1. Recombinant Human Epidermal Growth Factor
Easyef® Spray
Recombinant Human Epidermal Growth Factor

2. Easyef® Spray General Information What is EGF?
Epidermal Growth Factor (EGF) is a single-chain polypeptide consisting of 53 amino acids with a molecular weight of about 6,200 Daltons. Six cysteine residues in the sequence of hEGF from three disulfide bonds are required for hEGF to be biologically active. EGF was first isolated from the submaxillary glands of adult male mice. Human EGF was discovered in human urine as an inhibitor of gastric acid secretion. Today, hEGF has become one of the most attractive growth factors in life sciences as well as biotechnological fields. Human EGF is a potent stimulator of epithelial and endothelial cells and fibroblast proliferation both in vitro and in vivo, which results in its potential as a promising healing agent for the treatment of various skin and corneal wounds. In dermatology, EGF can be used as a healing agent for skin wounds, such as diabetic ulcers, bed sores, venous stasis ulcers, skin burns and surgical incisions. In ophthalmology, EGF can be utilized as a healing agent for corneal ulcers and ophthalmic surgery, such as corneal transplantation and excimer laser keratectomy, and the prevention of corneal degeneration. It is also a good candidate for the treatment of gastric ulcers because it inhibits gastric acid secretion and regenerates gastric mucosal layer. 1

3. Easyef® Spray Mechanism of EGF Action 1. Re-epithelialization
EGF promotes epithelial cells to proliferate and move to fill wounds.
2. Promotion of granulation tissue
EGF stimulates fibroblasts in dermal tissue to facilitate dermal cells to differentiate and proliferate.
3. Angiogenesis
EGF promotes endothelial cells to proliferate to regenerate blood vessels. 2

4. Easyef® Spray Clinical Study Diabetic Foot Ulcer (Phase II)
► Indication: Diabetic foot ulcer, Grade 2 and 3 by Wagner classification
► Methodology: Double-blind, controlled, randomized comparative method, multi-center study
► Dose strength: Easyef® Spray (10 μg/ml and 50 μg/ml), placebo
► Treatment: Sprayed on wound area twice a day for 12 weeks
► Primary endpoint: Complete healing rate of foot ulcer
► Result: Easyef® Spray accelerated healing of diabetic foot ulcer and apparently increased the percentage of complete healing.
Comparison of Complete Healing Rate
Case Example 3

5. Easyef® Spray Radiation-Induced Oral Mucositis (Phase II)
► Indication: Oral mucositis in patients receiving radiation therapy with or without
chemotherapy
► Methodology: Double-blind, placebo-controlled, randomized comparative method, multi-center study
► Dose strength: Easyef® Spray (10 μg/ml, 50 μg/ml and 100 μg/ml), placebo
► Treatment: Sprayed on wound area twice a day for 5 weeks
► Primary endpoint: Radiation Therapy Oncology Group (RTOG) scale for acute mucosal morbidity
► Result: Easyef® Spray conveys a therapeutic effect and local application of Easyef® Spray significantly reduces the incidence of severe oral mucositis.
Proportion of Patients with Oral Mucositis (RTOG scale: ≥ 3)
Case Example
(a)
(b)
Appearances of oral mucosa at treatment week four.
(a) No change of oral mucosa over baseline (RTOG grade 0) in responders to EGF
(b) RTOG grade 3 confluent mucositis in placebo arm 4

6. Variables (AUC of score)
Easyef® Spray
Oral Mucositis Induced by Chemotherapy with SCT (Phase II, Interim analysis)
► Indication: Oral mucositis induced by intensive chemotherapy with SCT for hematologic malignancies
► Methodology: Double-blind, placebo-controlled, randomized, prospective study
► Dose strength: Easyef® Spray (50 μg/ml), placebo
► Treatment: Sprayed on wound area twice a day
► Primary endpoint: Incidence and duration of oral mucositis
► Result: Easyef® Spray significantly reduced the limitation of swallowing and drinking, the duration of TPN use and hospitalization in patients with WHO grade 3-4 oral mucositis.
Effects on WHO grade 3-4 Oral Mucositis: Duration
Grade 3-4 OM
rhEGF
Placebo P
Median (range)
Duration – days
8.0 ( )
18.5 ( )
0.108
Oral Mucositis Daily Questionnaire (OMDQ)
Variables (AUC of score)
rhEGF
Placebo p
Median (range)
Q3. Limitations in daily activities
A. Swallowing
B. Drinking
C. Eating
D. Talking
E. Sleeping
26.0 ( )
25.0 ( )
40.5 ( )
32.0 ( )
14.0 ( )
51.5 ( )
55.5 ( )
70.3 ( )
56.5 ( )
46.0 ( )
0.039
0.042
0.121
0.203
0.124
Secondary Endpoints: Patients with WHO Grade 3-4 Oral Mucositis
Variables – days
rhEGF
Placebo p
Median (range)
Duration of rhEGF treatment
28.0 ( )
39.5 ( )
0.050
Duration of TPN use
7.0 (0-25.0)
16.5 ( )
0.012
Duration of opioid analgesics use
6.0 (0-25.0)
17.0 (0-48.0)
0.117
Duration of hospitalization
27.0 ( )
41.0 ( )
0.047 5

