BACKGROUND

Design

RESULTS

Demographic data

THE ENDOCRINE SOCIETY`S 97TH ANNUAL MEETING (ENDO 2015), SAN DEIGO, CALIFORNIA, MARCH 5-8, 2015 For any questions, please contact Hanmi Pharm. Co., Ltd., Rep. of Korea Jahoon Kang*, Tel: 82-2-410-9041, Email: jhkang@hanmi.co.kr Hanmi Hanmi Pharm. Co., Ltd.

FRI-444 A Novel Long Acting Growth Hormone (HM10560A) Demonstrated Good Tolerability and Weekly Potential in Healthy Male Subjects after Single Administration

Jahoon Kang1, Pankyung Kim1, Eun Hwa Kwak1, Mei-Ying Xu1, OakPil Han1, Youngmin Kim1, Yeamin Huh2, Sunny Chapel2

1 Hanmi Pharm. Co., Ltd, Seoul, South Korea, 2 Ann Arbor Pharmacometrics Group (A2PG), Inc., MI, USA

HM10560A is a long acting recombinant growth hormone (synthesized from E. coli) chemically conjugated to

N-terminus of recombinant immunoglobulin G4 Fc fragment (HMC001) by non-peptidyl linker. In non-clinical

studies, the extended half-life and efficacy of HM10560A were successfully demonstrated.

This study is a dose block-randomized, double-blind, placebo-controlled, single dosing, dose-escalation phase I

clinical trial to investigate the safety, tolerability and PK/PD of HM10560A after s.c. administration in Korean

healthy male subjects. A total of 32 subjects were enrolled and randomized to one of the 4 dose cohorts

according to dose of HM10560A by body weight (0.089 mg/kg, 0.179 mg/kg, 0.357 mg/kg, and 0.714 mg/kg). In

each dose cohort, 6 subjects to the test group and 2 subjects to the placebo group were assigned, with the mean

age of 29.84±5.46 years old and BMI of 22.88±1.67 kg/m2.

No serious adverse event related to the study drug occurred throughout the study and all of adverse events (47

cases out of 22 subjects) were mild, did not require any treatment, and spontaneously disappeared. There was

no statistically significant difference between different dose groups in terms of the frequency of the number of

subjects who experienced adverse events (p=0.767). Among total 32 cases of adverse events (68%) that were

deemed possibly related to the study drug, the most frequent adverse events were headache (4 cases) and

injection site tenderness (16 cases).

Population PK and PK/PD modeling was conducted; 1) to develop a PK model to describe the

pharmacokinetic profiles of HM10560A; 2) to relate the IGF-I-time profile to the HM10560A exposure, where

IGF-1 serves a PD marker; 3) to predict relevant HM10560A doses in adult growth hormone deficient(GHD)

patients.

The mean duration of sustaining above the baseline IGF-1 values were longer than 1 week, and the mean

serum elimination half-life of HM10560A were between 49.42 and 95.42 hr. HM10560A exhibited a higher

exposure than the proportion of dose increase in studied dose range. A population PK model with a non-linear

two compartmental disposition model with a dose-dependent dual absorption process successfully described

the concentration-time profile of HM10560A. An indirect exposure-response model with a precursor transit

compartment described the IGF-1-time profile as a function of HM10560A concentration. Using the exposure-

IGF-1 model and based on the efficacy target that duration of IGF-1 SDS between 0 and +2 of at least 60% of

the dosing interval, 0.03 mg/kg, 0.06 mg/kg and 0.09 mg/kg were recommended to explore for the next Phase II

study in adult GHD.

In conclusion, a single dose of HM10560A administered subcutaneously to healthy male volunteers was well

tolerated and safe. With current results, Phase II study has been initiated in adult GHD patients.

