Public Disclosure Synopsis
Protocol GENASG-0021-007 (A6281225) – 18 May 2016 – Final

PFIZER INC.
These results are supplied for informational purposes only.
Prescribing decisions should be made based on the approved package insert.
PROPRIETARY DRUG NAME / GENERIC DRUG NAME: Genotropin /Somatropin (PNU-180307)
PROTOCOL NO.: GENASG-0021-007 (A6281225)
PROTOCOL TITLE: Long-Term Study of PNU-180307 for Short Children Born Small
for Gestational Age (SGA) Without Epiphyseal Closure (Extension of theStudy 307-MET-0021-002)
Study Centers: Twenty (20) centers in Japan took part in the study and enrolled subjects.
Study Initiation Date and Final Completion Date: 14 October 2002 to 20 August 2015

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Phase of Development: Phase 4
Study Objectives:
Primary: The primary objective was to evaluate safety (laboratory test parameters andadverse events [AEs]) of long-term administration of somatropin until a final height wasreached in short children born small for gestational age (SGA) without epiphyseal closure.
Secondary:

To examine height velocity, height velocity Standard Deviation Score (SDS) for
chronological age, height SDS for chronological age and  height SDS for
chronological age.



To comprehensively evaluate height velocity SDS for bone age, height SDS for bone
age and  height SDS for bone age to examine the relationship between bone age andheight increase.

To examine changes in day-to-day activities of children treated with somatropin bymeans of questionnaires.

METHODS
Study Design: This study was a multi-center, long-term extension (LTE) study in subjects
who participated in the previous study (Examination of Effects on Growth Promoting and
Safety of PNU-180307 in Short Children Born Small for Gestational Age Without
Epiphyseal Closing). During this LTE, growth hormone therapy was approved for theindication of short stature due to SGA; therefore, this study continued as a post-marketingclinical study after approval. After entering this study, subjects who had been treated with
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Public Disclosure Synopsis
Protocol GENASG-0021-007 (A6281225) – 18 May 2016 – Finalsomatropin 0.033 mg/kg/day in the previous study received a dose of 0.067 mg/kg/day as the‘dose-increasing’ group. However, if any AE occurred and the dose increase was not welltolerated, the dose could be reduced to 0.033 mg/kg/day.
Subjects in the 0.067 mg/kg/day dose group in previous study were maintained on the same
dose as the ‘dose-remaining’ group.

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The schedule of activities is presented in Table 1.

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Protocol GENASG-0021-007 (A6281225) – 18 May 2016 – Final

Table 1.

Schedule of Activities

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Observation Time Point
Observation Item

Time window (day)a
Informed consent
Inclusion/exclusion
criteria
Height/body weight
Physical changes(secondary sex
characteristics etc)
Bone age (left-hand X-P)
Questionnaires (APSASS)
Questionnaires at the End
of Treatment (or at thetime of discontinuation)
IGF-I
Change in treatment(injection)compliance/injection site
Concomitanttherapy/medication
Laboratoryb
Anti-GH antibody
Pregnancy test
Oral glucose tolerance test
Adverse events

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During the Period of the StudyAt the End of
At the time of
the Study/
Proceeding to
Discontinuation
thePost-Marketing
Study

At the Start
of
Treatment(12 Months
After theStart of thePrevious
Study)X
X

Every
3 MonthsofTreatment

Every
12 MonthsofTreatment

14

14

-

X
X

X
X

X
X
X
X

X
X

Every
6 Months
After theStart ofthe Study

Every
12 Months
After theStart ofthe Study

At the End of
the Study/
Discontinuation

14
X
X

14

14

-

X
X

X
X

X
X

X
X

X
X

X
X
X

X
X

X

X
X

X
X

X
X

X
X

X
X

X
X

X
X

X
X

X
X

X

X

X

X

X

X

X

X

X
X
X
X
X

X

X
X

X
X

X
X

X
X

X

X
X

X
X

X
X

X
X
X
X
X

X
X

Page 3

X

X

Public Disclosure Synopsis
Protocol GENASG-0021-007 (A6281225) – 18 May 2016 – Final

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Table 1.

Schedule of Activities

The specified test day was based on the start day of treatment, namely Day 0 in this study.
Every 6 months: height/body weight, physical changes (secondary sex characteristics etc), IGF-I, laboratory tests, and concomitant therapy/medication.
Every 12 months: bone age (left-hand X-P), anti-GH antibody and pregnancy test (for a woman of childbearing potential).
During the treatment period: change in the treatment (injection) compliance/injection site, concomitant therapy/medication, and adverse events.
APSASS = Assessment of Psycho-Social Activities on Short Stature; IGF-I = insulin-like growth factor I; GH = growth hormone.
a. The time window was expressed as the difference from the specified test day. Observations/examinations immediately before the start of treatment was tobe performed on the start day of treatment as much as possible.
b. Among laboratory tests, follicle stimulating hormone was measured for female subjects only, and androgenic hormone was measured for male subjects only.

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Protocol GENASG-0021-007 (A6281225) – 18 May 2016 – Final

Number of Subjects (Planned and Analyzed): Target sample size was not determined as
this was an extension study. Sixty-two (62) subjects (29 subjects in the dose-increasinggroup and 33 subjects in the dose-remaining group) were enrolled in the study.
Diagnosis and Main Criteria for Inclusion and Exclusion: Children with short stature due
to SGA who had completed the 1-year treatment in the previous study and who were deemed
eligible for enrolment by the Investigators.
Exclusion Criteria: Subjects who had any chronic disease requiring treatment with steroid
hormone that could affect growth promotion including estrogen, androgen, anabolic
hormone, and corticosteroids (except those for external use), and who received the treatment;
received radiotherapy or chemotherapy; had serious cardiac disease, renal disease, or hepaticdisease; had diabetes mellitus with a manifestation of abnormal glucose metabolism; hadserious chronic disease; had a malignant tumor; or were allergic to m-cresol were excluded
from the study.

