitting Height). The ratio of derived sitting height and derived standing height was also calculated. FAS Randomized population includes randomized vosoritide (32 participants) and randomized placebo (32 participants). FAS analysis population includes All vosoritide (43 participants) and Placebo (32 participants).

End point type

Secondary

End point timeframe

Baseline to Week 52

Notes
[10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Statistical analysis for FAS (All Vosoritide and Placebo) includes Sentinel participants.

End point values	Randomized Vosoritide	Randomized Placebo	All Vosoritide	Placebo
Number of subjects analysed	32	32	43	32
Units: Ratio
least squares mean (confidence interval 95%)	-0.20 (-0.28 to -0.13)	-0.13 (-0.21 to -0.06)	-0.19 (-0.25 to -0.13)	-0.13 (-0.20 to -0.06)

Upper-Lower Body Placebo Vs Vosoritide (FAS Rand)

Statistical analysis description

Upper to lower body segment ratio. Difference in LS means were obtained from an analysis of covariance model.

Comparison groups

Randomized Vosoritide v Randomized Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[11]

Method

Parameter type

Mean difference (final values)

Point estimate

-0.07

Confidence interval

level

95%

sides

2-sided

lower limit

-0.17

upper limit

0.04

Notes
[11] - Covariance model.

Upper-Lower Body Ratio Placebo Vs Vosoritide (FAS)

Statistical analysis description

Upper to lower body segment ratio. Difference in LS means were obtained from an analysis of covariance model.

Comparison groups

All Vosoritide v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[12]

Method

Parameter type

Mean difference (final values)

Point estimate

-0.06

Confidence interval

level

95%

sides

2-sided

lower limit

-0.15

upper limit

0.03

Notes
[12] - Covariance model.

Secondary: Change from baseline in other growth measures (upper body length, head circumference, arm span, upper arm length, lower arm length, Lower Body Length, upper leg length, knee to heel length, and tibial length) at Week 52

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End point title

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

End point description

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. The number of participants analyzed is reported in sequence: (n=Cohort 1 Placebo, Cohort 1 Vosoritide, Cohort 2 Placebo, Cohort 2 Vosoritide, Cohort 3 Placebo, Cohort 3 Vosoritide) vosoritide including sentinel and randomized participants for each category. Upper body length: (n=16, 19, 7, 12, 8, 11) Head Circumference: (n=16, 19, 7, 11, 8, 11) Arm Span: (n=16, 19, 7, 10, 8, 10) Upper Arm Length: (n=16, 19, 7, 11, 8, 11) Lower Arm (Forearm) Length : (n=16, 19, 7, 10, 8, 11) Lower Body Length: (n=16, 19, 7, 12, 8, 11) Upper Leg Length (Thigh): (n=16, 19, 7, 10, 8, 11) Knee to Heel Length: (n=16, 19, 7, 11, 8, 11) Tibial Length: (n=16, 19, 7, 11, 8, 11)

End point type

Secondary

End point timeframe

Baseline to Week 52

End point values	Cohort 1: Placebo	Cohort 1: Vosoritide	Cohort 2: Placebo	Cohort 2: Vosoritide	Cohort 3: Placebo	Cohort 3: Vosoritide
Number of subjects analysed	16	19	8	12	8	12
Units: cm
arithmetic mean (standard deviation)
Upper body length	3.04 ± 1.52	3.54 ± 1.81	5.45 ± 1.75	5.20 ± 1.50	6.58 ± 0.99	6.75 ± 0.86
Head Circumference	0.68 ± 0.66	0.74 ± 0.49	2.29 ± 1.28	3.10 ± 1.45	5.35 ± 0.71	6.29 ± 0.81
Arm Span	4.86 ± 1.99	5.82 ± 3.65	7.13 ± 1.59	7.22 ± 1.45	8.22 ± 1.93	8.99 ± 4.77
Upper Arm Length	1.02 ± 1.13	0.77 ± 0.96	1.08 ± 0.93	1.44 ± 1.26	1.95 ± 1.23	1.44 ± 1.33
Lower Arm (Forearm) Length	0.49 ± 0.96	0.79 ± 0.90	1.78 ± 0.44	1.57 ± 0.98	1.66 ± 0.82	1.49 ± 0.79
Lower Body Length	2.41 ± 1.31	2.89 ± 1.99	2.39 ± 1.27	3.79 ± 1.56	3.86 ± 1.55	4.41 ± 1.53
Upper Leg Length (Thigh)	0.82 ± 1.75	1.55 ± 1.46	0.38 ± 1.71	1.10 ± 1.42	1.98 ± 2.21	1.93 ± 1.65
Knee to Heel Length	1.52 ± 0.76	2.21 ± 0.67	2.70 ± 0.75	2.29 ± 1.91	2.93 ± 0.68	3.12 ± 0.85
Tibial Length	0.85 ± 0.69	1.16 ± 1.35	1.97 ± 1.49	1.99 ± 0.80	1.83 ± 0.88	1.39 ± 0.77

No statistical analyses for this end point

Secondary: Change from baseline in other body proportion ratios (arm span to height ratio, upper arm length to lower arm [forearm] length ratio, upper leg length [thigh] to knee to heel length ratio, and upper leg length (thigh) to tibial length ratio) at Week 52

Top of page

End point title

Change from baseline in other body proportion ratios (arm span to height ratio, upper arm length to lower arm [forearm] length ratio, upper leg length [thigh] to knee to heel length ratio, and upper leg length (thigh) to tibial length ratio) at Week 52

End point description

The number of participant analyzed is reported in sequence: (n=Cohort 1 Placebo, Cohort 1 Vosoritide, Cohort 2 Placebo, Cohort 2 Vosoritide, Cohort 3 Placebo, Cohort 3 Vosoritide) vosoritide including sentinel and randomized participants for each category. Upper Arm Length to Lower Arm (Forearm) Length Ratio: (n=16, 19, 7, 10, 8, 11) Upper Leg Length(Thigh)-Knee to Heel Length Ratio: (n=16, 19, 7, 10, 8, 11) Upper Leg Length (Thigh) to Tibial Length Ratio: (n=16, 19, 7, 10, 8, 11) Arm Span to Standing Height Ratio: (n=16,19, 7, 10, 8, 10)

End point type

Secondary

End point timeframe

Baseline to Week 52

End point values	Cohort 1: Placebo	Cohort 1: Vosoritide	Cohort 2: Placebo	Cohort 2: Vosoritide	Cohort 3: Placebo	Cohort 3: Vosoritide
Number of subjects analysed	16	19	7	10	8	12
Units: Ratio
arithmetic mean (standard deviation)
Upper Arm Length to Lower Arm(Forearm)Length Ratio	0.05 ± 0.15	0.00 ± 0.12	-0.09 ± 0.06	0.01 ± 0.10	0.02 ± 0.11	-0.01 ± 0.12
Upper Leg Length(Thigh)-Knee to Heel Length Ratio	-0.01 ± 0.08	0.01 ± 0.07	-0.09 ± 0.10	-0.03 ± 0.08	0.01 ± 0.16	-0.02 ± 0.11
Upper Leg Length (Thigh) to Tibial Length Ratio	0.00 ± 0.12	0.02 ± 0.17	-0.16 ± 0.24	-0.10 ± 0.07	0.00 ± 0.29	0.04 ± 0.22
Arm Span to Standing Height Ratio	0.00 ± 0.02	0.00 ± 0.06	0.00 ± 0.02	-0.01 ± 0.02	-0.01 ± 0.04	-0.02 ± 0.07

No statistical analyses for this end point

Secondary: Change from baseline in body mass index (BMI) at Week 52

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End point title

Change from baseline in body mass index (BMI) at Week 52

End point description

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. There were no meaningful differences in BMI between treatment groups from baseline to Week 52 (change of <1 BMI score at Week 52 across all cohorts).

End point type

Secondary

End point timeframe

Baseline to Week 52

End point values	Cohort 1: Placebo	Cohort 1: Vosoritide	Cohort 2: Placebo	Cohort 2: Vosoritide	Cohort 3: Placebo	Cohort 3: Vosoritide
Number of subjects analysed	16	19	8	12	8	12
Units: kg/m^2
arithmetic mean (standard deviation)	0.20 ± 1.34	-0.45 ± 0.94	0.55 ± 1.17	0.08 ± 0.75	0.74 ± 1.70	0.94 ± 1.42

No statistical analyses for this end point

Secondary: Change from baseline in BMI Z-score at Week 52

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End point title

Change from baseline in BMI Z-score at Week 52

End point description

BMI 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. 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.

End point type

Secondary

End point timeframe

Baseline to Week 52

End point values	Cohort 1: Placebo	Cohort 1: Vosoritide
Number of subjects analysed	16	19
Units: Z-Score
arithmetic mean (standard deviation)	-0.12 ± 0.48	-0.18 ± 0.65

No statistical analyses for this end point

Secondary: Change from baseline in weight Z-score at Week 52

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End point title

Change from baseline in weight Z-score at Week 52

End point description

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.

End point type

Secondary

End point timeframe

Baseline to Week 52

End point values	Cohort 1: Placebo	Cohort 1: Vosoritide	Cohort 2: Placebo	Cohort 2: Vosoritide	Cohort 3: Placebo	Cohort 3: Vosoritide
Number of subjects analysed	16	19	7	12	8	11
Units: Z-score
arithmetic mean (standard deviation)	0.14 ± 0.44	0.14 ± 0.42	0.74 ± 0.82	0.70 ± 0.64	-0.81 ± 0.49	-0.66 ± 0.77

No statistical analyses for this end point

Secondary: Change from baseline in Infant Toddler Quality of Life (ITQoL) scores at Week 52

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End point title

Change from baseline in Infant Toddler Quality of Life (ITQoL) scores at Week 52

End point description

# of participants analyzed reported in sequence:(n=C1 Placebo,C1 Vosoritide,C2 Placebo,C2 Vosoritide,C3 Placebo,C3 Vosoritide)incl sentinel for each category. Overall Health Score:(n=12, 15, 5,10, 6, 10) Physical Abilities Score:(n=14, 17, 7, 12, 7, 6) Growth and Development Scores:(n=14, 17, 7, 12, 8, 10) Pain Score:(n=14, 17, 7,12, 8, 10) Temperament and mood Score:(n=14, 17, 7,12, 8, 10) Behavior score:(n=13, 17, 5, 8, 0, 1) Ref PDF Global behavior score:(n=13, 17, 5, 9, 0, 1) Ref PDF Getting on with others score:(n=12, 17, 5, 8, 0,0) Ref PDF Global health perceptions score:(n=13, 17, 7, 12, 8, 9) Change in health score:(n=13, 16, 5, 6, 0, 1) Ref PDF Parental impact emotional score:(n=14, 17, 7, 12, 8, 10) Parental Impact Time Score:(n=14, 17, 7, 12, 8, 10) Family Cohesion Score:(n=14, 16, 7, 12, 8, 10) 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)