Longest Duration by

Monomeric form helps to reduce receptor

mediated clearance

FcRn mediated endothelium recycling /

Avoiding renal filtration

Strongest Efficacy by

Flexible linker minimizes loss of intrinsic

activity

Monomeric form helps to reduce RMC

Highest bioavailability reduces dose level

Flexible Linker

• 3.4 kDa plyehylene glycol

• Reduce Immunogenicity

• Minimized loss of activity

• No loss of FcRn binding

Aglycosylated Fc

• HMC001 (Human lgG4 Fc fragment)

• Homodimeric form with single

cysteine bridge

• Increase solubility

Dose cohort Treatment No. of subjects Treatment

1 Placebo 2 Placebo

Test drug 6 HM10560A 0.089mg/kg (0.5IU)

2 Placebo 2 Placebo

Test drug 6 HM10560A 0.179mg/kg (1.0IU)

3 Placebo 2 Placebo

Test drug 6 HM10560A 0.357mg/kg (2.0IU)

4 Placebo 2 Placebo

Test drug 6 HM10560A 0.714mg/kg (4.0IU)

Methodology A total of 32 healthy male volunteers were enrolled and received either HM10560A or placebo. In

each dose level (4 dose cohorts in total), 8 subjects (6 subjects to the test group and 2 subjects to

the placebo group) were assigned.

Objectives 1) To assess the safety and tolerability of a single dose of HM10560A in humans

2) To assess the pharmacokinetics and pharmacodynamics of HM10560A in humans

Safety and adverse events (AEs)

Monte Carlo simulations using the age and gender specific conversion of IGF-I to IGFI-SDS

published by Elmlinger et al. [1].

Dosing HM10560A every 7 days in females/males – based on healthy volunteer PKPD model

The Monte Carlo simulation predicted the fraction of patients achieving both the safety and

efficacy target. Across the various age groups for females and males, doses of 0.02, 0.04, 0.06,

and 0.08 mg/kg/week of HM10560A given every 7 days had the best combination of achieving

the safety and efficacy targets. Therefore dose range of 0.04 to 0.12 mg/kg/week HM10560A will

be assessed in the single dose PK/PD run-in period in the present phase II study.

[1] Elmlinger MW et al. Clin Chem Lab Med 2004;42:654-64.

• A single dose of HM10560A administered subcutaneously to healthy male volunteers was well tolerated and safe.

• The mean duration of sustaining above the baseline IGF-1 values are longer than 1 week at all dose, and T1/2 of HM10560A are between 49 hr and 95 hr, demonstrating that

long –acting HM10560A is suitable for weekly regimen.

• The Monte Carlo simulation predicted the fraction of patients achieving both the safety and efficacy target. Based on simulation results in healthy subjects and updated with

results in 9 adult GHD patients, 0.03 mg/kg ~ 0.12 mg/kg weekly or biweekly dose/regimen is used in the present phase II study.

Parameter Placebo

N=8

0.5 IU/kg

N=6

1.0 IU/kg

N=6

2.0 IU/kg

N=6

4.0 IU/kg

N=6

HM10560A

Cmax, ng/mL 37 (20) 40 (19) 292 (175) 944 (244)

Tmax, hr 9 (2) 17 (9) 24 (9) 27 (8)

AUClast,

hr·ng/mL 1,521 (528) 2,824 (694) 16,648 (8815) 53,152 (25872)

T1/2, hr 49 (12) 80 (33) 56 (15) 95 (44)

IGF-1

Cmax, ng/mL 213 (29) 340 (78) 459 (119) 495 (106) 788 (160)

Tmax, hr 34 (14) 39 (8) 57 (31) 78 (27) 88 (20)

AUClast,

hr·ng/mL 113,869 (9,905) 139,473 (23,053) 197,191 (60,673) 157,187 (30,503) 227,982 (63,006)

IGF-1 change from

baseline

Cmax, ng/mL 30 (21) 152 (53) 222 (48) 353 (94) 591 (125)

AUClast,

hr·ng/mL -831 (3,569) 20,562 (10,896) 35983 (7162) 60,838 (20718) 934,677 (25,623)

Duration (hr) of sustaining above the baseline IGF-1 values

of each treatment (Mean/SD) 204.6 (172) 444.1 (210.5) 572.2 (175.8) 504.5 (183.9)

Pharmacokinetics/Pharmacodynamics (PK/PD) and Monte Carlo simulations to select doses for the phase II study in healthy male subjects

Pharmacokinetics/Pharmacodynamics (PK/PD) and Monte Carlo simulations to select doses for the phase II study in adults growth hormone deficiency subjects (AGHD)

Ser

um

HM

105

60

A c

on

cen

tra

tio

n (

ng

/mL

)

Time (hr)

Ser

um

IG

F-1

co

nce

ntr

ati

on

(n

g/m

L)

