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.

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

Mechanism of EGF Action

Easyef

®

Spray

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.

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Easyef

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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 the percentage of complete healing. 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

Comparison of Complete Healing Rate Case Example

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Easyef

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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 ® significantly reduces the incidence of severe oral mucositis.

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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

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

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 Median (range)

Duration – days 8.0 (2.0-23.0) 18.5 (2.0-34.0)

P

0.108

Oral Mucositis Daily Questionnaire (OMDQ)

rhEGF Variables (AUC of score) Placebo 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)

p 0.039

0.042

0.121

0.203

0.124

Secondary Endpoints: Patients with WHO Grade 3-4 Oral Mucositis

Variables – days rhEGF Placebo Median (range) Duration of rhEGF treatment

28.0 (17.0-44.0) 39.5 (17.0-61.0)

Duration of TPN use

Duration of opioid analgesics use

Duration of hospitalization

7.0 (0-25.0) 6.0 (0-25.0) 27.0 (18.0-65.0) 16.5 (10.0-32.0) 17.0 (0-48.0) 41.0 (27.0-90.0)

p 0.050

0.012

0.117

0.047

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Easyef

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Non-clinical Study

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Pharmacokinetics (ADME)

Item

Pharmacokinetics Metabolism Biliary Excretion Pharmacokinetics after Local Administration Pharmacokinetics after Repeated Administration Pharmacokinetics after Repeated Local Administration

Animal

SD rat Cynomolgus monkey SD rat SD rat hairless mouse SD rat SD rat, 1 week SD rat, 3 days

Route

S.C./I.V.

S.C./I.V.

I.V.

S.C./I.V.

Topical Topical S.C.

Topical 

Toxicity Studies

Item

Single dose toxicity Repeated dose toxicity

In vitro

chromosomal abbreation Genotoxicity Reverse mutation Bone marrow micronucleus Fertility and early embryonic development Reproductive toxicity Embryofetal development Embryofetal development Other toxicity Prenatal and postnatal toxicity Skin irritation / Eye irritation Skin sensitization

Animal

ICR mouse, SD rat Cynomolgus monkey ICR mouse, 13 weeks SD rat, 13 weeks Cynomolgus monkey, 4 weeks Chinese hamster ovary (CHO) cell Salmonella typimurium Male and female mice SD rat Newzealand white rabbit SD rat SD rat Newzealand white rabbit Guinea pig

Route

S.C./P.O.

S.C./I.V.

S.C.

S.C

I.V.

I.P.

S.C.

S.C.

S.C.

S.C.

Topical Topical 6

Easyef

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CMC Result

Item

Structural characterization and confirmation Physicochemical properties Immunological characterisation Biological activity

Methods Results

Amino acid sequence Amino acid composition Terminal amino acid sequence N-terminal C-terminal Peptide mapping Disulfide bridges Molecular weight or size SDS-PAGE SEC-HPLC MALDI-TOF MS Isoform pattern Electrophoretic Patterns Liquid chromatographic patterns Spectroscopic profiles Non-reducing Reducing RP-HPLC SEC-HPLC UV Circular dichroism Western blotting Immunoelectrophoresis Radioimmunoassay Mitogenic assay Thymidine incorporation assay BrdU incorporation assay Receptor binding assay Identical to natural form of human EGF Similar to NIBSC standard 7

Easyef

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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 system

E.coli

expression 

INN (generic name): Nepidermin

•

Ref)

WHO Drug Information (2008), 22(1):59 8

Easyef

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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: [email protected] 163-3, Samsung-dong, Gangnam-gu, Seoul 135-715, KOREA 9