End point type

Secondary

End point timeframe

Baseline to Week 52

End point values	Cohort 1: Placebo	Cohort 1: Vosoritide	Cohort 2: Placebo	Cohort 2: Vosoritide	Cohort 3: Placebo	Cohort 3: Vosoritide
Number of subjects analysed	16	19	8	12	8	12
Units: Score on a scale
arithmetic mean (standard deviation)
Overall Health Score	3.75 ± 17.60	4.33 ± 15.10	-5.00 ± 15.41	-3.50 ± 14.15	-5.00 ± 7.75	0.50 ± 13.01
Physical Abilities Score	-6.01 ± 9.83	8.82 ± 23.06	3.36 ± 8.62	1.30 ± 16.05	2.35 ± 29.29	-15.91 ± 22.74
Growth and Development Scores	4.82 ± 11.62	4.34 ± 9.40	-0.71 ± 8.75	1.46 ± 26.01	3.57 ± 6.35	-3.50 ± 13.19
Pain Score	-1.19 ± 20.37	-1.47 ± 18.22	-1.19 ± 18.90	-7.64 ± 27.63	-4.69 ± 27.77	2.50 ± 22.58
Temperament and mood Score	4.79 ± 9.60	0.54 ± 5.40	0.66 ± 7.18	-0.49 ± 9.78	-2.43 ± 6.76	4.62 ± 10.48
Global health perceptions score	-1.07 ± 15.43	2.24 ± 12.37	-2.73 ± 11.29	-4.55 ± 12.18	-2.84 ± 13.62	0.50 ± 17.11
Parental impact emotional score	2.04 ± 23.13	-0.84 ± 8.89	0.51 ± 14.64	-6.85 ± 11.94	9.82 ± 20.89	-2.50 ± 19.05
Parental Impact Time Score	9.52 ± 29.06	4.76 ± 10.78	-8.05 ± 19.70	-2.38 ± 35.61	-10.7 ± 17.59	2.38 ± 14.93
Family Cohesion Score	1.79 ± 13.53	-1.25 ± 10.72	0.00 ± 15.00	-7.08 ± 28.08	-3.13 ± 8.84	-4.50 ± 15.54

No statistical analyses for this end point

Secondary: Change from Baseline in functional independence measure for children (WeeFIM-II) Score at Week 52

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End point title

Change from Baseline in functional independence measure for children (WeeFIM-II) Score at Week 52

End point description

The Pediatric Functional Independence Measure-II (WeeFIM®-II) is designed to measure the functional independence of children between the ages of 6 months and 18 years who have physical or general developmental limitations (Msall 1994b). 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], and cognition [score range 8 to 35]) and provides a total score between 18 (worst) and 126 (Best). The Wee-FIM-II is only validated in children ages 6 months to 18 years. Therefore results for Cohort 3 is not summarized. The number of participants analyzed is reported in sequence: (n=Cohort 1 Placebo, Cohort 1 Vosoritide, Cohort 2 Placebo, Cohort 2 Vosoritide) incl sentinel for each category. WeeFIM-II Total Score: (n=14, 19, 6,11) WeeFIM : Self-Care Score: (n=14, 19, 6, 11) WeeFIM: Mobility Score: (n=14, 19, 6, 11) WeeFIM: Cognitive Score: (n=14, 19, 6, 11)

End point type

Secondary

End point timeframe

Baseline to Week 52

End point values	Cohort 1: Placebo	Cohort 1: Vosoritide	Cohort 2: Placebo	Cohort 2: Vosoritide
Number of subjects analysed	16	19	8	12
Units: Score on a scale
arithmetic mean (standard deviation)
WeeFIM-II Total Score	11.2 ± 11.1	14.7 ± 17.3	16.2 ± 14.6	16.5 ± 28.1
WeeFIM : Self-Care Score	6.4 ± 6.0	6.6 ± 7.2	3.7 ± 2.3	5.6 ± 14.1
WeeFIM: Mobility Score	2.2 ± 3.4	4.5 ± 5.6	7.0 ± 7.5	6.7 ± 9.4
WeeFIM: Cognitive Score	2.6 ± 4.0	3.6 ± 6.0	5.5 ± 7.6	4.2 ± 8.4

No statistical analyses for this end point

Secondary: Change from baseline in Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III) scores at Week 52

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End point title

Change from baseline in Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III) scores at Week 52

End point description

The number of participants analyzed is reported in sequence: (n=Cohort 1 Placebo, Cohort 1 Vosoritide, Cohort 2 Placebo, Cohort 2 Vosoritide, Cohort 3 Placebo, Cohort 3 Vosoritide) for each category. Motor Composite Score: (n=2, 4, 4, 9, 5,8) Cognitive scaled score: (n=2, 4, 3, 8, 6,9) Cognitive composite score: (n=2, 4, 3, 8, 6, 9) Receptive communication language scaled score: (n=2, 4, 3, 9, 5,9) Expressive communication language scaled score: (n=2, 4, 4, 8, 5, 8) Language sum of scaled score: (n=2, 4, 4, 9, 6,9) Language composite score: (n=2, 4, 4, 9, 5, 9) Fine motor scaled score: (n=2, 4, 4, 9, 5, 8) Gross motor scaled score: (n=2, 4, 4, 9, 5, 9) 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. Each (sub)scale yields a total raw score, standardized according to the participant’s chronological age (scaled scores)

End point type

Secondary

End point timeframe

Baseline to Week 52

End point values	Cohort 1: Placebo	Cohort 1: Vosoritide	Cohort 2: Placebo	Cohort 2: Vosoritide	Cohort 3: Placebo	Cohort 3: Vosoritide
Number of subjects analysed	16	19	8	12	8	12
Units: Score on a scale
arithmetic mean (standard deviation)
Motor Composite Score	-2.0 ± 5.7	4.8 ± 11.5	12.0 ± 17.5	-2.3 ± 12.3	5.4 ± 22.2	11.1 ± 18.1
Cognitive scaled score	-1.0 ± 2.8	-0.5 ± 1.7	3.3 ± 4.9	0.6 ± 3.2	1.5 ± 1.9	2.1 ± 4.4
Cognitive composite score	-5.0 ± 14.1	-2.5 ± 8.7	16.7 ± 24.7	3.1 ± 16.0	7.5 ± 9.4	10.6 ± 22.1
Receptive communication language scaled score	-1.0 ± 0.0	-1.8 ± 2.5	3.3 ± 4.0	1.0 ± 1.2	-3.0 ± 2.1	0.7 ± 5.2
Expressive communication language scaled score	2.5 ± 0.7	0.3 ± 1.3	2.8 ± 2.9	-0.1 ± 2.2	-1.8 ± 1.6	-0.1 ± 3.3
Language sum of scaled score	1.5 ± 0.7	-1.5 ± 3.3	6.0 ± 5.2	1.8 ± 4.0	-7.3 ± 6.4	-0.3 ± 6.6
Language composite score	4.5 ± 2.1	-4.5 ± 9.9	17.8 ± 15.2	5.3 ± 12.1	-13.4 ± 5.8	-0.9 ± 19.5
Fine motor scaled score	-0.5 ± 3.5	0.0 ± 2.9	1.5 ± 3.3	-2.1 ± 2.5	2.2 ± 4.8	2.6 ± 2.7
Gross motor scaled score	0.0 ± 5.7	1.0 ± 0.8	2.8 ± 3.2	1.3 ± 2.8	-0.2 ± 3.1	0.1 ± 3.0

No statistical analyses for this end point

Secondary: Change from Baseline in Child Behaviour Checklist (CBCL) at Week 52

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End point title

Change from Baseline in Child Behaviour Checklist (CBCL) at Week 52

End point description

The number of participants analyzed is reported in sequence: (n=Cohort 1 Placebo, Cohort 1 Vosoritide, Cohort 2 Placebo, Cohort 2 Vosoritide) vosoritide including sentinel and randomized participants for each category. Emotionally Reactive Total: (n=15, 18, 4, 5) Anxious/Depressed Total: (n=15, 18, 4, 5) Withdrawn Total: (n=15, 18, 4, 5) Somatic Complaints Total: (n=15, 18, 4, 5) Sleep Problems Total: (n=15, 18, 4, 5) Attention Problems Total: (n=15, 18, 4, 5) Aggressive Behavior Total: (n=15, 18, 4, 5) Total Problems Total: (n=15, 18, 4, 5) 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 time frame for item responses was the past 2 months. Raw scores, t-scores, and percentiles are calculated for all subscales and syndromes, with higher scores indicating higher problems.

End point type

Secondary

End point timeframe

Baseline to Week 52

End point values	Cohort 1: Placebo	Cohort 1: Vosoritide	Cohort 2: Placebo	Cohort 2: Vosoritide
Number of subjects analysed	16	19	8	12
Units: Score on a scale
arithmetic mean (standard deviation)
CBCL Pre-School : Emotionally Reactive Total	-0.2 ± 1.5	0.1 ± 1.4	1.0 ± 2.0	1.0 ± 3.9
CBCL Pre-School : Anxious/Depressed Total	0.3 ± 1.7	0.2 ± 1.4	0.0 ± 2.2	0.8 ± 3.1
CBCL Pre-School : Withdrawn Total	-0.6 ± 1.7	0.6 ± 1.5	0.8 ± 2.2	-0.2 ± 1.6
CBCL Pre-School : Somatic Complaints Total	0.1 ± 1.7	0.3 ± 1.0	0.5 ± 1.0	1.8 ± 4.1
CBCL Pre-School : Sleep Problems Total	-0.3 ± 3.2	0.1 ± 1.9	-0.3 ± 1.7	1.4 ± 4.3
CBCL Pre-School : Attention Problems Total	-0.1 ± 1.9	-0.1 ± 1.6	-0.3 ± 1.0	-0.2 ± 2.0
CBCL Pre-School : Aggressive Behavior Total	-1.1 ± 2.4	0.3 ± 4.1	-0.8 ± 1.5	-0.4 ± 2.7
CBCL Pre-School : Total Problems Total	-3.0 ± 13.0	2.8 ± 11.7	-2.3 ± 6.0	3.6 ± 23.2

No statistical analyses for this end point

Secondary: Change from baseline in bilateral X-rays of lower extremities at Wee 52

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End point title

Change from baseline in bilateral X-rays of lower extremities at Wee 52

End point description

The number of participants analyzed is reported in sequence: (n= All Vosoritide, Placebo) for each category. Left Femur Length: (n= 17, 14) Right Femur Length: (n= 17, 14) Left Fibula Length: (n= 40,,27) Right Fibula Length: (n= 39, 27) Left Tibia Length: (n= 40, 27) Right Tibia Length: (n= 39, 27) Left Distance Between Ankle Joint and Distal Growth Plate of Fibula: (n= 38, 26) Right Distance Between Ankle Joint and Distal Growth Plate of Fibula: (n= 37, 26) Left Lower Extremity: (n= 18, 14) Right Lower Extremity: (n= 18, 14)