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Subjects who had achieved a height SDS for chronological age of 0; experienced puberty,
and showed height velocity of <2 cm/year; reached bone age of 17 years for male subjects
and 15 years for female subjects were also excluded from the study.
Study Treatment: Somatropin 5.3 mg or somatropin 12 mg for two-chamber cartridge (TC)injection (marketed formula) were supplied by the Sponsor. Somatropin 5.3 mg andsomatropin 12 mg for TC injection both contained, in a 2-compartment cartridge, thelyophilized and sterilized recombinant somatropin powder and a diluent.
Subjects received a dose corresponding to their body weight once daily before bedtime.
Somatropin was administered to either buttock (the study drug could be injected into thefemoral region) using a special injection device. The administered dose was adjusted
according to body weight, which was measured at each hospital visit.
Somatropin was administered at a dose of 0.067 mg/kg/day or 0.033 mg/kg/day. As theJapanese guideline for growth hormone (GH) treatment recommends a dose of
0.033 mg/kg/day, the dose could be changed to 0.033 mg/kg/day depending on age, puberty,
growth rate, and safety.
The study treatment was to be stopped if either of the following items applied:

If the height SDS for chronological age achieved 0 during the treatment period.



If height velocity for chronological age was <1 cm/year.



If the period of maximum growth during puberty ends, and height velocity decreases to<2 cm/year.



If the subject has reached bone age of 17 years for male subjects and 15 years for female
subjects.

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Protocol GENASG-0021-007 (A6281225) – 18 May 2016 – Final

Efficacy and Safety Endpoints:
Primary Endpoint: Laboratory test abnormalities and AEs.

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Secondary Endpoints:


Height velocity SDS for chronological age,Height velocity,

Height SDS for chronological age,Height velocity SDS for bone age,Height SDS for bone age.

Safety Evaluations: AEs were recorded from when subjects received at least 1 dose of thestudy drug until the last visit. Serious adverse events (SAEs) were reported from the time ofobtaining informed consent through 28 days after the last administration of the study drug.
Laboratory tests were performed every 3 months before the entry into the post-marketing
study, at the entry into the post-marketing study, and every 6 months starting from theinitiation of the this study and at the completion of the study drug (discontinuation) after theentry into the post-marketing study (for anti-human GH antibody, every 12 months, at theentry into the post-marketing study, and at the completion of the study drug
[discontinuation]). Changes in injection site were examined at each visit and the results wererecorded. Bone age was evaluated based on radiographs of carpal bones in the left hand
performed every 12 months, at the entry into the post-marketing study, and at the completionof the study drug (discontinuation). Oral glucose tolerance test (OGTT) was performed
every 12 months before the entry into the post-marketing study, at the entry into thepost-marketing study, and at the completion of the study drug (discontinuation).
Statistical Methods: The full analysis set (FAS) was comprised of subjects who met theinclusion/exclusion criteria and were enrolled in the study except for subjects who were
never given any administration of study medication after enrollment and who had no study
assessment data after enrollment. Efficacy and safety analyses were performed on the FAS.
Summary statistics were calculated by treatment group in observed values at the start oftreatment in the previous study and at the evaluation time points, and in their changes fromthe start of treatment for the efficacy parameters.
Shift tables were prepared for scores in each Assessment of Psycho-Social Activities on
Short Stature (APSASS) questionnaire item at the start of treatment in the previous study andat the evaluation time points every 12 months of treatment. In addition, changes (improved,
unchanged, worsened, and other) in scores in each APSASS item at the evaluation time
points every 12 months of treatment from the start of treatment in the previous study weretabulated.

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Protocol GENASG-0021-007 (A6281225) – 18 May 2016 – Final

Safety Analysis: The incidence of AEs by treatment group was tabulated by system organclass and by preferred term of the World Health Organization (WHO) Adverse Reaction
Terminology (ART), the glossary for WHO adverse reaction reporting system. In addition,
the incidence of abnormal changes in laboratory tests was tabulated by treatment group.
Changes in injection site and bone age were listed by treatment group. Shift tables wereprepared by treatment group for OGTT results at the start of treatment in the previous study
and at the evaluation time points every 12 months of treatment up to entry into thepost-marketing study.
RESULTS

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Subject Disposition and Demography: Sixty-two (62) subjects (29 subjects in thedose-increasing group and 33 subjects in the dose-remaining group) were enrolled. One (1)subject in the dose-remaining group did not receive study drug during the study period,
therefore, 61 subjects were analyzed for efficacy and safety as the FAS. One (1) subject who
received the 0.033 mg/kg/day dose in the previous study was included in the dose-increasinggroup in this study. Because the Investigator considered that this subject would benefit fromthe 0.033 mg/kg/day dose, the dose was not increased in the entry.
Subject disposition is shown in Table 2. The mean duration of treatment with somatropin
including the duration of treatment in previous study (including discontinued cases) was
2612.7 days (range: 545 to 4942 days) in the dose increasing group and 2352.2 days (range:
658 to 4469 days) in the dose-remaining group.

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Table 2.

Subject Disposition

Number of Subjects
Enrolled
TreatedCompleted until the date of marketing approval (not entered thepost-marketing study)
Completed
Reaching a height SDS for chronological age of 0 SD during
treatment
Discontinued until the date of marketing approval (not entered thepost-marketing study)
Adverse eventsProtocol deviation
Withdrawn consent
OthersEntered the post-marketing study
Completed
Reaching a height SDS for chronological age of 0 SD during
treatment
Height velocity for chronological age <1.0 cm/year
Annual height velocity <2 cm after achieving peak velocity at
puberty
Reaching a bone age of 17 years in male or 15 years in female
Discontinued
Protocol deviation
Withdrawn consent
Others
Efficacy analysis set: full analysis set
Safety analysis set: full analysis set
SD = standard deviation; SDS = standard deviation score.

The discontinuations from this study is presented in Table 3.

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Page 80.033/0.067 mg
29
29
50.067/0.067 mg
33
32
5

2
3

0
5

8

12

0
0
8
0
16
10
2

1
1
8
2
15
10
0

0
0

1
1

8
6
1
3
2
29
29

8
5
0
2
3
32
32

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Protocol GENASG-0021-007 (A6281225) – 18 May 2016 – Final

Table 3.

Discontinuations From the Study

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Number of Subjects
Clinical trial:
Subject died
Discontinuations
Relation to study drug not definedProtocol violation
No longer willing to participate in study
Lost to follow-up
Other
Related to study drug
Adverse event
Not related to study drug
Adverse event
Transition to post-marketing clinical trial:
Subject died
Discontinuations
Relation to study drug not definedProtocol violation
No longer willing to participate in study
Lost to follow-up
Other
Related to study drug
Adverse event
Not related to study drug
Adverse event
Safety analysis set was used.