Time (hr)

Ser

um

HM

10

56

0A

co

nce

ntr

ati

on

(n

g/m

L)

Ser

um

IG

F-1

co

nce

ntr

ati

on

(n

g/m

L)

Single injection in 9 AGHD subjects

Parameter 0.04 mg/kg

N=3

0.08 mg/kg

N=3

0.12 mg/kg

N=3

HM10560A

Cmax, ng/mL 4 (3) 35 (25) 38 (12)

Tmax, hr 6 (2) 16 (18) 8 (1)

AUClast, hr·ng/mL 361 (351) 1624 (839) 1836 (634)

IGF-1

Cmax, ng/mL 96 (59) 174 (17) 187 (82)

Tmax, hr 121 (84) 48 (21) 52 (19)

AUClast, hr·ng/mL 42,051 (29,848) 66,703 (11,114) 60,749 (36,505)

Growth hormone (GH) is a protein consisting of 191 amino acids, and is produced from an anterior pituitary.

Growth hormone plays an important role in stimulating vertical body growth and has a significant effect on

protein, lipid and carbohydrate metabolism. Since the introduction of recombinant human growth hormone in

the market in 1985, growth hormone has been widely used in the treatment of children with short stature due

to growth hormone deficiency, Turner’s syndrome, or chronic renal failure and adults with growth hormone

deficiency. Many of recombinant human growth hormone products that are currently available have a short

half-life and therefore require a subcutaneous administration once daily. In previous studies, it was suggested

that such inconvenience contributed to decreased treatment compliance in at least 50% of patients receiving

growth hormone therapy.

HM10560A is a recombinant growth hormone (synthesized from E. coli) chemically conjugated to N-terminus

of recombinant immunoglobulin G4 Fc fragment (HMC001) by non-peptidyl linker. HMC001, one of the most

common proteins in the body, stays in the body for several weeks without expressing a particular function,

except that it stabilizes growth hormone, and extends the half-life of growth hormone, therefore extending its

effectiveness.

ABSTRACT

Parameter

Mean(SD)

Placebo

N=8

0.5 IU/kg

N=6

1.0 IU/kg

N=6

2.0 IU/kg

N=6

4.0 IU/kg

N=6

Total

N=32

Age (years) 27.13 (2.59) 32.83 (9.11) 25.83 (3.55) 27.50 (5.47) 26.17 (3.31) 27.84 (5.46)

Height (cm) 175.16 (4.40) 170.72 (4.03) 178.07 (7.17) 173.90 (4.04) 172.92 (6.45) 174.22 (5.52)

Weight (kg) 70.64 (7.71) 66.10 (5.60) 77.82 (4.87) 66.10 (2.27) 66.83 (7.27) 69.57 (7.16)

BMI (kg/m2) 23.01 (2.06) 22.67 (1.62) 24.53 (0.96) 21.85 (0.72) 22.30 (1.51) 22.88 (1.67)

N (%) Placebo

N=8

0.5 IU/kg

N=6

1.0 IU/kg

N=6

2.0 IU/kg

N=6

4.0 IU/kg

N=6

Total

N=32

Any TEAEs 5 (62.5%) 3 (50.0%) 4 (66.7%) 4 (66.7%) 4 (66.7%) 20 (62.5%)

TEAEs by Severity

Mild 4 (50.0%) 3 (50.0%) 4 (66.7%) 4 (66.7%) 3 (50.0%) 18 (56.3%)

Moderate 0 0 0 0 1 (16.7%) 1 ( 3.1%)

Severe 1 (12.5%) 0 0 0 0 1 ( 3.1%)

Any Serious TEAEs (SAE) 0 0 1* (16.7%) 0 0 1 (3.1%)

Any TEAEs Related to study drug 3 (37.5%) 2 (33.3%) 2 (33.3%) 2 (33.3%) 4 (66.7%) 13 (40.6%)

Injection Site Tenderness 1 (12.5%) 0 1 (16.7%) 1 (16.7%) 4 (66.7%) 7 (21.9%)

Upper Respiratory Tract Infection 1 (12.5%) 2 (33.3%) 2 (33.3%) 0 0 5 (15.6%)

Headache 0 1 (16.7%) 1 (16.7%) 0 2 (33.3%) 4 (12.5%)

The most frequently reported AEs

* GHA 308: The subject had multiple injuries from a car crush while riding a motorcycle. A week of hospitalization was required in

the aftermath of the accident. This was determined to be definitely not related to study drug.