End point type

Secondary

End point timeframe

Baseline to Week 52

End point values	All Vosoritide	Placebo
Number of subjects analysed	43	32
Units: cm
arithmetic mean (standard deviation)
Left Femur Length	2.29 ± 0.58	2.01 ± 0.62
Right Femur Length	2.35 ± 0.49	2.20 ± 0.73
Left Fibula Length	2.00 ± 0.61	1.97 ± 0.69
Right Fibula Length	2.00 ± 0.64	1.89 ± 0.75
Left Tibia Length	1.92 ± 0.55	1.69 ± 0.70
Right Tibia Length	1.96 ± 0.57	1.68 ± 0.77
Lt Dis btw Ankle Joint&Distal Growth Plate Fibula	-0.02 ± 0.23	0.07 ± 0.23
Rt Dis btw Ankle Joint&Distal Growth Plate Fibula	-0.05 ± 0.23	0.05 ± 0.22
Left Lower Extremity	6.02 ± 6.67	3.87 ± 1.56
Right Lower Extremity	6.08 ± 6.54	4.26 ± 1.85

No statistical analyses for this end point

Secondary: Change from baseline in bilateral X-rays of Left/Right Tibia bowing angle at Week 52

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End point title

Change from baseline in bilateral X-rays of Left/Right Tibia bowing angle at Week 52

End point description

The number of participants analyzed is reported in sequence: (n=All vosoritide , Placebo) for each category. Left Tibia Bowing Angle : (n= 39, 27) Right Tibia Bowing Angle : (n=38, 27)

End point type

Secondary

End point timeframe

Baseline to Week 52

End point values	All Vosoritide	Placebo
Number of subjects analysed	43	32
Units: Degrees
arithmetic mean (standard deviation)
Left Tibia Bowing Angle	-0.97 ± 5.88	1.07 ± 5.38
Right Tibia Bowing Angle	-2.34 ± 5.37	-0.93 ± 5.54

No statistical analyses for this end point

Secondary: Change from baseline in bilateral X-rays of Left Femur Length (cm) to Tibia Length (cm) Ratio and Right Femur Length (cm) to Tibia Length (cm) Ratio & Right Femur Length (cm) to Tibia Length (cm) Ratio at Week 52

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End point title

Change from baseline in bilateral X-rays of Left Femur Length (cm) to Tibia Length (cm) Ratio and Right Femur Length (cm) to Tibia Length (cm) Ratio & Right Femur Length (cm) to Tibia Length (cm) Ratio at Week 52

End point description

The number of participants analyzed is reported in sequence: (n= All Vosoritide, Placebo) Left Femur Length (cm) to Tibia Length (cm) Ratio : (n= 17, 14) Right Femur Length (cm) to Tibia Length (cm) Ratio: (n= 17, 14)

End point type

Secondary

End point timeframe

Baseline to Week 52

End point values	All Vosoritide	Placebo
Number of subjects analysed	43	32
Units: Ratio
arithmetic mean (standard deviation)
Left Femur Length (cm) to Tibia Length (cm) Ratio	-0.03 ± 0.06	-0.05 ± 0.05
Right Femur Length (cm) to Tibia Length (cm) Ratio	-0.05 ± 0.06	-0.02 ± 0.03

No statistical analyses for this end point

Secondary: Change from baseline in bilateral X-rays of Left Tibia Length (cm) to Fibula Length (cm) Ratio & Right Tibia Length (cm) to Fibula Length (cm) Ratio at Week 52

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End point title

Change from baseline in bilateral X-rays of Left Tibia Length (cm) to Fibula Length (cm) Ratio & Right Tibia Length (cm) to Fibula Length (cm) Ratio at Week 52

End point description

The number of participants analyzed is reported in sequence: (n= All vosoritide, Placebo) Left Tibia Length (cm) to Fibula Length (cm) Ratio: (n=40, 27) Right Tibia Length (cm) to Fibula Length (cm) Ratio: (n=39, 27)

End point type

Secondary

End point timeframe

Baseline to Week 52

End point values	All Vosoritide	Placebo
Number of subjects analysed	43	32
Units: Ratio
arithmetic mean (standard deviation)
Left Tibia Length (cm) to Fibula Length (cm) Ratio	-0.02 ± 0.04	-0.04 ± 0.04
Right Tibia Length (cm) to Fibula Length(cm) Ratio	-0.02 ± 0.05	-0.03 ± 0.04

No statistical analyses for this end point

Secondary: Change from baseline in X-ray of Lumbar spine vertebral ratios at Week 52

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End point title

Change from baseline in X-ray of Lumbar spine vertebral ratios at Week 52

End point description

The number of participants analyzed is reported in sequence: (n= All Vosoritide, Placebo) for each category. Anterior Height to Medial Height Ratio (L1): (n= 30, 23) Anterior Height to Medial Height Ratio (L2): (n= 23, 13) Anterior Height to Medial Height Ratio (L3): (n= 19, 11) Anterior Height to Medial Height Ratio (L4): (n=26, 15) Anterior Height to Medial Height Ratio (L5): (n=27, 12) Anterior Height to Posterior Height Ratio (L1): (n= 40, 27) Anterior Height to Posterior Height Ratio (L2): (n= 40, 27) Anterior Height to Posterior Height Ratio (L3): (n= 40, 27) Anterior Height to Posterior Height Ratio (L4): (n= 40, 27) Anterior Height to Posterior Height Ratio (L5): (n= 40, 27) Medial Height to Posterior Height Ratio (L1): (n= 30, 23) Medial Height to Posterior Height Ratio (L2): (n= 23, 13) Medial Height to Posterior Height Ratio (L3): (n= 19, 11) Medial Height to Posterior Height Ratio (L4): (n= 26, 15) Medial Height to Posterior Height Ratio (L5):(n= 27,12)

End point type

Secondary

End point timeframe

Baseline to Week 52

End point values	All Vosoritide	Placebo
Number of subjects analysed	43	32
Units: Ratio
arithmetic mean (standard deviation)
Anterior Height to Medial Height Ratio (L1)	-0.04 ± 0.16	-0.04 ± 0.20
Anterior Height to Medial Height Ratio (L2)	-0.06 ± 0.16	-0.07 ± 0.16
Anterior Height to Medial Height Ratio (L3)	-0.02 ± 0.19	0.04 ± 0.09
Anterior Height to Medial Height Ratio (L4)	0.02 ± 0.12	-0.01 ± 0.11
Anterior Height to Medial Height Ratio (L5)	-0.02 ± 0.15	0.04 ± 0.17
Anterior Height to Posterior Height Ratio (L1)	-0.03 ± 0.13	-0.08 ± 0.17
Anterior Height to Posterior Height Ratio (L2)	-0.02 ± 0.13	-0.03 ± 0.12
Anterior Height to Posterior Height Ratio (L3)	-0.01 ± 0.16	0.04 ± 0.12
Anterior Height to Posterior Height Ratio (L4)	0.03 ± 0.11	0.02 ± 0.13
Anterior Height to Posterior Height Ratio (L5)	0.01 ± 0.13	0.02 ± 0.15
Medial Height to Posterior Height Ratio (L1)	-0.01 ± 0.15	-0.04 ± 0.12
Medial Height to Posterior Height Ratio (L2)	0.05 ± 0.11	0.03 ± 0.09
Medial Height to Posterior Height Ratio (L3)	-0.02 ± 0.10	-0.02 ± 0.10
Medial Height to Posterior Height Ratio (L4)	-0.03 ± 0.13	0.04 ± 0.10
Medial Height to Posterior Height Ratio (L5)	0.02 ± 0.16	-0.04 ± 0.21

No statistical analyses for this end point

Secondary: Change from baseline in X-ray of Lumbar Spine Transverse Diameter at Week 52

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End point title

Change from baseline in X-ray of Lumbar Spine Transverse Diameter at Week 52

End point description

End point type

Secondary

End point timeframe

Baseline to Week 52

End point values	All Vosoritide	Placebo
Number of subjects analysed	40	27
Units: cm
arithmetic mean (standard deviation)
Transverse Diameter (L1)	0.12 ± 0.17	0.12 ± 0.11
Transverse Diameter (L2)	0.12 ± 0.16	0.09 ± 0.13
Transverse Diameter (L3)	0.08 ± 0.15	0.09 ± 0.12
Transverse Diameter (L4)	0.09 ± 0.13	0.06 ± 0.11
Transverse Diameter (L5)	0.10 ± 0.13	0.05 ± 0.14

No statistical analyses for this end point

Secondary: Change from baseline in X-ray of Lumbar Spine Sagittal Width and Week 52

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End point title

Change from baseline in X-ray of Lumbar Spine Sagittal Width and Week 52

End point description

The number of participants analyzed is reported in sequence: (n=All Vosoritide, Placebo) for each category. Sagittal Width (L1): (n=34, 26) Sagittal Width (L2): (n=34, 26) Sagittal Width (L3): (n=34, 26) Sagittal Width (L4): (n=34, 26) Sagittal Width (L5): (n=31, 25)

End point type

Secondary

End point timeframe

Baseline to Week 52

End point values	All Vosoritide	Placebo
Number of subjects analysed	43	32
Units: cm
arithmetic mean (standard deviation)
Sagittal Width (L1)	0.07 ± 0.26	0.00 ± 0.22
Sagittal Width (L2)	0.05 ± 0.18	0.01 ± 0.18
Sagittal Width (L3)	0.08 ± 0.20	0.04 ± 0.19
Sagittal Width (L4)	0.16 ± 0.24	0.03 ± 0.16
Sagittal Width (L5)	0.13 ± 0.34	0.06 ± 0.26

No statistical analyses for this end point

Secondary: Change from baseline in X-ray of Lumbar Spine Angles at Week 52

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End point title

Change from baseline in X-ray of Lumbar Spine Angles at Week 52

End point description

The number of participants analyzed is reported in sequence: (n=All Vosoritide, Placebo) Sacral Tilt: (n= 40, 27) Lordosis Angle: (n= 40, 27) Kyphosis Angle: (n= 39, 27)

End point type

Secondary

End point timeframe

Baseline to Week 52

End point values	All Vosoritide	Placebo
Number of subjects analysed	43	32
Units: Degree
arithmetic mean (standard deviation)
Sacral Tilt	10.6 ± 13.2	5.7 ± 15.9
Lordosis Angle	12.5 ± 17.4	8.4 ± 14.2
Kyphosis Angle	-2.2 ± 13.9	-2.1 ± 10.3

No statistical analyses for this end point

Secondary: Changes from Baseline in X-ray of lumbar spine angle changes: Number of participants with an increase in Lumbar Spine Angle at Week 52

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End point title

Changes from Baseline in X-ray of lumbar spine angle changes: Number of participants with an increase in Lumbar Spine Angle at Week 52

End point description

End point type

Secondary

End point timeframe

Baseline to Week 52

End point values	All Vosoritide	Placebo
Number of subjects analysed	43	32
Units: Number of participants
Increase in sacral tilt (deg) >=5 to <10	3	6
Increase in sacral tilt (deg) >=10	24	10
Increase in lordosis angle (deg) >=5 to <10	5	1
Increase in lordosis angle (deg) >=10	19	14
Increase in kyphosis angle (deg) >=5 to <10	3	2
Increase in kyphosis angle (deg) >=10	9	4

No statistical analyses for this end point

Secondary: MRI Parameter: Change from baseline to Week 52 for Volume of Face, Sinus, Calvarium, Whole Brain Total Volume, Ventricles Total Volume.