0.033/0.067 mg
29

0.067/0.067 mg
32

Total
61

0

0

0

8 (27.6)08 (27.6)
0
0
0
0
0
0

11 (34.4)
1 (3.1)8 (25.0)02 (6.3)1 (3.1)1 (3.1)00

19 (31.1)
1 (1.6)16 (26.2)
02 (3.3)
1 (1.6)
1 (1.6)
0
0

0

0

0

6 (20.7)
1 (3.4)3 (10.3)
02 (6.9)0000

5 (15.6)02 (6.3)0
3 (9.4)00
00

11 (18.0)
1 (1.6)5 (8.2)05 (8.2)00
00The dose-increasing group consisted of 15 males and 14 females, and the dose-remaining
group consisted of 18 males and 14 females. The sex ratio was similar between these groups.
The mean age at the start of treatment in previous study was 5.20 years in the dose-increasinggroup and 5.4 years in the dose-remaining group. The demographic characteristics arepresented in Table 4.
The mean height velocity SDS for chronological age at the start of treatment in previous
study was −1.866 standard deviation (SD) in the dose-increasing group and −1.450 SD in thedose-remaining group. The mean height SDS for chronological age at the start of treatmentin previous study was −3.14 SD in the dose-increasing group and −3.09 SD in thedose-remaining group. There was no obvious imbalance between the treatment groups
regarding those values.
Table 4.

Demographic Characteristics – All Subjects

Number of Subjects
Age (SD)
GenderFemaleMale
SD = standard deviation.

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0.033/0.067 mg
29
5.20 (1.64)
01415Page 90.067/0.067 mg
32
5.40 (1.27)
0
14
18

Total
61
5.31 (1.45)
028
33

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Protocol GENASG-0021-007 (A6281225) – 18 May 2016 – Final

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Efficacy Results: In the dose-increasing group, the mean height velocity SDS for
chronological age from Month 12 to Month 24 indicated that the growth-promoting effectwas similar to that observed from Month 0 to Month 12. In the dose-remaining group, themean height velocity SDS for chronological age from Month 12 to Month 24 indicated thatthe growth-promoting effect was similar to that observed in the dose-increasing group fromMonth 0 to Month 12 and from Month 12 to Month 24. From Month 24, the mean height
velocity SDS for chronological age decreased gradually in both groups up until Month 72 toMonth 84, remaining at positive values up until Month 36 to Month 48 in the dose-increasinggroup and Month 48 to Month 60 in the dose-remaining group. From Month 84, when
numbers of evaluable subjects fell by half or less in both groups, the mean height velocity
SDS for chronological age showed a leveling-off or slightly increasing trend. Throughout
the entire study period, the mean change from the start of treatment in height velocity SDS
for chronological age was positive (Table 5).

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Table 5.

Height Velocity SDS for Chronological Age and Change Over Time (SD)Start ofTreatment(Previous
Study)
Mean  SD(n)−1.8661.221(29)―

MonthsMonthsMonths0 to 1212 to 24
24 to 36
(Previous(Current(Current
Study)
Study)
Study)
Mean  SD
Mean  SD
Mean  SD
(n)
(n)
(n)
0.033/0.067 mg
Score
2.5201.790
2.7821.978
1.8121.526
(29)
(28)
(26)
Change4.3831.992
4.6472.029
3.7581.710
(29)
(28)
(26)
0.067/0.067 mg
Score−1.4501.600
4.7682.056
2.5951.731
1.6962.111
(32)
(32)
(32)
(28)
Change―6.2182.193
4.0462.015
3.2202.356
(32)
(32)
(28)
MonthsMonthsMonthsMonths72 to 84
84 to 96
96 to 108108 to 120(Current(Current(Current(Current
Study)
Study)
Study)
Study)
Mean  SD
Mean  SD
Mean  SD
Mean  SD
(n)
(n)
(n)
(n)
0.033/0.067 mg
Score−0.4883.117
0.2631.802
0.5212.058−0.6682.126
(15)
(11)
(9)
(6)
Change2.0033.738
2.7302.204
3.1041.749
1.8922.106
(15)
(11)
(9)
(6)
0.067/0.067 mg
Score−1.5112.692−0.1141.964−0.4662.055−0.5902.693
(16)
(14)
(8)
(6)
Change0.1893.147
1.8043.107
1.0292.511
1.0222.469
(16)
(14)
(8)
(6)
― = not applicable; n = number of subjects; SD = standard deviation; SDS = standard deviation score.

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Page 11Months36 to 48
(Current
Study)
Mean  SD(n)1.4801.543(24)
3.4381.926(24)
0.8241.527(23)
2.2761.650(23)Months
120 to 132(Current
Study)
Mean  SD(n)1.0801.953(5)
1.4382.425(5)1.1733.042(4)2.6452.372(4)Months48 to 60
(Current
Study)
Mean  SD(n)−0.0412.081(21)
2.0722.111(21)0.4801.651(20)
1.9952.257(20)Months
132 to 144(Current
Study
Mean  SD(n))
2.6554.329(4)5.3904.332(4)0.7302.022(2)2.2150.757(2)Months60 to 72
(Current
Study)
Mean  SD(n)−0.2931.585(20)
1.8871.779(20)−0.0462.434(16)
1.6512.862(16)Months
144 to 156(Current
Study)
Mean  SD(n)3.3731.995(3)
6.7072.188(3)――

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Protocol GENASG-0021-007 (A6281225) – 18 May 2016 – Final

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In both groups, the mean height velocity peaked between Month 0 and Month 12, thereafter
decreased and remained constant from Month 24 to Month 72. The mean height velocity
further decreased from Month 72 to Month 84, and thereafter remained constant (Table 6).

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Table 6.

Height Velocity and Change Over Time (cm/year)
Start ofTreatment(Previous
Study)
Mean  SD(n)
5.360.99(29)―Months0 to 12(Previous
Study)
Mean  SD(n)0.033/0.067 mg
Score
8.091.27(29)
Change2.751.51(29)
0.067/0.067 mg
Score
5.451.21
9.721.45(32)(32)
Change―4.281.61(32)
MonthsMonths72 to 84
84 to 96
(Current(Current
Study)
Study)
Mean  SD
Mean  SD(n)(n)
0.033/0.067 mg
Score
4.892.18
5.161.20(15)(11)
Change−0.192.58−0.111.23
(15)
(11)
0.067/0.067 mg
Score
4.881.86
4.822.12(16)(14)
Change−0.452.28−0.382.36
(16)
(14)
― = not applicable; n = number of subjects; SD = standard deviation.