Time (hr)

Sc r e en

ing

-4 -

0H

0.5

- 1

.5H

2 -

4H

7 -

12H

16 -

30H

36 -

60H

72 -

100H

120 -

150H

200 -

250H

400 -

450H

600 -

672H

-6

-4

-2

0

2

4

IG

F-1

S

DS

le

ve

l

0 .0 4 m g /k g (N = 3 )

0 .0 8 m g /k g (N = 3 )

0 .1 2 m g /k g (N = 3 )

0.04 mg/kg (N=3)

0.08 mg/kg (N=3)

0.12 mg/kg (N=3)

0

10

20

30

40

50

60

70

0 48 96 144 192 240 288 336

0

50

100

150

200

250

300

0 48 96 144 192 240 288 336

0 4 8 9 6 1 4 4 1 9 2 2 4 0 2 8 8 3 3 6

0

2 0 0

4 0 0

6 0 0

8 0 0

1 0 0 0P la c e b o

0 .5 I U /K g (0 .0 8 9 m g /k g )

1 I U /K g (0 .1 7 9 m g /k g )

2 I U /K g (0 .3 5 7 m g /k g )

4 I U /K g (0 .7 1 4 m g /k g )

0 4 8 9 6 1 4 4 1 9 2 2 4 0 2 8 8 3 3 6

0 .1

1

1 0

1 0 0

1 0 0 0

1 0 0 0 0P la c e b o

0 .5 I U /K g (0 .0 8 9 m g /k g )

1 I U /K g (0 .1 7 9 m g /k g )

2 I U /K g (0 .3 5 7 m g /k g )

4 I U /K g (0 .7 1 4 m g /k g )

0 4 8 9 6 1 4 4 1 9 2 2 4 0 2 8 8 3 3 6

0

2 0 0

4 0 0

6 0 0

8 0 0

1 0 0 0P la c e b o

0 .5 I U /K g (0 .0 8 9 m g /k g )

1 I U /K g (0 .1 7 9 m g /k g )

2 I U /K g (0 .3 5 7 m g /k g )

4 I U /K g (0 .7 1 4 m g /k g )

Sc r e en

ing

-4 -

0H

0.5

- 1

.5H

2 -

4H

7 -

12H

16 -

30H

36 -

60H

72 -

100H

120 -

150H

200 -

250H

400 -

450H

600 -

672H

-6

-4

-2

0

2

4

IG

F-1

S

DS

le

ve

l

0 .0 4 m g /k g (N = 3 )

0 .0 8 m g /k g (N = 3 )

0 .1 2 m g /k g (N = 3 )

0.04 mg/kg (N=3)

0.08 mg/kg (N=3)

0.12 mg/kg (N=3)

Fractions of patients achieving target - dosing HM10560A every 7 days

Time (hr)

CONCLUSIONS

Design

RESULTS

Demographic data

THE ENDOCRINE SOCIETY`S 97TH ANNUAL MEETING (ENDO 2015), SAN DEIGO, CALIFORNIA, MARCH 5-8, 2015 For any questions, please contact Hanmi Pharm. Co., Ltd., Rep. of Korea Jahoon Kang*, Tel: 82-2-410-9041, Email: jhkang@hanmi.co.kr Hanmi Hanmi Pharm. Co., Ltd.

FRI-447 6 Month Results of a Phase II, Randomized, Active Controlled, Open Label Study of Safety and Efficacy of HM10560A

a Long Acting r-Hgh-HMC001 Conjugate in Adult Patients with Growth Hormone Deficiency (AGHD) Jahoon Kang1, Pankyung Kim1, Eun Hwa Kwak1, Mei-Ying Xu1, OakPil Han1, Youngmin Kim1, Yeamin Huh2, Sunny Chapel2

1 Hanmi Pharm. Co., Ltd, Seoul, South Korea, 2 Ann Arbor Pharmacometrics Group (A2PG), Inc., MI, USA

ABSTRACT

CONCLUSIONS

Monte Carlo simulations to select doses for the phase III study

HM10560A is highly purified chemical conjugate of recombinant human growth hormone (hGH) and HMC001

(constant region of human immunoglobulin fragment) linked via a non-peptidyl 3.4 kDa PEG linker. The

tolerability and extended half-life of HM10560A was well established in Phase I, single ascending dose study in

healthy volunteers.