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End point title

MRI Parameter: Change from baseline to Week 52 for Volume of Face, Sinus, Calvarium, Whole Brain Total Volume, Ventricles Total Volume.

End point description

The number of participants analyzed is reported in sequence: (n=All Vosoritide, Placebo) for each category. Volume of Face: (n=30, 21) Volume of Sinus: (n=35, 24) Volume of Calvarium: (n=34, 24) Whole Brain Total Volume: (n=34, 24) Ventricles Total Volume: (n=34, 25)

End point type

Secondary

End point timeframe

Baseline to Week 52

End point values	All Vosoritide	Placebo
Number of subjects analysed	43	32
Units: cm^3
arithmetic mean (standard deviation)
Volume of Face	80.527 ± 59.211	78.107 ± 33.369
Volume of Sinus	2.362 ± 3.578	1.195 ± 3.769
Volume of Calvarium	213.075 ± 202.415	183.427 ± 183.210
Whole Brain Total Volume	175.399 ± 158.088	146.247 ± 115.274
Ventricles Total Volume	11.394 ± 20.416	8.515 ± 16.325

No statistical analyses for this end point

Secondary: MRI Parameter: Change from baseline to Week 52 for area of Area of Foramen Magnum & Area of Spinal Cord at the Foramen Magnum Level

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End point title

MRI Parameter: Change from baseline to Week 52 for area of Area of Foramen Magnum & Area of Spinal Cord at the Foramen Magnum Level

End point description

End point type

Secondary

End point timeframe

Baseline to Week 52

End point values	All Vosoritide	Placebo
Number of subjects analysed	43	32
Units: cm^2
arithmetic mean (standard deviation)
Area of Foramen Magnum	0.002 ± 0.034	0.006 ± 0.020
Area of Spinal Cord at the Foramen Magnum Level	0.001 ± 0.020	0.007 ± 0.016

No statistical analyses for this end point

Secondary: MRI Parameter: Change from baseline to Week 52 for Ratio of Face Volume to Calvarium, Ratio of Area of Spinal Cord to Foramen Magnum, Ratio of Face Volume to Sinus

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End point title

MRI Parameter: Change from baseline to Week 52 for Ratio of Face Volume to Calvarium, Ratio of Area of Spinal Cord to Foramen Magnum, Ratio of Face Volume to Sinus

End point description

The number of participants analyzed is reported in sequence: (n=All Vosoritide, Placebo) Ratio of face volume to calvarium: (n=29, 20) Ratio of area of spinal cord to foramen magnum: (n=35, 25) Ratio of face volume to sinus: (n=30, 21)

End point type

Secondary

End point timeframe

Baseline to Week 52

End point values	All Vosoritide	Placebo
Number of subjects analysed	43	32
Units: Ratio
arithmetic mean (standard deviation)
Ratio of face volume to calvarium	0.002 ± 0.031	0.003 ± 0.033
Ratio of area of spinal cord to foramen magnum	0.005 ± 0.120	0.037 ± 0.100
Ratio of face volume to sinus	-6.798 ± 175.646	14.505 ± 284.950

No statistical analyses for this end point

Secondary: DEXA parameter: Change from baseline to Week 52 for Whole Body Less Head bone mineral content (BMC)

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End point title

DEXA parameter: Change from baseline to Week 52 for Whole Body Less Head bone mineral content (BMC)

End point description

The number of participants analyzed is reported in sequence: (n=All Vosoritide, Placebo) for each category. GE - Lunar Prodigy: Whole Body Less Head BMC: (n=8, 12) Hologic - Discovery Horizon Whole Body Less Head BMC: (n=18, 8) Dual Energy X-Ray Absorptiometry (DEXA)

End point type

Secondary

End point timeframe

Baseline to Week 52

End point values	All Vosoritide	Placebo
Number of subjects analysed	43	32
Units: gm
arithmetic mean (standard deviation)
GE - Lunar Prodigy: Whole Body Less Head BMC	55.87 ± 14.68	50.26 ± 17.44
Hologic Discovery Horizon Whole Body Less Head BMC	44.61 ± 12.62	47.19 ± 12.55

No statistical analyses for this end point

Secondary: DEXA parameter: Change from baseline to Week 52 of Whole Body Less Head bone mineral density (BMD)

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End point title

DEXA parameter: Change from baseline to Week 52 of Whole Body Less Head bone mineral density (BMD)

End point description

GE - Lunar Prodigy Whole Body Less Head BMD: (n=8,12) Hologic - Discovery Horizon Whole Body Less Head BMD: (18, 8)

End point type

Secondary

End point timeframe

Baseline to Week 52

End point values	All Vosoritide	Placebo
Number of subjects analysed	43	32
Units: g/cm^2
arithmetic mean (standard deviation)
GE - Lunar Prodigy Whole Body Less Head BMD	0.04 ± 0.02	0.05 ± 0.03
Hologic Discovery Horizon Whole Body Less Head BMD	0.03 ± 0.01	0.04 ± 0.02

No statistical analyses for this end point

Secondary: DEXA parameter: Change from baseline to Week 52 of Whole Body BMC

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End point title

DEXA parameter: Change from baseline to Week 52 of Whole Body BMC

End point description

The number of participants analyzed is reported in sequence: (n=All Vosoritide, Placebo) for each category. GE - Lunar Prodigy Whole Body BMC: (n=8, 12) Hologic - Discovery Horizon Whole Body BMC: (n=18, 8)

End point type

Secondary

End point timeframe

Baseline to Week 52

End point values	All Vosoritide	Placebo
Number of subjects analysed	43	32
Units: gm
arithmetic mean (standard deviation)
GE - Lunar Prodigy Whole Body BMC	96.85 ± 39.82	98.99 ± 32.45
Hologic - Discovery Horizon Whole Body BMC	87.97 ± 32.35	101.33 ± 33.34

No statistical analyses for this end point

Secondary: DEXA parameter: Change from baseline to Week 52 of Whole Body BMD

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End point title

DEXA parameter: Change from baseline to Week 52 of Whole Body BMD

End point description

The number of participants analyzed is reported in sequence: (n=All Vosoritide, Placebo) for each category. GE - Lunar Prodigy Whole Body BMD: (n=8, 12) Hologic - Discovery Horizon Whole Body BMD: (n=18, 8)

End point type

Secondary

End point timeframe

Baseline to Week 52

End point values	All Vosoritide	Placebo
Number of subjects analysed	43	32
Units: g/cm^2
arithmetic mean (standard deviation)
GE - Lunar Prodigy Whole Body BMD	0.06 ± 0.06	0.07 ± 0.04
Hologic - Discovery Horizon Whole Body BMD	0.05 ± 0.02	0.07 ± 0.03

No statistical analyses for this end point

Secondary: DEXA parameter: Change from baseline to Week 52 of Lumbar Spine BMC

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End point title

DEXA parameter: Change from baseline to Week 52 of Lumbar Spine BMC

End point description

The number of participants analyzed is reported in sequence: (n=All Vosoritide, Placebo) for each category. GE - Lunar Prodigy Lumbar Spine BMC: (n=9, 10) Hologic - Discovery Horizon Lumbar Spine BMC: (n=27, 13)

End point type

Secondary

End point timeframe

Baseline to Week 52

End point values	All Vosoritide	Placebo
Number of subjects analysed	43	32
Units: gm
arithmetic mean (standard deviation)
GE - Lunar Prodigy Lumbar Spine BMC	2.73 ± 0.83	2.09 ± 0.97
Hologic - Discovery Horizon Lumbar Spine BMC	2.19 ± 0.68	1.94 ± 0.72

No statistical analyses for this end point

Secondary: DEXA parameter: Change from baseline to Week 52 of Lumbar Spine BMD

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End point title

DEXA parameter: Change from baseline to Week 52 of Lumbar Spine BMD

End point description

The number of participants analyzed is reported in sequence: (n=All Vosoritide, Placebo) for each category. GE - Lunar Prodigy Lumbar Spine BMD: (n=9, 10) Hologic - Discovery Horizon Lumbar Spine BMD: (27, 13)

End point type

Secondary

End point timeframe

Baseline to Week 52

End point values	All Vosoritide	Placebo
Number of subjects analysed	43	32
Units: g/cm^2
arithmetic mean (standard deviation)
GE - Lunar Prodigy Lumbar Spine BMD	0.07 ± 0.04	0.05 ± 0.03
Hologic - Discovery Horizon Lumbar Spine BMD	0.05 ± 0.03	0.06 ± 0.04

No statistical analyses for this end point

Secondary: Change from baseline to Week 52 in whole body BMD Z-score

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End point title

Change from baseline to Week 52 in whole body BMD Z-score

End point description

Hologic - Discovery Horizon Whole Body BMD Z-Score

End point type

Secondary

End point timeframe

Baseline to Week 52

End point values	All Vosoritide	Placebo
Number of subjects analysed	6	4
Units: Z-score
arithmetic mean (standard deviation)
Hologic - Discovery Horizon Whole Body BMD Z-Score	-0.20 ± 0.35	0.30 ± 0.47

No statistical analyses for this end point

Secondary: Change from baseline to Week 52 in Lumbar Spine BMD Z-Score

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End point title

Change from baseline to Week 52 in Lumbar Spine BMD Z-Score

End point description

Hologic - Discovery Horizon Lumbar Spine BMD Z-Score

End point type

Secondary

End point timeframe

Baseline to Week 52

End point values	All Vosoritide	Placebo
Number of subjects analysed	7	4
Units: Z-score
arithmetic mean (standard deviation)	0.17 ± 0.24	0.03 ± 0.45

No statistical analyses for this end point

Secondary: Immunogenicity: Number of participants with Incidence of Antibody Positivity at Scheduled Visits

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End point title

Immunogenicity: Number of participants with Incidence of Antibody Positivity at Scheduled Visits

End point description

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.