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Months12 to 24(Current
Study)
Mean  SD(n)
7.831.33(28)
2.491.50(28)
7.701.19(32)
2.261.43(32)
Months96 to 108
(Current
Study)
Mean  SD(n)
5.182.16(9)−0.091.95(9)
5.552.42(8)−0.212.17(8)Page 13Months24 to 36
(Current
Study)
Mean  SD(n)
6.880.94(26)
1.591.31(26)
6.751.52(28)
1.351.63(28)
Months108 to 120(Current
Study)
Mean  SD(n)
5.722.24(6)
0.102.24(6)
5.031.86(6)−0.931.92(6)

Months36 to 48
(Current
Study)
Mean  SD(n)
6.680.98(24)
1.441.51(24)
6.081.14(23)
0.641.20(23)
Months
120 to 132(Current
Study)
Mean  SD(n)
4.841.30(5)−0.942.15(5)
4.301.84(4)−1.751.86(4)Months48 to 60
(Current
Study)
Mean  SD(n)
6.061.49(21)
0.911.84(21)
6.301.24(20)
0.911.70(20)Months
132 to 144(Current
Study)
Mean  SD(n)
4.381.10(4)−1.252.11(4)
2.600.14(2)−3.400.28(2)Months60 to 72
(Current
Study)
Mean  SD(n)
6.081.45(20)
0.931.94(20)
6.491.37(16)
1.182.17(16)Months
144 to 156(Current
Study)
Mean  SD(n)
3.101.92(3)−2.072.51(3)――

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Protocol GENASG-0021-007 (A6281225) – 18 May 2016 – Final

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The mean height SDS for chronological age was higher up to Month 36 in thedose-remaining group than in the dose-increasing group, but, from Month 48, remained
similar between the groups. The mean height SDS for chronological age increased as thetreatment period increased up to Month 48 in the dose-increasing group and up to Month 72
in the dose-remaining group, but thereafter remained at around −1.5 SD up to Month 156 in
the dose-increasing group and up to Month 120 in the dose-remaining group. The meanheight SDS for chronological age exceeded −2.0 SD at Month 36 in the dose-increasinggroup and at Month 24 in the dose-remaining group (Table 7). Throughout the entire study
period, the mean changes from the start of treatment in height SDS for chronological age ateach observation time point were 0.60 SD to 2.50 SD in both groups.

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Table 7.

Height SDS for Chronological Age and Change Over Time (SD)Month 36
(Current
Study)
Mean  SD(n)

Month 48
(Current
Study)
Mean  SD(n)

Month 60
(Current
Study)
Mean  SD(n)

Month 72
(Current
Study)
Mean  SD(n)−2.530.92−2.020.97−1.800.99
(29)
(28)
(26)
Change0.600.29
1.110.40
1.370.48
(29)
(28)
(26)
0.067/0.067 mg
Score−3.090.83−2.170.96−1.701.03−1.531.10
(32)
(32)
(32)
(28)
Change―0.930.34
1.400.44
1.650.54
(32)
(32)
(28)
Month 84
Month 96
Month 108Month 120
(Current(Current(Current(Current
Study)
Study)
Study)
Study)
Mean  SD
Mean  SD
Mean  SD
Mean  SD
(n)
(n)
(n)
(n)
0.033/0.067 mg
Score−1.731.13−1.520.89−1.521.01−1.521.20
(15)
(11)
(9)
(6)
Change1.780.87
1.990.46
2.010.63
1.830.89
(15)
(11)
(9)
(6)
0.067/0.067 mg
Score−1.581.17−1.871.36−1.631.48−1.250.59
(16)
(14)
(8)
(6)
Change1.910.57
1.730.81
2.010.92
2.250.45
(16)
(14)
(8)
(6)
― = not applicable; n = number of subjects; SD = standard deviation; SDS = standard deviation score.

−1.481.05(24)
1.700.56(24)−1.491.15(23)
1.820.58(23)Month 132
(Current
Study)
Mean  SD(n)−1.961.11(5)
1.480.82(5)−0.980.51(4)
2.280.32(4)−1.531.06(21)
1.790.66(21)−1.441.10(20)
1.910.51(20)Month 144
(Current
Study)
Mean  SD(n)−1.730.87(4)
1.630.73(4)−0.700.42(2)
2.500.14(2)−1.561.11(20)
1.800.72(20)−1.431.06(16)
2.060.44(16)Month 156
(Current
Study)
Mean  SD(n)−1.770.76(3)
1.730.67(3)―

0.033/0.067 mg

Template version 1.5

Score

Start ofTreatment(Previous
Study)
Mean  SD(n)−3.140.76(29)―Month 12(Previous
Study)
Mean  SD(n)

Month 24(Current
Study)
Mean  SD(n)

Page 15―

Public Disclosure Synopsis
Protocol GENASG-0021-007 (A6281225) – 18 May 2016 – Final

090177e1880f3310\Approved\Approved On: 23-May-2016 01:31

The mean height velocity SDS for bone age was generally similar to the mean height velocity
SDS for chronological age up until Month 48 to Month 60 in both groups. Thereafter, themean height velocity SDS for bone age was slightly higher than the mean height velocity
SDS for chronological age in both groups, except from Month 72 to Month 84, fromMonth 96 to Month 108 and after Month 132 in the dose-increasing group (Table 8).

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Public Disclosure Synopsis
Protocol GENASG-0021-007 (A6281225) – 18 May 2016 – Final

090177e1880f3310\Approved\Approved On: 23-May-2016 01:31

Table 8.

Height Velocity SDS for Bone Age and Change Over Time (SD)Start ofTreatment(Previous
Study)
Mean  SD(n)−1.8361.386(27)―MonthsMonthsMonths0 to 1212 to 24
24 to 36
(Previous(Current(Current
Study)
Study)
Study)
Mean  SD
Mean  SD
Mean  SD
(n)
(n)
(n)
0.033/0.067 mg
Score
2.1052.066
2.5862.268
1.5031.830
(27)
(26)
(24)
Change3.9412.089
4.4312.144
3.4301.687
(27)
(26)
(24)
0.067/0.067 mg
Score−1.6351.734
4.4792.190
2.4611.990
1.0911.852
(31)
(31)
(31)
(27)
Change―6.1142.159
4.0962.064
2.7451.977
(31)
(31)
(27)
MonthsMonthsMonthsMonths72 to 84
84 to 96
96 to 108108 to 120(Current(Current(Current(Current
Study)
Study)
Study)
Study)
Mean  SD
Mean  SD
Mean  SD
Mean  SD
(n)
(n)
(n)
(n)
0.033/0.067 mg
Score−1.2492.558
0.8043.440−0.6342.419−0.0704.120
(13)
(10)
(8)
(5)
Change1.4493.280
3.0473.355
1.8162.741
2.2864.650
(13)
(10)
(8)
(5)
0.067/0.067 mg
Score
0.9322.545
0.2862.351−0.2231.352
0.5321.809
(13)
(13)
(7)
(5)
Change2.9692.107
2.5402.626
1.8791.533
2.9262.486
(13)
(13)
(7)
(5)
― = not applicable; n = number of subjects; SD = standard deviation; SDS = standard deviation score.