Current Phase II study was designed with three parts; Part 1, a pilot single dose PK/PD run-in period to bridge

the IGF-1 level between healthy volunteers and AGHD patients: Part 2, 24 weeks fixed titration period to assess

the safety, tolerability and PK/PD profile of HM10560A to select the optimal dose and dosing regimen; Part 3,

48 weeks individual titration period for safety follow up. In Part 2, IGF-1 SDS of HM10560A was compared

with Genotropin and all patients were switched to HM10560A in Part 3 for long term follow up. Recommended

doses for 24 weeks fixed titration period (Part 2) was obtained by population modeling and simulation, from 32

healthy volunteers received a single dose of HM10560A from Phase I and 9 AGHD patients received a single

dose of HM10560A from Part 1 of current Phase II. Total 69 patients (29 males/40 females, 68 Caucasian/1

Asian) were randomized to 5 cohorts (0.03 mg/kg/week, 0.06 mg/kg/week, 0.10 mg/kg/week, 1.2 mg/kg/every

other week, and Genotropin daily). Baseline demographic characteristics were similar between the groups with

the mean age of 38.2 (±12) years old and had been 13.9 (±9.3) years since GHD diagnosis.

After 24 weeks treatment of HM10560A, 71% of patients in Cohort 2 (0.06 mg/kg/week), 79% of patients in

Cohort 3 (0.10 mg/kg/week) and 86% of Cohort 5 (Genotropin daily) achieved the IGF-1 SDS between ±2. In

Cohort 4, where HM10560A was administered in every other week, only 55% of patients achieved the IGF-1

SDS between ±2. Lean body mass was increased in all 4 cohorts treated with HM10560A, but the changes were

marginal, due to a relative short treatment period. However, the exploratory exposure-response analysis

suggested a strong relationship between HM10560A exposure and lean body mass. The most frequently

reported AEs were headache, nasopharyngitis, oedema peripheral and injection site atrophy, as 7.2%

respectively. An indirect exposure-response model with a precursor transit compartment described the IGF-1-

time profile as a function of HM10560A concentration. Using the exposure-IGF-1 model and based on efficacy

target to maintain IGF-1 SDS level between ±2, 0.1 mg/kg was predicted to an optimum in the next adult GHD

patients study.

In conclusion, 24 weeks treatment with long acting HM10560A was safe, local tolerable and effective in AGHD.

Dose for Phase III was selected as 0.1 mg/kg with weekly regimen from the PK/PD modeling. The results of

current study warrants further development of HM10560A in adult GHD and pediatric GHD patients.

Overall study design

Objectives 1) To assess the safety, tolerability and Pharmacokinetic/Pharmacodynamic (PK/PD) profile of three doses of HM10560A

on an every week regimen and one dose on every other week (EOW) regimen administered for a period of 24 weeks initial

study

2) To select the optimal dose and dosing regimen of HM10560A for the subsequent phase III study on the basis of the safety

and PK/PD profile after 24 weeks of treatment

3) To assess the long term safety of HM10560A when administered in optimal dose range and dose frequency for additional

48 weeks (followed with 2 weeks safety follow up)

• 24 weeks treatment with long acting HM10560A was safe and local tolerable in AGHD patients.

• Mean IGF-1 and IGFBP3 SDS levels were maintained in the target range (±2) with weekly HM10560A treatment.

• The Monte Carlo simulation predicted the fraction of patients achieving both the safety and efficacy target . Simulation results of IGF-1 SDS, lean body mass, and trunk fat mass

indicate that 0.1 mg/kg weekly treatment is an optimal dose/regimen compared with Genotropin.

• The results of current study warrants further development of HM10560A in adult and pediatric GHD patients.

• Each study consists of 100 subjects resampled from 201 study subjects at the fixed weekly doses ranging from 0.02 to 0.16 mg/kg.

• 1000 datasets were simulated using 1000 sets of population parameter values generated from multivariate normal distribution

with mean vector set to the population parameter estimates and the covariance matrix set to the covariance matrix of the

estimates from the final PKPD model.