7. Easyef® Spray Non-clinical Study Pharmacokinetics (ADME)
Item
Animal
Route
Pharmacokinetics
SD rat
S.C./I.V.
Cynomolgus monkey
Metabolism
I.V.
Biliary Excretion
Pharmacokinetics after Local Administration
hairless mouse
Topical
Pharmacokinetics after Repeated Administration
SD rat, 1 week
S.C.
Pharmacokinetics after Repeated Local Administration
SD rat, 3 days
Toxicity Studies
Item
Animal
Route
Single dose toxicity
ICR mouse, SD rat
S.C./P.O.
Cynomolgus monkey
S.C./I.V.
Repeated dose toxicity
ICR mouse, 13 weeks
S.C.
SD rat, 13 weeks
S.C
Cynomolgus monkey, 4 weeks
I.V.
Genotoxicity
In vitro chromosomal abbreation
Chinese hamster ovary (CHO) cell -
Reverse mutation
Salmonella typimurium
Bone marrow micronucleus
Male and female mice
I.P.
Reproductive toxicity
Fertility and early embryonic development
SD rat
Embryofetal development
Newzealand white rabbit
Prenatal and postnatal toxicity
Other toxicity
Skin irritation / Eye irritation
Topical
Skin sensitization
Guinea pig 6

8. Easyef® Spray CMC Result Item Methods Results Structural
characterization
and confirmation
Amino acid sequence
Identical to natural form
of human EGF
Amino acid composition
Terminal amino
acid sequence
N-terminal
C-terminal
Peptide mapping
Disulfide bridges
Physicochemical
properties
Molecular weight
or size
SDS-PAGE
SEC-HPLC
MALDI-TOF MS
Isoform pattern
Electrophoretic
Patterns
Non-reducing
Reducing
Liquid
chromatographic
patterns
RP-HPLC
Spectroscopic
profiles UV
Circular dichroism
Immunological
characterisation
Western blotting
Immunoelectrophoresis
Radioimmunoassay
Biological activity
Mitogenic assay
Thymidine incorporation assay
Similar to NIBSC standard
BrdU incorporation assay
Receptor binding assay 7

9. Key Benefits and Features
Easyef® Spray
Key Benefits and Features
First pharmaceutical EGF product to gain worldwide approval in the world
Currently marketed in Jordan, Vietnam and many other countries
Highly potent and safe compared with other EGF products
Identical to natural human EGF, ultra-pure and homogeneous
Manufactured by the innovative and proprietary E.coli expression system
INN (generic name): Nepidermin
Ref) WHO Drug Information (2008), 22(1):59 8

10. Easyef® Spray Product Information [Composition]
Active ingredient: 1mL contains
Recombinant human epidermal growth factor mg
(600,000 IU)
(Host cell: E. coli JM101, Vector: pTE105)
Solvent: 9mL contains
Methyl parahydroxybenzoate mg
[Appearance]
Both active ingredient and solvent are colorless, odorless and transparent solution with pH of 6.5±1.0
[Indications] Diabetic foot ulcers
[Dosage & Administration]
After mixing active ingredient with attached solvent, apply to wound twice a day.
[Storage] Store at 2~8℃ in a refrigerator.
[Package] Box of 1 set of 10mL
[Shelf-Life]
2 years before use (not mixed)
6 months after use (mixed)
Release Date :
For More Information Contact:
Chang Woo Suh
Tel:
163-3, Samsung-dong,
Gangnam-gu, Seoul , KOREA 9