Template version 1.5

Page 17Months36 to 48
(Current
Study)
Mean  SD(n)1.1961.409(22)
3.0901.930(22)0.5101.809(22)
2.0791.641(22)Months
120 to 132(Current
Study)
Mean  SD(n)1.5533.019(4)
3.5283.651(4)2.7180.864(4)
4.9930.740(4)Months48 to 60
(Current
Study)
Mean  SD(n)−0.0621.775(20)
1.9792.239(20)
0.9132.146(19)
2.5842.947(19)Months
132 to 144(Current
Study)
Mean  SD(n)2.3101.711(3)3.9072.034(3)2.1850.304(2)4.6301.513(2)Months60 to 72
(Current
Study)
Mean  SD(n)0.2812.814(16)
2.2093.172(16)
0.9492.729(14)
3.1013.442(14)Months
144 to 156(Current
Study)
Mean  SD(n)2.7102.942(2)5.0803.776(2)――

Public Disclosure Synopsis
Protocol GENASG-0021-007 (A6281225) – 18 May 2016 – Final

090177e1880f3310\Approved\Approved On: 23-May-2016 01:31

The mean height SDS for bone age was slightly higher than the mean height SDS for
chronological age up to Month 60 in the dose-increasing group and up to Month 48 in thedose-remaining group. Thereafter, the mean height SDS for bone age was slightly lower thanthe mean height SDS for chronological age in both groups, except at Month 108 and afterMonth 144 in the dose-increasing group and at Month 144 in the dose-remaining group.
Throughout the entire study period, the mean changes from the start of treatment in heightSDS for bone age at each observation time point ranged between 0.10 SD to 1.60 SD in bothgroups (Table 9).

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Public Disclosure Synopsis
Protocol GENASG-0021-007 (A6281225) – 18 May 2016 – Final

090177e1880f3310\Approved\Approved On: 23-May-2016 01:31

Table 9.

Height SDS for Bone Age and Change Over Time (SD)Month 36
(Current
Study)
Mean  SD(n)

Month 48
(Current
Study)
Mean  SD(n)

Month 60
(Current
Study)
Mean  SD(n)

Month 72
(Current
Study)
Mean  SD(n)−1.191.20−1.151.15−1.201.35
(27)
(26)
(24)
Change1.060.96
1.041.18
1.061.08
(27)
(26)
(24)
0.067/0.067 mg
Score−2.101.20−0.681.54−0.881.79−1.171.62
(31)
(31)
(31)
(27)
Change―1.420.77
1.191.18
1.091.09
(31)
(31)
(27)
Month 84
Month 96
Month 108Month 120
(Current(Current(Current(Current
Study)
Study)
Study)
Study)
Mean  SD
Mean  SD
Mean  SD
Mean  SD
(n)
(n)
(n)
(n)
0.033/0.067 mg
Score−1.851.17−1.771.12−1.410.97−1.581.50
(13)
(10)
(8)
(5)
Change0.211.59
0.551.51
0.711.51
0.462.12
(13)
(10)
(8)
(5)
0.067/0.067 mg
Score−2.150.92−2.271.06−1.941.37−1.380.98
(13)
(13)
(7)
(5)
Change0.380.92
0.150.79
0.100.74
0.260.66
(13)
(13)
(7)
(5)
― = not applicable; n = number of subjects; SD = standard deviation; SDS = standard deviation score.

−0.741.32(22)
1.561.29(22)−1.461.01(22)
1.000.88(22)Month 132
(Current
Study)
Mean  SD(n)−2.101.21(4)
0.352.25(4)−0.980.74(4)
0.380.53(4)−1.161.21(20)
1.091.15(20)−1.800.97(19)
0.660.99(19)Month 144
(Current
Study)
Mean  SD(n)−1.400.17(3)
1.600.46(3)−0.650.64(2)
0.250.92(2)−1.781.02(16)
0.801.23(16)−1.700.77(14)
0.710.90(14)Month 156
(Current
Study)
Mean  SD(n)−1.550.92(2)
1.250.49(2)―0.033/0.067 mg

Template version 1.5

Score

Start ofTreatment(Previous
Study)
Mean  SD(n)−2.241.32(27)―

Month 12(Previous
Study)
Mean  SD(n)

Month 24(Current
Study)
Mean  SD(n)

Page 19―

Public Disclosure Synopsis
Protocol GENASG-0021-007 (A6281225) – 18 May 2016 – Final

The mean bone age increased by approximately 1 year per 12 months in both groups. The
mean ratio of bone age to chronological age remained at approximately 1 throughout the
study period in both groups, and as a whole, there was no trend indicating excessive bone
maturation.
In both groups, the mean predicted adult height SDS was higher than the mean height SDS
for chronological age, except Month 144 in the dose-remaining group, when the number of
evaluable subjects was 2, although the values remained negative.
Safety Results:

090177e1880f3310\Approved\Approved On: 23-May-2016 01:31

SAEs: All-causality SAEs were observed in 15 subjects. Treatment-related SAEs wereobserved in 1 subject in the dose-increasing group (adenoidal hypertrophy) and in 1 subject
in the dose-remaining group (tonsillar hypertrophy, adenoidal hypertrophy, and diseaseprogression). Except for these events, the causal relationship to the study drug was ruled out
for all SAEs. Treatment-emergent SAEs by system organ class, and preferred term(all-causality) are presented in Table 10.