• Mean of lean body mass increase (LBM) and trunk fat mass (TF) decrease after 6 month for each study was collected and

summarized in median, and 5th and 95th percentiles of 1000 datasets.

02

46

81

01

2

LBM increase after 6 months

Weekly Dose (mg/kg)

%in

cre

ase

in

LB

M

0.02 0.04 0.06 0.08 0.10 0.12 0.16

50th percentile of mean90% PI of mean

Ge

no

. 6

mth

s

05

10

15

TF decrease after 6 months

Weekly Dose (mg/kg)

%d

ecre

ase

in

TF

0.02 0.04 0.06 0.08 0.10 0.12 0.16

50th percentile of mean90% PI of mean

Ge

no

. 6

mth

s

Demographic Data Statistics

0.03

mg/kg/week

0.03->0.06

mg/kg/week

0.03->0.06->0.1

mg/kg/week

0.04->0.08->0.12

mg/kg/biweek Genotropin Overall

N=15 N=14 N=14 N=12 N=14 N=69

Gender [N(%)] Male 5 (33.3%) 6 (42.9%) 6 (42.9%) 6 (50%) 6 (42.9%) 29 (42.0%)

Female 10 (66.7%) 8 (57.1%) 8 (57.1%) 6 (50%) 8 (57.1%) 40 (58.0%)

Race [N(%)] Caucasian 15 14 14 12 13 68 (98.6%)

Asian 0 0 0 0 1 1 (1.4%)

Age [years] Mean (SD) 38.2 (12) 38.6 (12.7) 36.2 (9.7) 41.7 (11.4) 37.4 (9.3) 38.3 (10.93)

BMI [kg/m2] Mean (SD) 26.71 (3.96) 25.41 (3.86) 25.71 (3.80) 26.83 (5.01) 27.61 (4.43) 26.45 (4.16)

Type of Onset [N (%)] Adult 8 (53.3%) 7 (50.0%) 7 (50.0%) 5 (41.7%) 9 (64.3%) 36 (52.2%)

Childhood 7 (46.7%) 7 (50.0%) 7 (50.0%) 7 (58.3%) 5 (35.7%) 33 (47.8%)

Type of insufficiency of

GH secretion [N (%)] Primary isolated GH insufficiency 0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (8.3%) 1 (7.1%) 2 (2.9%)

Primary multiple hormone deficiency 7 (46.7%) 4 (28.6%) 8 (57.1%) 5 (41.7%) 4 (28.6%) 28 (40.6%)

Secondary isolated GH insufficiency 0 (0.0%) 1 (7.1%) 0 (0.0%) 0 (0.0%) 1 (7.1%) 2 (2.9%)

Secondary multiple hormone deficiency 8 (53.3%) 9 (64.3%) 6 (42.9%) 6 (50.0%) 8 (57.1%) 37 (53.6%)

Time since GHD diagnosis

[years] Mean(SD) 13.9 (9.32) 12.2 (11.43) 12.0 (12.47) 11.4 (11.46) 9.4 (9.01) 11.8 (10.55)

Medical history [N(%)]

Type 2 Diabetes mellitus 0 2 0 0 0 2 (2.9%)

Hypertension 0 0 0 1 2 3 (4.3%)

Obesity 0 0 0 1 1 2 (2.9%)

Early Term N 2 0 0 1 0 3 (4.3%)

Early Term

UA1202 (Cohort 1): Withdrawal of patient`s consent after PK/PD run in period.

UA1218 (Cohort 1): Military actions.

UA1315 (Cohort 4): Withdrawal of patient`s consent.

Background Clinically satisfactory efficacy of somatropin therapy has been achieved with current daily r-hGH products with an

adequate safety profile. However, the requirement of daily subcutaneous (s.c.) administrations, especially for pediatric GH

therapy, causes a significant burden and interruption of normal daily life, and may cause compliance issues.

HM10560A is highly purified chemical conjugate of recombinant human growth hormone (hGH) and HMC001 (constant

region of human immunoglobulin fragment) linked via a non-peptidyl 3.4 kDa PEG linker which is based on a novel

strategy for developing long-acting proteins with an approximate molecular mass of 75.8 kDa.

