Easyef Spray Recombinant Human Epidermal Growth Factor Easyef

Easyef® Spray Recombinant Human Epidermal Growth Factor

Easyef® Spray General Information Ø 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 h. EGF from three disulfide bonds are required for h. EGF 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, h. EGF 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 Ø 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 Ø 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 Ø 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 Ø 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 Duration – days rh. EGF Placebo Median (range) 8. 0 (2. 0 -23. 0) 18. 5 (2. 0 -34. 0) P 0. 108 Oral Mucositis Daily Questionnaire (OMDQ) rh. EGF Placebo Variables (AUC of score) p Median (range) Q 3. 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 Duration of rh. EGF treatment rh. EGF Placebo Median (range) p 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 Ø Pharmacokinetics (ADME) 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 Item Pharmacokinetics after Local Administration Ø 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 Biological activity Mitogenic assay Thymidine incorporation assay Brd. U incorporation assay Similar to NIBSC standard Receptor binding assay 7

Easyef® Spray Key Benefits and Features Ø 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 Ø Identical to natural human EGF, ultra-pure and homogeneous • Manufactured by the innovative and proprietary E. coli expression system Ø INN (generic name): Nepidermin • Ref) WHO Drug Information (2008), 22(1): 59 8

Easyef® Spray Product Information [Composition] l Active ingredient: 1 m. L contains Recombinant human epidermal growth factor --------------- 0. 5 mg (600, 000 IU) (Host cell: E. coli JM 101, Vector: p. TE 105) l Solvent: 9 m. L contains Methyl parahydroxybenzoate -------------------------- 20 mg [Appearance] Both active ingredient and solvent are colorless, odorless and transparent solution with p. H 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 10 m. L [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