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Public Disclosure Synopsis
Protocol GENASG-0021-007 (A6281225) – 18 May 2016 – Final

090177e1880f3310\Approved\Approved On: 23-May-2016 01:31

Table 10. Treatment-Emergent Serious Adverse Events by System Organ Class, and Preferred Term (All-Causality)
Number (%) of Subjects With Adverse Events by:
System Organ Class and
WHOART Preferred Term
Evaluable for adverse events
With adverse events
Vision disorders
Retinal detachment
Hearing and vestibular disorders
Deafness
Gastro-intestinal system disorders
Gastroenteritis
Liver and biliary system disorders
Hepatic function abnormal
Endocrine disorders
Adenoid hypertrophy
Respiratory system disorders
Pharyngitis
Pneumonia
Upper respiratory tract infection
Bronchitis
AsthmaReproductive disorders, male
Hernia inguinal
Reproductive disorders, female
Ovarian disorder
Foetal disorders
Hypospadias
Cryptorchism
Resistance mechanism disorders
Infection viral
Otitis media
Healing impaired
Secondary terms
Inflicted injury

Template version 1.5

0.033/0.067 mg
Number ofn (%)
Adverse Events
29
16
10 (34.5)
00
001
1 (3.4)1
1 (3.4)22 (6.9)22 (6.9)1
1 (3.4)1
1 (3.4)1
1 (3.4)1
1 (3.4)5
4 (13.8)
1
1 (3.4)1
1 (3.4)1
1 (3.4)1
1 (3.4)1
1 (3.4)1
1 (3.4)1
1 (3.4)1
1 (3.4)1
1 (3.4)22 (6.9)1
1 (3.4)1
1 (3.4)1
1 (3.4)001
1 (3.4)001
1 (3.4)1
1 (3.4)

Page 210.067/0.067 mg
Number ofn (%)
Adverse Events32
95 (15.6)
1
1 (3.1)1
1 (3.1)
0
0
0
0
0
0
0
0
0
0
0
0
2
2 (6.3)22 (6.3)22 (6.3)22 (6.3)
0
0
0
0
0
0
0
0
1
1 (3.1)1
1 (3.1)
0
0
0
0
0
0
0
0
0
0
3
3 (9.4)1
1 (3.1)1
1 (3.1)1
1 (3.1)
0
0
0
0

Total
Number ofAdverse Events
25
1
1
1
1
2
2
1
1
3
3
7
3
1
1
1
1
2
2
1
1
2
1
1
4
1
2
1
1
1

n (%)
61
15 (24.6)
1 (1.6)
1 (1.6)
1 (1.6)
1 (1.6)2 (3.3)2 (3.3)
1 (1.6)
1 (1.6)3 (4.9)3 (4.9)6 (9.8)3 (4.9)1 (1.6)
1 (1.6)
1 (1.6)
1 (1.6)2 (3.3)2 (3.3)
1 (1.6)
1 (1.6)2 (3.3)
1 (1.6)
1 (1.6)4 (6.6)
1 (1.6)2 (3.3)
1 (1.6)
1 (1.6)
1 (1.6)

Public Disclosure Synopsis
Protocol GENASG-0021-007 (A6281225) – 18 May 2016 – Final

Table 10. Treatment-Emergent Serious Adverse Events by System Organ Class, and Preferred Term (All-Causality)

090177e1880f3310\Approved\Approved On: 23-May-2016 01:31

Subjects were only counted once per treatment for each row.
Included all data collected during study.
n = number of subjects; WHOART = World Health Organization Adverse Reaction Terminology.

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Public Disclosure Synopsis
Protocol GENASG-0021-007 (A6281225) – 18 May 2016 – Final

Non-serious AEs: Table 11 presents the summary of treatment-emergent non-serious
adverse events (all-causalities) in 5% subjects.

090177e1880f3310\Approved\Approved On: 23-May-2016 01:31

The most common all-causality non-serious AEs were upper respiratory tract infection in
53 subjects (86.9%), influenza-like symptoms in 31 subjects (50.8%), otitis media in
27 subjects (44.3%), gastroenteritis in 27 subjects (44.3%), conjunctivitis in 20 subjects(32.8%), and rhinitis in 20 subjects (32.8%) based on the total of both treatment groups asshown in Table 11.

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Public Disclosure Synopsis
Protocol GENASG-0021-007 (A6281225) – 18 May 2016 – Final

090177e1880f3310\Approved\Approved On: 23-May-2016 01:31

Table 11. Treatment-Emergent Non-Serious Adverse Events (All Causality) in 5% of Subjects
Number (%) of Subjects With Adverse Events by:
System Organ Class and
WHOART Preferred Term
Evaluable for adverse events
With adverse events
Skin and appendages disorders
Acne
Dermatitis
EczemaPruritus
Rash
Rash erythematous
Rash pustular
Skin disorder
Urticaria
Dermatitis contact
Otitis externa
Bullous eruption
VerrucaMusculo-skeletal system disorders
Arthralgia
Central & peripheral nervous system disorders
Headache
Vision disorders
Conjunctivitis
Eye abnormality
MyopiaGastro-intestinal system disorders
Constipation
Diarrhoea
Vomiting
Abdominal pain
Gastroenteritis
NauseaStomatitis
Tooth caries

Template version 1.5

0.033/0.067 mg
Number ofn (%)
Adverse Events
29586
27 (93.1)
56
17 (58.6)22 (6.9)12
3 (10.3)20
6 (20.7)
00
4
3 (10.3)
22 (6.9)44 (13.8)
33 (10.3)
22 (6.9)00
3
3 (10.3)
3
2 (6.9)1
1 (3.4)4
4 (13.8)
44 (13.8)
54 (13.8)
54 (13.8)24
10 (34.5)
17
8 (27.6)
5
4 (13.8)
22 (6.9)65
22 (75.9)
53 (10.3)
5
5 (17.2)
7
5 (17.2)
0034
17 (58.6)
1
1 (3.4)6
2 (6.9)6
4 (13.8)

Page 240.067/0.067 mg
Number ofn (%)
Adverse Events
32538
31 (96.9)38
18 (56.3)
3
3 (9.4)3
2 (6.3)10
5 (15.6)22 (6.3)1
1 (3.1)1
1 (3.1)2
2 (6.3)1
1 (3.1)4
2 (6.3)22 (6.3)22 (6.3)22 (6.3)5
4 (12.5)7
5 (15.6)
7
5 (15.6)
4
3 (9.4)4
3 (9.4)24
15 (46.9)
16
12 (37.5)
85 (15.6)
0047
18 (56.3)
64 (12.5)
22 (6.3)3
3 (9.4)22 (6.3)22
10 (31.3)
2
2 (6.3)3
1 (3.1)2
2 (6.3)