End point type

Secondary

End point timeframe

At Day 1, Week 3, Week 13, Week 26, Week 52, & Ever Positive.

End point values	All Vosoritide	Placebo
Number of subjects analysed	43	32
Units: Number of participants
TAb Titer Positive: Day 1	0	0
TAb Titer Positive: Week 3	0	0
TAb Titer Positive: Week 13	0	0
TAb Titer Positive: Week 26	2	0
TAb Titer Positive: Week 52	8	0
TAb Titer Ever Positive	8	0
NAb Titer Positive: Day 1	0	0
NAb Titer Positive: Week 3	0	0
NAb Titer Positive: Week 13	0	0
NAb Titer Positive: Week 26	0	0
NAb Titer Positive: Week 52	0	0
NAb Titer Ever Positive	0	0
ANP Reactivity Positive: Day 1	3	5
ANP Reactivity Positive: Week 3	0	0
ANP Reactivity Positive: Week 13	1	0
ANP Reactivity Positive: Week 26	6	0
ANP Reactivity Positive: Week 52	11	0
ANP Reactivity Ever Positive	12	0
BNP Reactivity Positive: Day 1	0	3
BNP Reactivity Positive: Week 3	0	0
BNP Reactivity Positive: Week 13	2	0
BNP Reactivity Positive: Week 26	3	0
BNP Reactivity Positive: Week 52	2	0
BNP Reactivity Ever Positive	3	0
CNP Reactivity Positive: Day 1	0	1
CNP Reactivity Positive: Week 3	0	0
CNP Reactivity Positive: Week 13	1	0
CNP Reactivity Positive: Week 26	2	0
CNP Reactivity Positive: Week 52	4	0
CNP Reactivity Ever Positive	4	0

No statistical analyses for this end point

Secondary: Biomarker: Bone Specific Alkaline Phosphatase (BSAP) overtime

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End point title

Biomarker: Bone Specific Alkaline Phosphatase (BSAP) overtime

End point description

The number of participants analyzed is reported in sequence: (n=All Vosoritide, Placebo) for each category. Baseline: (n= 43, 32) Day 8: (n=42, 27) Change from baseline to Day 8: (n=42, 27) Week 6: (n=41, 29) Change from baseline to Week 6: (n=41, 29) Week 20: (n=40, 28) Change from baseline to Week 20: (n=40, 28) Week 39: (n=34, 24) Change from baseline to Week 39 : (n=34, 24)

End point type

Secondary

End point timeframe

At Baseline, Day 8, Week 6, Week 20, & Week 39.

End point values	All Vosoritide	Placebo
Number of subjects analysed	43	32
Units: U/L
arithmetic mean (standard deviation)
BSAP: Baseline	140.28 ± 183.23	113.43 ± 33.56
BSAP: Day 8	122.32 ± 99.09	104.12 ± 29.12
BSAP: Change from baseline to Day 8	-19.39 ± 202.90	-7.67 ± 17.53
BSAP: Week 6	130.38 ± 140.08	109.46 ± 29.04
BSAP: Change from baseline to Week 6	2.63 ± 218.60	-6.17 ± 24.32
BSAP: Week 20	109.67 ± 30.88	104.46 ± 29.69
BSAP: Change from baseline to Week 20	-7.21 ± 96.94	-11.32 ± 18.19
BSAP: Week 39	108.49 ± 32.02	208.13 ± 363.56
BSAP: Change from baseline to Week 39	-12.21 ± 105.04	95.41 ± 352.78

No statistical analyses for this end point

Secondary: Biomarker: Type II Collagen C-Telopeptides Normalized for Creatinine (CTX-II)

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End point title

Biomarker: Type II Collagen C-Telopeptides Normalized for Creatinine (CTX-II)

End point description

End point type

Secondary

End point timeframe

Baseline to Week 52.

End point values	All Vosoritide	Placebo
Number of subjects analysed	31	24
Units: ng/ mmol Cr
arithmetic mean (standard deviation)	-9364.7 ± 65244.1	-7607.6 ± 54614.9

No statistical analyses for this end point

Secondary: Biomarker: Plasma cGMP Change from Pre-Dose to Maximum Post-Dose at Week 52

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End point title

Biomarker: Plasma cGMP Change from Pre-Dose to Maximum Post-Dose at Week 52

End point description

End point type

Secondary

End point timeframe

Week 52 Pre-Dose to Week 52 Maximum Post-Dose.

End point values	All Vosoritide	Placebo
Number of subjects analysed	33	21
Units: nM
arithmetic mean (standard deviation)	39.079 ± 25.706	9.460 ± 26.307

No statistical analyses for this end point

Secondary: Change in Sleep Study Indices at Week 52

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End point title

Change in Sleep Study Indices at Week 52

End point description

A sleep study was performed in a limited number of qualified sleep centers. A sleep-testing device was used to assess the presence and severity of sleep-disordered breathing by measurement of blood oxygen saturation, pulse rate, and airflow during overnight monitoring. Assessment of episodes of sleep apnea included but were not limited to the number of episodes of apnea and hypopnea per hour (Apnea/Hypopnea Index).

End point type

Secondary

End point timeframe

Baseline to Week 52

End point values	Cohort 1: Placebo	Cohort 1: Vosoritide	Cohort 2: Placebo	Cohort 2: Vosoritide	Cohort 3: Placebo	Cohort 3: Vosoritide
Number of subjects analysed	14	16	5	9	7	10
Units: Number per Hour
arithmetic mean (standard deviation)
Apnea Hypopnea Index	-0.54 ± 2.70	-1.45 ± 4.63	1.06 ± 4.80	-0.72 ± 1.41	1.89 ± 6.31	-0.94 ± 2.78
Apnea Index	-1.07 ± 2.12	-0.83 ± 1.93	0.40 ± 2.34	-0.71 ± 1.61	-1.09 ± 1.22	-0.36 ± 2.54
Central Apnea Index	-1.26 ± 2.66	-0.74 ± 1.86	-0.28 ± 0.89	-0.71 ± 1.61	-1.00 ± 0.97	0.50 ± 0.92
Hypopnea Index	0.52 ± 1.35	-0.61 ± 3.63	0.66 ± 2.53	-0.01 ± 1.32	2.97 ± 5.45	-0.56 ± 0.54
Desaturation per Hour >=3%	-0.41 ± 1.51	-1.24 ± 3.98	0.98 ± 3.60	-0.69 ± 1.30	1.71 ± 6.63	-0.93 ± 2.60
Obstructive Index	0.19 ± 0.73	-0.09 ± 0.45	0.68 ± 1.52	-0.01 ± 0.08	-0.07 ± 0.64	-0.86 ± 2.08

No statistical analyses for this end point

Secondary: PK parameter: Area under the plasma concentration-time curve from time 0 to infinity (AUC0-∞) at Day1, Week 13, Week 26, Week 39, & Week 52

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End point title

PK parameter: Area under the plasma concentration-time curve from time 0 to infinity (AUC0-∞) at Day1, Week 13, Week 26, Week 39, & Week 52

End point description

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. The number of participants analyzed are reported in sequence (n = Day 01, Week 13, Week 26, Week 39, Week 52) Cohort 1 15 µg/kg/day: (n=16, 15, 16, 16, 15) Cohort 2 15 µg/kg/day: (n=1, 1, 4, 4, 3) Refer PDF Cohort 2 30 µg/kg/day: (n=7, 6, 3, 2, 3) Cohort 3 30 µg/kg/day: (n=8, 6, 6, 3,7)

End point type

Secondary

End point timeframe

At Day1, Week 13, Week 26, Week 39, & Week 52.

End point values	All Vosoritide
Number of subjects analysed	43
Units: min*pg/ml
arithmetic mean (standard deviation)
Cohort 1 15 µg/kg/day: Day 01	149000 ± 98000
Cohort 1 15 µg/kg/day: Week 13	197000 ± 144000
Cohort 1 15 µg/kg/day: Week 26	306000 ± 252000
Cohort 1 15 µg/kg/day: Week 39	284000 ± 137000
Cohort 1 15 µg/kg/day: Week 52	303000 ± 208000
Cohort 2 15 µg/kg/day: Week 26	233000 ± 132000
Cohort 2 15 µg/kg/day: Week 39	204000 ± 39700
Cohort 2 15 µg/kg/day: Week 52	137000 ± 48900
Cohort 2 30 µg/kg/day: Day 01	557000 ± 278000
Cohort 2 30 µg/kg/day: Week 13	670000 ± 312000
Cohort 2 30 µg/kg/day: Week 26	429000 ± 163000
Cohort 2 30 µg/kg/day: Week 39	387000 ± 53800
Cohort 2 30 µg/kg/day: Week 52	768000 ± 391000
Cohort 3 30 µg/kg/day: Day 01	353000 ± 133000
Cohort 3 30 µg/kg/day: Week 13	382000 ± 268000
Cohort 3 30 µg/kg/day: Week 26	305000 ± 82100
Cohort 3 30 µg/kg/day: Week 39	575000 ± 455000
Cohort 3 30 µg/kg/day: Week 52	622000 ± 455000

No statistical analyses for this end point

Secondary: PK parameter: Area under the plasma concentration-time curve from time 0 to nominal 120 minutes postdose (AUC 0- 120 min) at Day 01, Week 13, Week 26, Week 39, & Week 52

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End point title

PK parameter: Area under the plasma concentration-time curve from time 0 to nominal 120 minutes postdose (AUC 0- 120 min) at Day 01, Week 13, Week 26, Week 39, & Week 52

End point description

The number of participants analyzed in Cohort 1 is reported in Cohort 1 Day 01, Week 13, Week 26, Week 39, Week 52) in sequence (n=18, 16, 17, 19, 16), Cohort 2 15 µg/kg/day: (n=3, 2, 5, 5, 5), Cohort 2 30 µg/kg/day: (n=7, 8, 3, 2, 3), & Cohort 3 30 µg/kg/day: (n=11, 7, 6, 4, 8)

End point type

Secondary

End point timeframe

At Day 01, Week 13, Week 26, Week 39, & Week 52

End point values	All Vosoritide
Number of subjects analysed	43
Units: min*pg/ml
arithmetic mean (standard deviation)
Cohort 1 15 µg/kg/day: Day 01	134000 ± 96500
Cohort 1 15 µg/kg/day: Week 13	183000 ± 126000
Cohort 1 15 µg/kg/day: Week 26	283000 ± 222000
Cohort 1 15 µg/kg/day: Week 39	257000 ± 132000
Cohort 1 15 µg/kg/day: Week 52	260000 ± 172000
Cohort 2 15 µg/kg/day: Day 01	83100 ± 48300
Cohort 2 15 µg/kg/day: Week 13	115000 ± 59300
Cohort 2 15 µg/kg/day: Week 26	197000 ± 121000
Cohort 2 15 µg/kg/day: Week 39	166000 ± 81000
Cohort 2 15 µg/kg/day: Week 52	125000 ± 76700
Cohort 2 30 µg/kg/day: Day 01	525000 ± 251000
Cohort 2 30 µg/kg/day: Week 13	642000 ± 353000
Cohort 2 30 µg/kg/day: Week 26	408000 ± 148000
Cohort 2 30 µg/kg/day: Week 39	365000 ± 44700
Cohort 2 30 µg/kg/day: Week 52	670000 ± 335000
Cohort 3 30 µg/kg/day: Day 01	312000 ± 119000
Cohort 3 30 µg/kg/day: Week 13	342000 ± 245000
Cohort 3 30 µg/kg/day: Week 26	300000 ± 79100
Cohort 3 30 µg/kg/day: Week 39	591000 ± 359000
Cohort 3 30 µg/kg/day: Week 52	558000 ± 400000

