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New Products Research Team RESEARCH PROJECT EGF03/CT

KOREAN SPONSOR : DAEWOONG PHARMACEUTICAL CO., LTD. CANADIAN SPONSOR/CRO: KRIGER RESEARCH CENTER INC. KRC INC. RESEARCH PROJECT: EGF03/CT PRODUCT: EASYEF

Recombinant Human Epidermal Growth Factor 0.005%


PROCEED TO CLINICAL TRIAL PROTOCOL SUMMARY PROCEED TO RESEARCH TEAM TASKS PROCEED TO RESEARCH TASKS SUBMISSION

EASYEF
Recombinant Human Epidermal Growth Factor 0.005%

New Products Research Team


RESEARCH PROJECT EGF03/CT
KOREAN SPONSOR : D. PHARMACEUTICAL CO., LTD. CANADIAN SPONSOR/CRO: KRIGER RESEARCH CENTER INC.
INFORM. USED EDITION NUMBER : DWP401-NC-02 RELEASE DATE : April, 20th, 2003 Replaces Previous Edition Number : DWP401-NC-01 ( March, 25 th , 2000 )

GO TO EGF03/CT PROTOCOL
Product Information Stability Mechanism of EGF Action

PROJECT STATUS: KRC INC. is checking out the licensing and marketing potential of Epidermal Growth Factor in Canada. Daewoong Co., Ltd. - Korea has agreed to export this product.

KRC Inc. background checks are needed in order to enable our to decide whether we would be interested to file Phase I Clinical New Drug Application with TPP Canada or may be it would be more plausible for our Company to find a local Sponsor and Study serve as CRO in this project.
Pre-clinical Study Management Phase II Clinical Study Efficacy of EASYEF

Now we are working in close contact with Mr. Yi, So Yong from Business Development Daewoong Co., Ltd. - Korea.

Patents Production Information Development Information

KRC Inc. would be able to sign the contract with Daewoong Co., Ltd. on importing of initial quantities of the product for clinical trials upon successful completion of background checks

PROTOCOL
EGF03/CT

Phase II Study the Efficacy of the healing effect of recombinant human epidermal growth factor (rhEGF) on diabetic foot ulcers Double-blind, controlled Phase II study (Randomized comparative method, multi-center study)

EASYEF
Recombinant Human Epidermal Growth Factor 0.005%

New Products Research Team


RESEARCH PROJECT EGF03/CT Product Information
Epidermal Growth Factor (EGF) is a single-chain polypeptide consisting of 53 amino acids with molecular weight of about 6,200 daltons. The six cysteine residues in the sequence of hEGF form three disulfide bonds, which 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. Later it was proved that EGF causes both proliferation of epithelial cells and inhibition of gastric acid secretion. Now, hEGF became one of the most attractive growth factors in the life sciences as well as the biotechnological fields Human EGF is a potent stimulator of epithelial cell, endothelial cell 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, 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.

Product Information

1. Bulk of rhEGF

Specifications Source Molecular Weight Appearance PH Sterility Identity Homogeneity Host-derived DNA Host-derived peptide Endotoxin PI Biological Activity

Parameters & Test methods Expressed in E. coli and purified from the culture media 5.7 0.5 kDa by SDS-PAGE & Coomassie staining White and amorphous lyophilized powder 6.5 1.0 by USP Sterile by USP SDS-PAGE & Coomassie staining, Western blot, RP-HPLC conform to standard EGF Purity : 98% by RP-HPLC Monomer : 98% by SE-HPLC 0.2 ppm by Slot blot hybridization 0.5% by ELISA 0.1 EU/g by LAL Test Single band , pI = 4.6 0.2 by Isoelectric focusing 0.9 mg/mg by Receptor binding assay 2.0 ng/ml of ED50 by Mitogenic assay

2. EASYEF

EASYEF was finished Phase II clinical trial in Korea, approved by Korea FDA for the treatment of diabetic foot ulcer as an orphan drug and launched in the Korea market in Sep. 2001.

The Phase III Clinical Trial have progressed favorably.

Easyef is spray solution consisting of active ingredient and the diluent. Both are colorless, odorless and transparent liquid with pH 6.51.0.

For 2.5X2.5cm2 diabetic foot ulcer , patients should pump it 3~4 times. 1 time pumping amount is 50ul.

According to the result of clinical trial , 2~3 bottles are needed in order to complete healing in diabetic foot ulcer.

Active Ingredient Indication Usage/Dosage Package Storage Expiration

RhEGF 1mg ( Host cell: E. coli JM101, Vector : pTE105 ) Diabetic Foot Ulcer After mixing active ingredient with the diluent , applying it to an wound twice a day 20ml ( 50ug/ml ) , Amount used during about 40 days Keep it at 2~8C in a refrigerator. 2 years ( Upon mixing, the mixture is stable for 6 months at 2~8C )

[ How to mix active ingredient with the diluent ]

EASYEF
Recombinant Human Epidermal Growth Factor 0.005%

New Products Research Team


RESEARCH PROJECT EGF03/CT ( Stability )
DWP401 is very stable at low temperature, regardless of the forms such as lyophilizes powder and solution. The pH, thermal, long-term stability and the stability under extreme conditions of DWP401 were tested by reverse-phase (RP) HPLC and the receptor binding assay. 1) Bulk of rhEGF There was no change observed in the content or activity of DWP401 at 4 or below for at least 58 weeks. DWP401 showed the highest stability at pH 5.5, and began to form hydrophobic degradation products at pH lower than 5.5. DWP401 displayed hydrophilic degradation products at pH higher than 5.5. These degradation products were still shown to have receptor binding activity. 2) EASYEF From the result of the stability study of EASYEF, a solution preparation contains DWP401, it showed stable for 24 months of storage life at 2~8. After mixing the EASYEF solution with Diluent, it is stable for at least 6 months of storage period at 2~8.

Long Term Stability of DWP401 Powder (Relative Quantity ;A and Relative Activity ;B)

EASYEF
Recombinant Human Epidermal Growth Factor 0.005%

New Products Research Team


RESEARCH PROJECT EGF03/CT

MECHANISM OF EGF ACTION


EGF completes wound healing through re-epithelialization, promotion of grunulation and angiogenesis.

Re-epithelialization : EGF promotes epithelial cells to multiply and move to fill wounds Promotion of Granulation Tissue : EGF stimulates fibroblasts in dermal tissue to facilitate dermal cells to differentiate and multiply. Angiogenesis : EGF promotes endothelial cells to multiply to regenerate blood vessels.
Ref> 1. Drug News & Perspective 13(3), 158-168, April 2000 2. Advances in Plastic and Reconstructive Surgery, Vol. 11, 151-166