In Phase I study, a single dose of 0.089 mg/kg, 0.179 mg/kg, 0.357 mg/kg, and 0.714 mg/kg HM10560A administered s.c.

were safe and well tolerable in healthy male subjects. The mean duration of sustaining above the baseline IGF-1 values

were longer than 1 week, and the mean serum elimination half-life of HM10560A were between 49.42 and 95.42 hr.

Safety and adverse events (AEs)

N (%)

0.03

mg/kg/week

0.03->0.06

mg/kg/week

0.03->0.06->0.1

mg/kg/week

0.04->0.08->0.12

mg/kg/biweek Genotropin Overall

N=15 N=14 N=14 N=12 N=14 N=69

Any TEAEs 6 (40 %) 11 (78.6 %) 8 (57.1 %) 4 (33.3 %) 8 (57.1 %) 37 (53.6 %)

TEAEs by Severity Mild 3 (20 %) 7 (50 %) 3 (21.4 %) 3 (25 %) 5 (35.7 %) 21 (30.4 %)

Moderate 3 (20 %) 3 (21.4 %) 2 (14.3 %) 0 2 (14.3 %) 10 (14.5 %)

Severe 0 1 (7.1 %) 3* (21.4 %) 1* (8.3 %) 1 (7.1 %) 6 (8.7 %)

Any Serious TEAEs (SAE) 0 0 1** (7.1 %) 0 0 1 (1.4 %)

Any TEAEs leading to

Discontinuation 0 0 0 0 1*** (7.1 %) 1 (1.4 %)

Any TEAEs Related to study drug 2 (13.3 %) 7 (50 %) 3 (21.4 %) 3 (25 %) 3 (21.4 %) 18 (26.1 %)

*Two Sever AEs were reported definitely (Injection site atrophy, cohort 3) and possibly (Arthralgia and Myalgia, cohort 4) related to study drug.

** One serious AE (Hyperpyrexia) was reported unlikely related to study drug, and resolved without sequelae.

***AE leading to discontinuation was unlikely related to study drug, and ongoing. But PL2418 (Cohort 5) was reported with AE leading to

withdraw before Visit 8, but this patient completed Visit 8 and early terminated during 48+2 weeks long term safety period.

Headache 1 ( 6.7%) 1 ( 7.1%) 0 1 ( 8.3%) 2 (14.3%) 5 ( 7.2%)

Injection site atrophy 1 ( 6.7%) 1 ( 7.1%) 1 ( 7.1%) 2 (16.7%) 0 5 ( 7.2%)

Nasopharyngitis 0 2 (14.3%) 0 1 ( 8.3%) 2 (14.3%) 5 ( 7.2%)

Oedema peripheral 0 1 ( 7.1%) 3 (21.4%) 0 1 ( 7.1%) 5 ( 7.2%)

Upper respiratory tract infection 0 1 ( 7.1%) 1 ( 7.1%) 0 2 (14.3%) 4 ( 5.8%)

The most frequently reported AEs

Mean change (SD)

0 4 8 1 2 1 6 2 0 2 4

-6

-4

-2

0

2

4

W e e k

0 4 8 1 2 1 6 2 0 2 4

-6

-4

-2

0

2

4

W e e k

0 4 8 1 2 1 6 2 0 2 4

-6

-4

-2

0

2

4

W e e k

IG F -1 S D S

IG F B P 3 S D S

0 4 8 1 2 1 6 2 0 2 4

-6

-4

-2

0

2

4

W e e k

IGF-1 SDS level

IGFBP3 SDS level

IGF-1 SDS/IGFBP3 SDS level

• IGF-1 level for HM10560 administration cohorts was measured at through concentrations (7 days since last administration).

• IGF-1 level for Genotropin administration cohort was measured at 9~13 hr since last administration.