No statistical analyses for this end point

Secondary: PK parameter: Area under the plasma concentration-time curve from time 0 to the time of last measurable concentration (AUC0-t) at Day 01, Week 13, Week 26, Week 39, & Week 52

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End point title

PK parameter: Area under the plasma concentration-time curve from time 0 to the time of last measurable concentration (AUC0-t) at Day 01, Week 13, Week 26, Week 39, & Week 52

End point description

The number of participants analyzed in Cohort 1 is reported in Cohort 1 Day 01, Week 13, Week 26, Week 39, Week 52) in sequence (n=18, 16, 17, 19, 16), Cohort 2 15 µg/kg/day: (n=3, 2, 5, 5, 5) Cohort 2 30 µg/kg/day: (n=7, 8, 3, 2, 3), & Cohort 3 30 µg/kg/day: (n=11, 7, 6, 4, 8)

End point type

Secondary

End point timeframe

At Day 01, Week 13, Week 26, Week 39, & Week 52

End point values	All Vosoritide
Number of subjects analysed	43
Units: min*pg/ml
arithmetic mean (standard deviation)
Cohort 1 15 µg/kg/day: Day 01	132000 ± 97300
Cohort 1 15 µg/kg/day: Week 13	182000 ± 127000
Cohort 1 15 µg/kg/day: Week 26	282000 ± 222000
Cohort 1 15 µg/kg/day: Week 39	256000 ± 132000
Cohort 1 15 µg/kg/day: Week 52	258000 ± 169000
Cohort 2 15 µg/kg/day: Day 01	65900 ± 33600
Cohort 2 15 µg/kg/day: Week 13	112000 ± 62900
Cohort 2 15 µg/kg/day: Week 26	196000 ± 121000
Cohort 2 15 µg/kg/day: Week 39	165000 ± 82400
Cohort 2 15 µg/kg/day: Week 52	122000 ± 75700
Cohort 2 30 µg/kg/day: Day 01	547000 ± 279000
Cohort 2 30 µg/kg/day: Week 13	645000 ± 357000
Cohort 2 30 µg/kg/day: Week 26	407000 ± 148000
Cohort 2 30 µg/kg/day: Week 39	365000 ± 44300
Cohort 2 30 µg/kg/day: Week 52	672000 ± 334000
Cohort 3 30 µg/kg/day: Day 01	323000 ± 129000
Cohort 3 30 µg/kg/day: Week 13	340000 ± 244000
Cohort 3 30 µg/kg/day: Week 26	297000 ± 80700
Cohort 3 30 µg/kg/day: Week 39	567000 ± 361000
Cohort 3 30 µg/kg/day: Week 52	557000 ± 401000

No statistical analyses for this end point

Secondary: PK parameter: Maximum observed plasma concentration (Cmax) at Day 01, Week 13, Week 26, Week 39, & Week 52

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End point title

PK parameter: Maximum observed plasma concentration (Cmax) at Day 01, Week 13, Week 26, Week 39, & Week 52

End point description

The number of participant analyzed in Cohort 1 is reported in Cohort 1 Day 01, Week 13, Week 26, Week 39, Week 52) in sequence (n=18, 16, 17, 19, 16) Cohort 2 15 µg/kg/day: (n=3, 2, 5, 5, 5) Cohort 2 30 µg/kg/day: (n=7, 8, 3, 2, 3), & Cohort 3 30 µg/kg/day: (n=11, 7, 6, 4, 8).

End point type

Secondary

End point timeframe

At Day 01, Week 13, Week 26, Week 39, & Week 52

End point values	All Vosoritide
Number of subjects analysed	43
Units: pg/ml
arithmetic mean (standard deviation)
Cohort 1 15 µg/kg/day: Day 01	4430 ± 3670
Cohort 1 15 µg/kg/day: Week 13	4350 ± 1670
Cohort 1 15 µg/kg/day: Week 26	5850 ± 3260
Cohort 1 15 µg/kg/day: Week 39	5600 ± 2200
Cohort 1 15 µg/kg/day: Week 52	5640 ± 2740
Cohort 2 15 µg/kg/day: Day 01	2840 ± 1230
Cohort 2 15 µg/kg/day: Week 13	5970 ± 2390
Cohort 2 15 µg/kg/day: Week 26	6800 ± 3360
Cohort 2 15 µg/kg/day: Week 39	4600 ± 2150
Cohort 2 15 µg/kg/day: Week 52	3870 ± 2120
Cohort 2 30 µg/kg/day: Day 01	14500 ± 5950
Cohort 2 30 µg/kg/day: Week 13	13400 ± 6070
Cohort 2 30 µg/kg/day: Week 26	10100 ± 2970
Cohort 2 30 µg/kg/day: Week 39	6980 ± 1140
Cohort 2 30 µg/kg/day: Week 52	12900 ± 6260
Cohort 3 30 µg/kg/day: Day 01	13400 ± 5710
Cohort 3 30 µg/kg/day: Week 13	10500 ± 6850
Cohort 3 30 µg/kg/day: Week 26	11500 ± 4290
Cohort 3 30 µg/kg/day: Week 39	18400 ± 11900
Cohort 3 30 µg/kg/day: Week 52	13500 ± 6770

No statistical analyses for this end point

Secondary: PK parameter: Time to reach maximum concentration (Tmax) at Day 01, Week 13, Week 26, Week 39, & Week 52

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End point title

PK parameter: Time to reach maximum concentration (Tmax) at Day 01, Week 13, Week 26, Week 39, & Week 52

End point description

The number of participants analyzed in Cohort 1 is reported in Cohort 1 Day 01, Week 13, Week 26, Week 39, Week 52) in sequence (n=18, 16, 17, 19, 16), Cohort 2 15 µg/kg/day: (n=3, 2, 5, 5, 5) Cohort 2 30 µg/kg/day: (n=7, 8, 3, 2, 3), & Cohort 3 30 µg/kg/day: (n=11, 7, 6, 4, 8).

End point type

Secondary

End point timeframe

At Day 01, Week 13, Week 26, Week 39, & Week 52.

End point values	All Vosoritide
Number of subjects analysed	43
Units: min
arithmetic mean (standard deviation)
Cohort 1 15 µg/kg/day: Day 01	13.1 ± 6.33
Cohort 1 15 µg/kg/day: Week 13	14.3 ± 5.5
Cohort 1 15 µg/kg/day: Week 26	16.1 ± 8.69
Cohort 1 15 µg/kg/day: Week 39	17.4 ± 11.9
Cohort 1 15 µg/kg/day: Week 52	16.1 ± 6.27
Cohort 2 15 µg/kg/day: Day 01	11.3 ± 6.35
Cohort 2 15 µg/kg/day: Week 13	6 ± 1.41
Cohort 2 15 µg/kg/day: Week 26	10.8 ± 5.5
Cohort 2 15 µg/kg/day: Week 39	15.4 ± 11.6
Cohort 2 15 µg/kg/day: Week 52	14.2 ± 5.76
Cohort 2 30 µg/kg/day: Day 01	12.9 ± 9.1
Cohort 2 30 µg/kg/day: Week 13	14 ± 8.42
Cohort 2 30 µg/kg/day: Week 26	12 ± 5.2
Cohort 2 30 µg/kg/day: Week 39	15 ± 0
Cohort 2 30 µg/kg/day: Week 52	14.3 ± 1.53
Cohort 3 30 µg/kg/day: Day 01	7.36 ± 3.53
Cohort 3 30 µg/kg/day: Week 13	9.43 ± 5.22
Cohort 3 30 µg/kg/day: Week 26	9 ± 4.69
Cohort 3 30 µg/kg/day: Week 39	11.3 ± 3.59
Cohort 3 30 µg/kg/day: Week 52	14.5 ± 3.51

No statistical analyses for this end point

Secondary: PK parameter: Apparent clearance (CL/F) at Day 01, Week 13, Week 26, Week 39, & Week 52

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End point title

PK parameter: Apparent clearance (CL/F) at Day 01, Week 13, Week 26, Week 39, & Week 52

End point description

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. The number of participants analyzed are reported in sequence (n = Day 01, Week 13, Week 26, Week 39, Week 52) Cohort 1 15 µg/kg/day: (n=16, 15, 16, 16, 15) Cohort 2 15 µg/kg/day: (n=1, 1, 4, 4, 3) Refer PDF Cohort 2 30 µg/kg/day: (n=7, 6, 3, 2, 3) Cohort 3 30 µg/kg/day: (n=8, 6, 6, 3, 7)

End point type

Secondary

End point timeframe

At Day 01, Week 13, Week 26, Week 39, & Week 52.

End point values	All Vosoritide
Number of subjects analysed	43
Units: ml/min/kg
arithmetic mean (standard deviation)
Cohort 1 15 µg/kg/day: Day 01	134 ± 59.8
Cohort 1 15 µg/kg/day: Week 13	111 ± 58.5
Cohort 1 15 µg/kg/day: Week 26	79.8 ± 48.3
Cohort 1 15 µg/kg/day: Week 39	65.3 ± 32.7
Cohort 1 15 µg/kg/day: Week 52	69 ± 41.2
Cohort 2 15 µg/kg/day: Week 26	79.5 ± 38.4
Cohort 2 15 µg/kg/day: Week 39	75.5 ± 14.8
Cohort 2 15 µg/kg/day: Week 52	122 ± 52.5
Cohort 2 30 µg/kg/day: Day 01	65.9 ± 31.6
Cohort 2 30 µg/kg/day: Week 13	58.7 ± 40.4
Cohort 2 30 µg/kg/day: Week 26	79.4 ± 37.7
Cohort 2 30 µg/kg/day: Week 39	78.3 ± 10.9
Cohort 2 30 µg/kg/day: Week 52	49.7 ± 32
Cohort 3 30 µg/kg/day: Day 01	95.9 ± 34
Cohort 3 30 µg/kg/day: Week 13	115 ± 78.1
Cohort 3 30 µg/kg/day: Week 26	104 ± 23.2
Cohort 3 30 µg/kg/day: Week 39	73.6 ± 41.6
Cohort 3 30 µg/kg/day: Week 52	76.5 ± 49.8

No statistical analyses for this end point

Secondary: PK parameter: Apparent volume of distribution (Vz/F) at Day 01, Week 13, Week 26, Week 39, & Week 52

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End point title

PK parameter: Apparent volume of distribution (Vz/F) at Day 01, Week 13, Week 26, Week 39, & Week 52

End point description

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. The number of participants analyzed are reported in sequence (n = Day 01, Week 13, Week 26, Week 39, Week 52) Cohort 1 15 µg/kg/day: (n=16, 15, 16, 16, 15) Cohort 2 15 µg/kg/day: (n=1, 1, 4, 4, 3) Refer PDF Cohort 2 30 µg/kg/day: (n=7, 6, 3, 2, 3) Cohort 3 30 µg/kg/day: (n=8, 6, 6, 3, 7)

End point type

Secondary

End point timeframe

At Day 01, Week 13, Week 26, Week 39, & Week 52.