Total
Number ofAdverse Events
1124
94
5
15
30
2
5
3
6
4
6
2
5
5
6
11
11
9
9
48
33
13
2
112
11
7
10
2
56
3
9
8

n (%)
61
58 (95.1)
35 (57.4)
5 (8.2)5 (8.2)
11 (18.0)
2 (3.3)4 (6.6)3 (4.9)6 (9.8)4 (6.6)4 (6.6)2 (3.3)5 (8.2)4 (6.6)5 (8.2)9 (14.8)
9 (14.8)
7 (11.5)
7 (11.5)
25 (41.0)
20 (32.8)
9 (14.8)
2 (3.3)40 (65.6)
7 (11.5)
7 (11.5)
8 (13.1)
2 (3.3)27 (44.3)
3 (4.9)3 (4.9)6 (9.8)

Public Disclosure Synopsis
Protocol GENASG-0021-007 (A6281225) – 18 May 2016 – Final

090177e1880f3310\Approved\Approved On: 23-May-2016 01:31

Table 11. Treatment-Emergent Non-Serious Adverse Events (All Causality) in 5% of Subjects
Number (%) of Subjects With Adverse Events by:
System Organ Class and
WHOART Preferred Term
Tooth disorderEnterocolitis
Liver and biliary system disorders
SGOT increased
SGPT increased
Metabolic and nutritional disorders
Glucose tolerance abnormal
Endocrine disorders
Sialoadenitis
Cardiovascular disorders, general
Hypotension postural
Respiratory system disorders
Coughing
Pharyngitis
Pneumonia
Rhinitis
Sinusitis
Upper respiratory tract infection
Bronchitis
AsthmaWhite cell and RES disorders
Eosinophilia
Leukocytosis
Lymphadenopathy
Lymphocytes atypical
Platelet, bleeding & clotting disorders
PurpuraHaematoma
Urinary system disorders
Urinary incontinence
Haematuria
Reproductive disorders, female
Ovarian disorder

Template version 1.5

0.033/0.067 mg
Number ofn (%)
Adverse Events
1
1 (3.4)00
6
3 (10.3)3
3 (10.3)3
3 (10.3)
1
1 (3.4)1
1 (3.4)3
3 (10.3)3
3 (10.3)
22 (6.9)22 (6.9)295
25 (86.2)
009
7 (24.1)
1
1 (3.4)14
8 (27.6)
6
5 (17.2)
214
25 (86.2)
31
9 (31.0)20
6 (20.7)
13
4 (13.8)
7
2 (6.9)32 (6.9)1
1 (3.4)22 (6.9)88 (27.6)6
6 (20.7)
22 (6.9)22 (6.9)22 (6.9)00
4
3 (10.3)4
3 (10.3)

Page 25

0.067/0.067 mg
Number ofn (%)
Adverse Events
3
3 (9.4)22 (6.3)2
1 (3.1)1
1 (3.1)1
1 (3.1)3
3 (9.4)3
3 (9.4)22 (6.3)22 (6.3)1
1 (3.1)1
1 (3.1)272
29 (90.6)22 (6.3)16
9 (28.1)
3
2 (6.3)29
12 (37.5)
6
4 (12.5)
157
28 (87.5)
25
10 (31.3)34
6 (18.8)129 (28.1)
4
3 (9.4)5
4 (12.5)
33 (9.4)00
8
5 (15.6)8
5 (15.6)00
6
3 (9.4)00
6
3 (9.4)
0
0
0
0

Total
Number ofAdverse Events
4
2
8
4
4
4
4
5
5
3
3
567
2
25
4
43
12
371
56
54
25
11
8
4
2
16
14
2
8
2
6
4
4

n (%)
4 (6.6)2 (3.3)4 (6.6)4 (6.6)4 (6.6)4 (6.6)4 (6.6)5 (8.2)5 (8.2)3 (4.9)3 (4.9)54 (88.5)
2 (3.3)16 (26.2)
3 (4.9)20 (32.8)
9 (14.8)
53 (86.9)
19 (31.1)
12 (19.7)
13 (21.3)
5 (8.2)6 (9.8)4 (6.6)2 (3.3)
13 (21.3)
11 (18.0)
2 (3.3)5 (8.2)2 (3.3)3 (4.9)3 (4.9)3 (4.9)Public Disclosure Synopsis
Protocol GENASG-0021-007 (A6281225) – 18 May 2016 – Final

090177e1880f3310\Approved\Approved On: 23-May-2016 01:31

Table 11. Treatment-Emergent Non-Serious Adverse Events (All Causality) in 5% of Subjects
Number (%) of Subjects With Adverse Events by:
0.033/0.067 mg
0.067/0.067 mg
Total
System Organ Class andNumber ofn (%)
Number ofn (%)
Number ofn (%)
WHOART Preferred Term
Adverse Events
Adverse Events
Adverse Events
Foetal disorders22 (6.9)33 (9.4)55 (8.2)
Skeletal malformation
00
2
2 (6.3)22 (3.3)Tooth malformation
22 (6.9)1
1 (3.1)3
3 (4.9)Body as a whole-general disorders
42
20 (69.0)
42
18 (56.3)
84
38 (62.3)
Allergic reaction00
93 (9.4)9
3 (4.9)Fever
18
11 (37.9)
3
1 (3.1)21
12 (19.7)
Pain
0
0
2
2 (6.3)22 (3.3)
Influenza-like symptoms
24
16 (55.2)
28
15 (46.9)52
31 (50.8)
Application site disorders22 (6.9)002
2 (3.3)
Injection site bleeding2
2 (6.9)002
2 (3.3)
Resistance mechanism disorders
44
16 (55.2)
47
19 (59.4)
91
35 (57.4)
Infection bacterial8
4 (13.8)96 (18.8)
17
10 (16.4)
Infection viral
22 (6.9)002
2 (3.3)
Otitis media
32
13 (44.8)
31
14 (43.8)
63
27 (44.3)
Herpes zoster
22 (6.9)4
1 (3.1)6
3 (4.9)Abscess003
2 (6.3)3
2 (3.3)
Secondary terms
7
6 (20.7)
16
11 (34.4)
23
17 (27.9)
Varicella33 (10.3)
22 (6.3)55 (8.2)
Inflicted injury
22 (6.9)5
4 (12.5)7
6 (9.8)
Molluscum contagiosum
0042 (6.3)4
2 (3.3)
Scoliosis
1
1 (3.4)22 (6.3)3
3 (4.9)Laceration
1
1 (3.4)3
3 (9.4)4
4 (6.6)
Poison specific terms
1
1 (3.4)4
4 (12.5)55 (8.2)Sting
1
1 (3.4)4
4 (12.5)55 (8.2)
Subjects were only counted once per treatment for each row.
Includes all data collected during the study.
n = number of subjects; RES = reticuloendothelial system; SGOT = Serum glutamic oxaloacetic transaminase; SGPT = serum glutamic-pyruvic transaminase;
WHOART = World Health Organization Adverse Reaction Terminology.

