Easyef® Spray
Recombinant Human Epidermal Growth Factor
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
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
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
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, multicenter 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
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
rhEGF
Placebo
Grade 3-4 OM
P
Median (range)
Duration – days
8.0 (2.0-23.0)
18.5 (2.0-34.0)
0.108
Oral Mucositis Daily Questionnaire (OMDQ)
rhEGF
Placebo
Variables (AUC of score)
p
Median (range)
Q3. Limitations in daily activities
A. Swallowing
B. Drinking
C. Eating
D. Talking
E. Sleeping
26.0 (8.0-75.0)
25.0 (7.0-73.5)
40.5 (15.0-90.0)
32.0 (6.0-74.0)
14.0 (0.0-72.0)
51.5 (19.0-92.0)
55.5 (20.0-86.0)
70.3 (22.0-104.0)
56.5 (3.0-97.0)
46.0 (0.0-72.0)
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 (17.0-44.0)
39.5 (17.0-61.0)
0.050
Duration of TPN use
7.0 (0-25.0)
16.5 (10.0-32.0)
0.012
Duration of opioid analgesics use
6.0 (0-25.0)
17.0 (0-48.0)
0.117
27.0 (18.0-65.0)
41.0 (27.0-90.0)
0.047
Duration of hospitalization
5
Easyef® Spray
Non-clinical Study
 Pharmacokinetics (ADME)
Item
Animal
Route
SD rat
S.C./I.V.
Cynomolgus monkey
S.C./I.V.
Metabolism
SD rat
I.V.
Biliary Excretion
SD rat
S.C./I.V.
hairless mouse
Topical
SD rat
Topical
Pharmacokinetics after Repeated Administration
SD rat, 1 week
S.C.
Pharmacokinetics after Repeated Local
Administration
SD rat, 3 days
Topical
Pharmacokinetics
Pharmacokinetics after Local Administration
 Toxicity Studies
Item
S.C./P.O.
Cynomolgus monkey
S.C./I.V.
ICR mouse, 13 weeks
S.C.
SD rat, 13 weeks
S.C
Cynomolgus monkey, 4 weeks
I.V.
In vitro chromosomal abbreation
Chinese hamster ovary (CHO)
cell
-
Reverse mutation
Salmonella typimurium
-
Bone marrow micronucleus
Male and female mice
I.P.
Fertility and early embryonic
development
SD rat
S.C.
Embryofetal development
Newzealand white rabbit
S.C.
Embryofetal development
SD rat
S.C.
Prenatal and postnatal toxicity
SD rat
S.C.
Skin irritation / Eye irritation
Newzealand white rabbit
Topical
Skin sensitization
Guinea pig
Topical
Repeated dose toxicity
Reproductive
toxicity
Other toxicity
Route
ICR mouse, SD rat
Single dose toxicity
Genotoxicity
Animal
6
Easyef® Spray
CMC Result
Item
Methods
Results
Amino acid sequence
Amino acid composition
Structural
characterization
and confirmation
Terminal amino
acid sequence
N-terminal
C-terminal
Peptide mapping
Disulfide bridges
SDS-PAGE
Molecular weight
or size
SEC-HPLC
MALDI-TOF MS
Identical to natural form
of human EGF
Isoform pattern
Physicochemical
properties
Electrophoretic
Patterns
Non-reducing
Liquid
chromatographic
patterns
RP-HPLC
Spectroscopic
profiles
UV
Reducing
SEC-HPLC
Circular dichroism
Western blotting
Immunological
characterisation
Immunoelectrophoresis
Radioimmunoassay
Mitogenic assay
Biological activity
Thymidine incorporation
assay
BrdU incorporation assay
Similar to NIBSC standard
Receptor binding assay
7
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
Easyef® Spray
Product Information
[Composition]
Active ingredient: 1mL contains
Recombinant human epidermal growth factor ------------------------------ 0.5mg
(600,000 IU)
(Host cell: E. coli JM101, Vector: pTE105)
Solvent: 9mL contains
Methyl parahydroxybenzoate --------------------------------------------------- 20mg
[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 : 2012.01.27
http://www.daewoong.com
For More Information Contact:
Chang Woo Suh
Tel: 82-2-2059-1632
E-mail: cwsuh@daewoong.co.kr
163-3, Samsung-dong,
Gangnam-gu, Seoul 135-715, KOREA
9