End point values	All Vosoritide
Number of subjects analysed	43
Units: ml/kg
arithmetic mean (standard deviation)
Cohort 1 15 µg/kg/day: Day 01	4070 ± 2310
Cohort 1 15 µg/kg/day: Week 13	3990 ± 2960
Cohort 1 15 µg/kg/day: Week 26	3400 ± 2520
Cohort 1 15 µg/kg/day: Week 39	2330 ± 1150
Cohort 1 15 µg/kg/day: Week 52	2660 ± 1420
Cohort 2 15 µg/kg/day: Week 26	3890 ± 2880
Cohort 2 15 µg/kg/day: Week 39	2250 ± 284
Cohort 2 15 µg/kg/day: Week 52	3770 ± 1410
Cohort 2 30 µg/kg/day: Day 01	3190 ± 1790
Cohort 2 30 µg/kg/day: Week 13	2090 ± 1360
Cohort 2 30 µg/kg/day: Week 26	1960 ± 829
Cohort 2 30 µg/kg/day: Week 39	2920 ± 205
Cohort 2 30 µg/kg/day: Week 52	3040 ± 2630
Cohort 3 30 µg/kg/day: Day 01	5240 ± 1890
Cohort 3 30 µg/kg/day: Week 13	4260 ± 2960
Cohort 3 30 µg/kg/day: Week 26	2750 ± 710
Cohort 3 30 µg/kg/day: Week 39	2200 ± 951
Cohort 3 30 µg/kg/day: Week 52	2620 ± 1950

No statistical analyses for this end point

Secondary: PK parameter: Elimination half-life (t1/2) at Day 01, Week 13, Week 26, Week 39, & Week 52

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End point title

PK parameter: Elimination half-life (t1/2) at Day 01, Week 13, Week 26, Week 39, & Week 52

End point description

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. The number of participants analyzed are reported in sequence (n = Day 01, Week 13, Week 26, Week 39, Week 52) Cohort 1 15 µg/kg/day: (n=16, 15, 16, 16, 15) Cohort 2 15 µg/kg/day: (n=1, 1, 4, 4, 3) Refer PDF Cohort 2 30 µg/kg/day: (n=7, 6, 3, 2, 3) Cohort 3 30 µg/kg/day: (n=8, 6, 6, 3, 7)

End point type

Secondary

End point timeframe

At Day 01, Week 13, Week 26, Week 39, & Week 52.

End point values	All Vosoritide
Number of subjects analysed	43
Units: min
arithmetic mean (standard deviation)
Cohort 1 15 µg/kg/day: Day 01	21.7 ± 7.99
Cohort 1 15 µg/kg/day: Week 13	25.4 ± 10.7
Cohort 1 15 µg/kg/day: Week 26	29.2 ± 7.06
Cohort 1 15 µg/kg/day: Week 39	25.7 ± 7.82
Cohort 1 15 µg/kg/day: Week 52	29 ± 9.12
Cohort 2 15 µg/kg/day: Week 26	32.7 ± 9.62
Cohort 2 15 µg/kg/day: Week 39	20.9 ± 2.18
Cohort 2 15 µg/kg/day: Week 52	24 ± 12.8
Cohort 2 30 µg/kg/day: Day 01	33.3 ± 8.41
Cohort 2 30 µg/kg/day: Week 13	25.6 ± 3.59
Cohort 2 30 µg/kg/day: Week 26	21 ± 13.1
Cohort 2 30 µg/kg/day: Week 39	26.2 ± 5.46
Cohort 2 30 µg/kg/day: Week 52	40.1 ± 15.2
Cohort 3 30 µg/kg/day: Day 01	41.1 ± 18.8
Cohort 3 30 µg/kg/day: Week 13	26.2 ± 7.1
Cohort 3 30 µg/kg/day: Week 26	19.2 ± 6.14
Cohort 3 30 µg/kg/day: Week 39	22.7 ± 5.36
Cohort 3 30 µg/kg/day: Week 52	24.3 ± 6.58

No statistical analyses for this end point

Secondary: Biomarker: Bone and Collagen Metabolism Biomarker Over Time-CNP Col X BM

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End point title

Biomarker: Bone and Collagen Metabolism Biomarker Over Time-CNP Col X BM

End point description

The number of participants analyzed is reported in sequence: (n=All Vosoritide, Placebo) for each category. Baseline: (n= 42, 32) Day 8: (n=42, 24) Change from baseline to Day 8: (n=41, 24) Week 6: (n=41, 29) Change from baseline to Week 6: (n=40, 29) Week 20: (n=42, 29) Change from baseline to Week 20: (n=41, 29) Week 39: (n=33, 22) Change from baseline to Week 39 : (n=32, 22)

End point type

Secondary

End point timeframe

At Baseline, Day 8, Week 6, Week 20, & Week 39.

End point values	All Vosoritide	Placebo
Number of subjects analysed	43	32
Units: pg/mL
arithmetic mean (standard deviation)
CNP Col X BM: Baseline	9833.8 ± 3444.7	9555.0 ± 4016.7
CNP Col X BM: Day 8	12093.8 ± 4443.8	10017.5 ± 3831.2
CNP Col X BM: Change from baseline to Day 8	2139.5 ± 3871.9	1391.3 ± 3354.2
CNP Col X BM: Week 6	13456.3 ± 4763.3	9464.8 ± 4243.3
CNP Col X BM: Change from baseline to Week 6	3400.3 ± 4554.6	200.3 ± 3867.5
CNP Col X BM: Week 20	12833.3 ± 4581.9	12064.8 ± 5277.3
CNP Col X BM: Change from baseline to Week 20	2928.0 ± 4385.9	2435.5 ± 4666.9
CNP Col X BM: Week 39	12249.7 ± 5056.5	9932.7 ± 4004.4
CNP Col X BM: Change from baseline to Week 39	2362.8 ± 5752.9	946.4 ± 3490.1

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Up to Week 56 Safety Follow-Up.

Adverse event reporting additional description

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

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

24.1

Reporting group title

Placebo

Reporting group description

Reporting group title

Vosoritide

Reporting group description

Serious adverse events	Placebo	Vosoritide
Total subjects affected by serious adverse events
subjects affected / exposed	6 / 32 (18.75%)	3 / 43 (6.98%)
number of deaths (all causes)	0	1
number of deaths resulting from adverse events	0	1
Investigations
Oxygen saturation decreased
subjects affected / exposed	0 / 32 (0.00%)	1 / 43 (2.33%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
Skull fracture
subjects affected / exposed	1 / 32 (3.13%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Petit mal epilepsy
subjects affected / exposed	1 / 32 (3.13%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
Sudden infant death syndrome
subjects affected / exposed	0 / 32 (0.00%)	1 / 43 (2.33%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Gastrointestinal disorders
Vomiting
subjects affected / exposed	1 / 32 (3.13%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Respiratory distress
subjects affected / exposed	1 / 32 (3.13%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Psychiatric disorders
Autism spectrum disorder
subjects affected / exposed	1 / 32 (3.13%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Pneumonia
subjects affected / exposed	0 / 32 (0.00%)	1 / 43 (2.33%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory syncytial virus bronchiolitis
subjects affected / exposed	0 / 32 (0.00%)	1 / 43 (2.33%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	1 / 32 (3.13%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Otitis media
subjects affected / exposed	1 / 32 (3.13%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Parainfluenzae virus infection
subjects affected / exposed	1 / 32 (3.13%)	0 / 43 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Placebo	Vosoritide
Total subjects affected by non serious adverse events
subjects affected / exposed	32 / 32 (100.00%)	43 / 43 (100.00%)
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	3 / 32 (9.38%)	7 / 43 (16.28%)
occurrences all number	5	9
Arthropod bite
subjects affected / exposed	2 / 32 (6.25%)	6 / 43 (13.95%)
occurrences all number	2	7
General disorders and administration site conditions
Injection site reaction
subjects affected / exposed	13 / 32 (40.63%)	34 / 43 (79.07%)
occurrences all number	154	3057
Injection site erythema
subjects affected / exposed	13 / 32 (40.63%)	33 / 43 (76.74%)
occurrences all number	1738	5100
Injection site swelling
subjects affected / exposed	2 / 32 (6.25%)	8 / 43 (18.60%)
occurrences all number	3	36
Injection site urticaria
subjects affected / exposed	1 / 32 (3.13%)	6 / 43 (13.95%)
occurrences all number	1	22
Injection site induration
subjects affected / exposed	0 / 32 (0.00%)	5 / 43 (11.63%)
occurrences all number	0	14
Gastrointestinal disorders
Constipation
subjects affected / exposed	2 / 32 (6.25%)	5 / 43 (11.63%)
occurrences all number	4	7
Respiratory, thoracic and mediastinal disorders
Sleep apnea syndrome
subjects affected / exposed	0 / 32 (0.00%)	3 / 43 (6.98%)
occurrences all number	0	3
Epistaxis
subjects affected / exposed	0 / 32 (0.00%)	3 / 43 (6.98%)
occurrences all number	0	3
Skin and subcutaneous tissue disorders
Dermatitis Diaper
subjects affected / exposed	1 / 32 (3.13%)	4 / 43 (9.30%)
occurrences all number	1	5
Infections and infestations
Viral Infection
subjects affected / exposed	4 / 32 (12.50%)	8 / 43 (18.60%)
occurrences all number	8	28
Lower respiratory tract infection
subjects affected / exposed	1 / 32 (3.13%)	4 / 43 (9.30%)
occurrences all number	3	4
Rhinitis
subjects affected / exposed	0 / 32 (0.00%)	4 / 43 (9.30%)
occurrences all number	0	8
Viral upper respiratory tract infection
subjects affected / exposed	0 / 32 (0.00%)	3 / 43 (6.98%)
occurrences all number	0	3

More information

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Were there any global substantial amendments to the protocol? Yes