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Public Disclosure Synopsis
Protocol GENASG-0021-007 (A6281225) – 18 May 2016 – Final

Treatment-emergent non-serious AEs by system organ class and preferred term(treatment-related) are presented in Table 12.
Table 12. Treatment-Emergent Non-Serious Adverse Events by System Organ Classand Preferred Term (Treatment-Related) in 5% of Subjects

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Number (%) of Subjects With Adverse Events by:
0.033/0.067 mg 0.067/0.067 mg
System Organ Class and
n (%)
n (%)
WHOART Preferred Term
Evaluable for adverse events
29
32
With adverse events
5 (17.2)
5 (15.6)
Central & peripheral nervous system disorders
2 (6.9)0
Headache
2 (6.9)0Metabolic and nutritional disorders
1 (3.4)3 (9.4)
Glucose tolerance abnormal
1 (3.4)3 (9.4)
Body as a whole – general disorders
2 (6.9)2 (6.3)Fever
2 (6.9)0
Pain
0
2 (6.3)
Application site disorders
2 (6.9)0Injection site bleeding
2 (6.9)0Subjects were only counted once per treatment for each row.
Included all data collected during study.
n = number of subjects; WHOART = World Health Organization Adverse Reaction Terminology.

Total
n (%)
61
10 (16.4)
2 (3.3)2 (3.3)4 (6.6)4 (6.6)4 (6.6)2 (3.3)2 (3.3)2 (3.3)2 (3.3)

Discontinuation due to AE: AEs leading to permanent discontinuation were reported in
1 subject in the dose-increasing group (sex chromosome disorder [verbatim term: turner
syndrome]) and in 1 subject in the dose-remaining group (jaw malformation [verbatim term:
mandibular protrusion]). The event jaw malformation was considered treatment-related; both
events were mild in severity and reported to be stable although the outcome was reported as‘not resolved’. For the 1 subject who discontinued the study treatment due to sex
chromosome disorder, the event was considered to meet the specified exclusion criterion(subjects who were considered ineligible by the Investigators) and the subject was
discontinued from the study due to this protocol deviation.
Deaths: No deaths were reported during this study.
Laboratory Abnormalities: Forty-nine (49) abnormal changes in laboratory test results werereported as AEs in 23 subjects (37.7%); most of these events resolved. An increased
hemoglobin A1c (HbA1c) was reported as an AE of mild hyperglycemia in 1 subject in thedose-increasing group, but resolved. No notable changes in HbA1c levels were observed ineither group, and the levels remained generally within the reference range.
Based on OGTT, 1 subject in dose-remaining group was judged to be diabetic at Month 36,
but recovered to normal at Month 48. The evaluation at Month 72 showed borderline
diabetes for this subject.
No clinically significant changes were observed for other safety parameters, such as changes
in injection site and bone age.

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Protocol GENASG-0021-007 (A6281225) – 18 May 2016 – Final

CONCLUSIONS:
Most of the observed AEs were mild to moderate in severity. AEs leading to permanent
discontinuation were reported in 1 subject in the dose-increasing group (sex chromosome
disorder [verbatim term: turner syndrome]) and in 1 subject in the dose-remaining group (jawmalformation [verbatim term: mandibular protrusion]). The event jaw malformation wasconsidered treatment-related; both events were mild in severity and reported to be stable
although the outcome was reported as ‘not resolved’. Treatment-related SAEs were observedin 1 subject in the dose-increasing group (adenoidal hypertrophy) and in 1 subject in thedose-remaining group (tonsillar hypertrophy, adenoidal hypertrophy, and diseaseprogression). All of these treatment-related SAEs were moderate in severity and reported tohave resolved.

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No new safety concerns or information arose from this LTE study.
The mean height velocity SDS for chronological age peaked from Month 12 to Month 24 in
the dose-increasing group and from Month 0 to Month 12 in the dose-remaining group.
Although the values gradually decreased up until Month 72 to Month 84 in both groups,
positive values were maintained over a long period of time, until Month 36 to Month 48 inthe dose-increasing group and until Month 48 to Month 60 in the dose-remaining group.
From Month 84, when numbers of evaluable subjects fell by half or less in both groups, themean height velocity SDS for chronological age showed a leveling-off or slightly increasing
trend.
In both groups, the mean height velocity peaked between Month 0 and Month 12, thereafter
decreased and remained constant from Month 24 to Month 72. The mean height velocity
further decreased from Month 72 to Month 84, and thereafter remained constant.
The mean height SDS for chronological age exceeded −2.0 SD at Month 36 in thedose-increasing group and at Month 24 in the dose-remaining group. Throughout the entire
study period, the mean changes from the start of treatment in height SDS for chronologicalage at each observation time point were 0.60 SD to 2.50 SD in both groups.
The mean height velocity SDS for bone age was generally similar to the mean height velocity
SDS for chronological age up until Month 48 to Month 60 in both groups. Thereafter, themean height velocity SDS for bone age was slightly higher than the mean height velocity
SDS for chronological age in both groups, except from Month 72 to Month 84, fromMonth 96 to Month 108 and after Month 132 in the dose-increasing group.
The mean height SDS for bone age was slightly higher than the mean height SDS for
chronological age up to Month 60 in the dose-increasing group and up to Month 48 in thedose-remaining group. Thereafter, the mean height SDS for bone age tended to be slightly
lower than the mean height SDS for chronological age in both groups, except at Month 108
and after Month 144 in the dose-increasing group and at Month 144 in the dose-remaining
group. Throughout the entire study period, the mean changes from the start of treatment inheight SDS for bone age at each observation time point ranged between 0.10 SD to 1.60 SD
in both groups.

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Protocol GENASG-0021-007 (A6281225) – 18 May 2016 – Final

The mean ratio of bone age to chronological age remained at levels around 1 throughout the
study period in both groups, and as a whole, there was no trend indicating excessive bone
maturation.

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Thus, the long-term treatment data demonstrated that somatropin at a dose of
0.067 mg/kg/day was safe and the growth-promoting effect of somatropin was maintained.

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