Statistics

0.03

mg/kg/week

0.03->0.06

mg/kg/week

0.03->0.06>0.1

mg/kg/week

0.04->0.08->0.12

mg/kg/biweek Genotropin

N=15 N=14 N=14 N=12 N=14

Total cholesterol

[mmol/L]

Baseline 5.92 (1.99) 6.30 (1.42) 5.19 (0.70) 5.73 (0.92) 5.16 (0.92)

Change to 24w -0.30 (0.72) -0.70 (1.19) 0.04 (0.75) 0.10 (0.93) -0.06 (0.90)

LSMean -0.18 (0.28) -0.49 (0.22) -0.12 (0.22) 0.14 (0.25) -0.27 (0.22)

HDL-cholesterol

[mmol/L]

Baseline 1.213 (0.241) 1.34 (0.321) 1.357 (0.438) 1.398 (0.452) 1.260(0.498)

Change to 24w 0.002 (0.279) -0.026 (0.349) 0.049 (0.374) 0.022 (0.428) 0.058 (0.266)

LSMean 0.007 (0.077) -0.004 (0.074) 0.096 (0.074) 0.001 (0.083) 0.088 (0.075)

LDL-cholesterol

[mmol/L]

Baseline 4.09 (1.79) 4.44 (1.20) 3.37 (0.54) 3.72 (0.72) 3.07 (0.81)

Change to 24w -0.35(0.63) -0.62(1.03) 0.09(0.63) 0.13(0.65) 0.12(0.81)

LSMean -0.20 (0.19) -0.35 (0.19) -0.08 (0.18) 0.17 (0.20) -0.22 (0.19)

Triglycerides

[mmol/L]

Baseline 1.42 (0.88) 1.51 (0.57) 1.09 (0.45) 1.30 (0.62) 2.05 (1.63)

Change to 24w 0.47 (1.00) -0.15 (0.80) -0.01 (0.48) 0.23 (0.51) -0.21 (0.97)

LSMean 0.35 (0.20) -0.14 (0.19) -0.22 (0.19) 0.20 (0.22) -0.01 (0.20)

Lipid parameters

Body composition

Statistics

0.03

mg/kg/week

0.03->0.06

mg/kg/week

0.03->0.06->0.1

mg/kg/week

0.04->0.08->0.12

mg/kg/biweek Genotropin

N=15 N=14 N=14 N=12 N=14

Body fat mass [Kg]

Baseline 22.59 (6.03) 23.24 (6.71) 23.19 (4.04) 24.34 (8.41) 29.11 (9.56)

Change to 24w -0.42 (1.56) -1.29 (2.21) 1.21 (3.28) -0.73 (2.29) -0.99 (2.94)

LSMean -0.49 (0.71) -1.34 (0.69) 1.12 (0.72) -0.50 (0.77) -0.86 (0.71)

Trunk fat mass [Kg]

Baseline 12.72 (3.62) 12.75 (3.59) 12.35 (2.35) 13.83 (4.69) 15.85 (5.83)

Change to 24w -0.50 (0.87) -1.10 (1.40) 0.21 (1.97) -0.82 (1.36) -0.93 (1.89)

LSMean -0.61 (0.43) -1.19 (0.42) 0.09 (0.44) -0.68 (0.47) -0.83 (0.43)

Lean body mass [Kg]

Baseline 43.68 (8.58) 41.88 (13.20) 41.20 (10.44) 41.73 (15.43) 44.26 (12.58)

Change to 24w 1.29 (1.93) 1.86 (1.67) 1.47 (1.46) 1.15 (1.60) 2.44 (2.09)

LSMean 1.09 (0.44) 1.68 (0.42) 1.29 (0.44) 1.11 (0.48) 2.38 (0.43)

LSMeans are adjusted for cohort, gender, GHD onset type, age and baseline value.

LSMeans are adjusted for cohort, gender, GHD onset type, age and baseline value.

Lean body mass increase after 6 months Trunk fat mass decrease after 6 months

Fractions of patients achieving target

Less than 72h above IGF-1 SDS of 2 and IGF-1 SDS = 60% within 0 to 2

IGF-1 SDS = 60% within -2 to 2

IGF-1 SDS = 60% within 0 to 2

IGF-1 SDS < 120h above 2

IGF-1 SDS < 72h above 2

IGF-1 SDS < 48h above 2

Lean body mass change [kg] at visit 8 Relative body fat change [%] at visit 8 Relative trunk fat change [%] at visit 8

0.03 mg/kg/week (N=15) 0.03 -> 0.06 mg/kg/week (N=14)

0.03 -> 0.06 -> 0.10 mg/kg/week (N=14) 0.04 -> 0.08 -> 0.12 mg/kg/biweek (N=12) Genotropin (N=14)