16 Aug 2018

• The lower age range of participating participants who have a >= 6-month period of pretreatment growth assessment in 111-901 immediately before study entry was revised from >= 3 months to >= 6 months. • Language updated to state that no two sentinel participants would be dosed on the same day for any cohort. • Echocardiogram would be performed at the Week 56Safety Follow-up and Early Termination visits • Use of residual plasma samples for cGMP PD biomarker assessment in all age groups was added to procedures. • An anti-vosoritide immunogenicity assessment was added at Week 3. • Bone metabolism urine biomarkers, vosoritide pharmacodynamic urine biomarkers, and urine chemistry assessments were added at Week 39. • The sleep study scheduled at the Week 26 visit was removed. • DXA scans would no longer include tibia scans. • If the 111-901 visit at which the participant entered 111-206 and the 111-206 Screening visit were on the same day, the procedures common to both visits were performed one time only. • On days when PK samples were being drawn, ECG would be performed within a 5-minute window prior to the 30-minute PK assessment. • Exclusion criterion #6 was revised from “…as determined by the Investigator based on the following assessments…) to (…as determined by theInvestigator and informed by the following assessments…). The determination about whether presence of cervicomedullary compression is likely to require surgical intervention will be informed by physical exam, polysomnography, and MRI. • Exclusion criterion #15 was revised to include cervicomedullary decompression surgery (Cohorts 2 and 3 only). • Inclusion/exclusion criteria was added for Cohort 3 participants enrolling in the observational period. • A table of restricted medications, including growth hormone, was added. For participants enrolled in Cohort 3 (0 to < 6 months old), the collection period for all AEs was to begin after informed consent is obtained.

08 Feb 2019

The following exploratory objectives were revised to secondary objectives. • Evaluate the effect of vosoritide on growth parameters and body proportions, including change from baseline in upper:lower segment ratio • Evaluate the effect of vosoritide on sleep apnea • Evaluate the effect of vosoritide on skull and brain morphology, including foramen magnum, ventricular and brain parenchymal dimensions • Describe the incidence of surgical interventions, including cervical decompression, adenotonsellectomy, and typanostomy The secondary imaging assessment procedures, excluding the MRI assessment, were moved to the secondary safety variables section. The hip imaging assessment was removed, the X-ray assessment was modified to include long bone growth, and the DXA assessment would no longer include the forearm. Also, the paragraph discussing the possibility of non-radiological methods of assessment for participants in Cohort 3 was deleted. The screening baseline hip assessment with pelvis X-ray was removed from the Schedule of Events. Footnotes were changed to modify procedures and to add early termination visits (ETV) for anthropomorphic measurements, DXA, and X-rays.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results: A Phase 2 Randomized, Double-Blind, Placebo-Controlled Clinical Trial to Evaluate the Safety and Efficacy of BMN 111 in Infants and Young Children with Achondroplasia, Age 0 to < 60 Months

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Number of participants with adverse events (AEs) by severity grade and study drug treatment-emergent adverse events (TEAEs)

Primary: Number of participants with adverse events (AEs) by severity grade and study drug treatment-emergent adverse events (TEAEs)

Primary: Change from baseline in height Z-score at Week 52

Primary: Change from baseline in height Z-score at Week 52

Secondary: Change from baseline in height at Week 52

Secondary: Change from baseline in height at Week 52

Secondary: Change from baseline in annualized growth velocity (AGV) at Week 52

Secondary: Change from baseline in annualized growth velocity (AGV) at Week 52

Secondary: Change from baseline in upper to lower body segment ratio at Week 52

Secondary: Change from baseline in upper to lower body segment ratio at Week 52

Secondary: Change from baseline in other growth measures (upper body length, head circumference, arm span, upper arm length, lower arm length, Lower Body Length, upper leg length, knee to heel length, and tibial length) at Week 52

Secondary: Change from baseline in other growth measures (upper body length, head circumference, arm span, upper arm length, lower arm length, Lower Body Length, upper leg length, knee to heel length, and tibial length) at Week 52

Secondary: Change from baseline in other body proportion ratios (arm span to height ratio, upper arm length to lower arm [forearm] length ratio, upper leg length [thigh] to knee to heel length ratio, and upper leg length (thigh) to tibial length ratio) at Week 52

Secondary: Change from baseline in other body proportion ratios (arm span to height ratio, upper arm length to lower arm [forearm] length ratio, upper leg length [thigh] to knee to heel length ratio, and upper leg length (thigh) to tibial length ratio) at Week 52

Secondary: Change from baseline in body mass index (BMI) at Week 52

Secondary: Change from baseline in body mass index (BMI) at Week 52

Secondary: Change from baseline in BMI Z-score at Week 52

Secondary: Change from baseline in BMI Z-score at Week 52

Secondary: Change from baseline in weight Z-score at Week 52

Secondary: Change from baseline in weight Z-score at Week 52

Secondary: Change from baseline in Infant Toddler Quality of Life (ITQoL) scores at Week 52

Secondary: Change from baseline in Infant Toddler Quality of Life (ITQoL) scores at Week 52

Secondary: Change from Baseline in functional independence measure for children (WeeFIM-II) Score at Week 52

Secondary: Change from Baseline in functional independence measure for children (WeeFIM-II) Score at Week 52

Secondary: Change from baseline in Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III) scores at Week 52

Secondary: Change from baseline in Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III) scores at Week 52

Secondary: Change from Baseline in Child Behaviour Checklist (CBCL) at Week 52

Secondary: Change from Baseline in Child Behaviour Checklist (CBCL) at Week 52

Secondary: Change from baseline in bilateral X-rays of lower extremities at Wee 52

Secondary: Change from baseline in bilateral X-rays of lower extremities at Wee 52

Secondary: Change from baseline in bilateral X-rays of Left/Right Tibia bowing angle at Week 52

Secondary: Change from baseline in bilateral X-rays of Left/Right Tibia bowing angle at Week 52

Secondary: Change from baseline in bilateral X-rays of Left Femur Length (cm) to Tibia Length (cm) Ratio and Right Femur Length (cm) to Tibia Length (cm) Ratio & Right Femur Length (cm) to Tibia Length (cm) Ratio at Week 52

Secondary: Change from baseline in bilateral X-rays of Left Femur Length (cm) to Tibia Length (cm) Ratio and Right Femur Length (cm) to Tibia Length (cm) Ratio & Right Femur Length (cm) to Tibia Length (cm) Ratio at Week 52

Secondary: Change from baseline in bilateral X-rays of Left Tibia Length (cm) to Fibula Length (cm) Ratio & Right Tibia Length (cm) to Fibula Length (cm) Ratio at Week 52

Secondary: Change from baseline in bilateral X-rays of Left Tibia Length (cm) to Fibula Length (cm) Ratio & Right Tibia Length (cm) to Fibula Length (cm) Ratio at Week 52

Secondary: Change from baseline in X-ray of Lumbar spine vertebral ratios at Week 52

Secondary: Change from baseline in X-ray of Lumbar spine vertebral ratios at Week 52

Secondary: Change from baseline in X-ray of Lumbar Spine Transverse Diameter at Week 52

Secondary: Change from baseline in X-ray of Lumbar Spine Transverse Diameter at Week 52

Secondary: Change from baseline in X-ray of Lumbar Spine Sagittal Width and Week 52

Secondary: Change from baseline in X-ray of Lumbar Spine Sagittal Width and Week 52

Secondary: Change from baseline in X-ray of Lumbar Spine Angles at Week 52

Secondary: Change from baseline in X-ray of Lumbar Spine Angles at Week 52

Secondary: Changes from Baseline in X-ray of lumbar spine angle changes: Number of participants with an increase in Lumbar Spine Angle at Week 52

Secondary: Changes from Baseline in X-ray of lumbar spine angle changes: Number of participants with an increase in Lumbar Spine Angle at Week 52

Secondary: MRI Parameter: Change from baseline to Week 52 for Volume of Face, Sinus, Calvarium, Whole Brain Total Volume, Ventricles Total Volume.

Secondary: MRI Parameter: Change from baseline to Week 52 for Volume of Face, Sinus, Calvarium, Whole Brain Total Volume, Ventricles Total Volume.

Secondary: MRI Parameter: Change from baseline to Week 52 for area of Area of Foramen Magnum & Area of Spinal Cord at the Foramen Magnum Level

Secondary: MRI Parameter: Change from baseline to Week 52 for area of Area of Foramen Magnum & Area of Spinal Cord at the Foramen Magnum Level

Secondary: MRI Parameter: Change from baseline to Week 52 for Ratio of Face Volume to Calvarium, Ratio of Area of Spinal Cord to Foramen Magnum, Ratio of Face Volume to Sinus

Secondary: MRI Parameter: Change from baseline to Week 52 for Ratio of Face Volume to Calvarium, Ratio of Area of Spinal Cord to Foramen Magnum, Ratio of Face Volume to Sinus

Secondary: DEXA parameter: Change from baseline to Week 52 for Whole Body Less Head bone mineral content (BMC)

Secondary: DEXA parameter: Change from baseline to Week 52 for Whole Body Less Head bone mineral content (BMC)

Secondary: DEXA parameter: Change from baseline to Week 52 of Whole Body Less Head bone mineral density (BMD)

Secondary: DEXA parameter: Change from baseline to Week 52 of Whole Body Less Head bone mineral density (BMD)

Secondary: DEXA parameter: Change from baseline to Week 52 of Whole Body BMC

Secondary: DEXA parameter: Change from baseline to Week 52 of Whole Body BMC

Secondary: DEXA parameter: Change from baseline to Week 52 of Whole Body BMD

Secondary: DEXA parameter: Change from baseline to Week 52 of Whole Body BMD

Secondary: DEXA parameter: Change from baseline to Week 52 of Lumbar Spine BMC

Secondary: DEXA parameter: Change from baseline to Week 52 of Lumbar Spine BMC

Secondary: DEXA parameter: Change from baseline to Week 52 of Lumbar Spine BMD

Secondary: DEXA parameter: Change from baseline to Week 52 of Lumbar Spine BMD

Secondary: Change from baseline to Week 52 in whole body BMD Z-score

Secondary: Change from baseline to Week 52 in whole body BMD Z-score

Secondary: Change from baseline to Week 52 in Lumbar Spine BMD Z-Score

Secondary: Change from baseline to Week 52 in Lumbar Spine BMD Z-Score

Secondary: Immunogenicity: Number of participants with Incidence of Antibody Positivity at Scheduled Visits

Secondary: Immunogenicity: Number of participants with Incidence of Antibody Positivity at Scheduled Visits

Clinical Trial Results:
A Phase 2 Randomized, Double-Blind, Placebo-Controlled Clinical Trial to Evaluate the Safety and Efficacy of BMN 111 in Infants and Young Children with Achondroplasia, Age 0 to < 60 Months