INCOSPHARM Ingredients for Cosmetic and Pharmaceutical Applications COSMETIC INGREDIENTS

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1 Incospharm Corporation , Daedeok-daero, Yuseong-gu, Daejeon, Korea Tel Fax INCOSPHARM Ingredients for Cosmetic and Pharmaceutical s COSMETIC INGREDIENTS

2 About Incospharm Autophagy Ingredients for Cosmetic and Pharmaceutical s What is Autophagy? Accumulation of damaged cellular components is characteristic of tissues in all organisms as they age and has been proposed to be responsible for their functional loss in ageing. Autophagy, a highly conserved catabolic mechanism of quality control inside cells, is essential for the maintenance of cellular homeostasis and for the orchestration of an efficient cellular response to stresses. The decrease in autophagic activity in cells may be a driver of different aspects of the ageing phenotype. Thus, enhancement of autophagic activity might decelerate ageing progression by guaranteeing continuous renewal of the cellular proteome, and damaged proteins that are no longer functional, to avoid their accumulation inside cells. In cosmetics and pharmaceutical industries, there is a growing interest in developing ingredients to enhance autophagic activity to slow-down ageing progression. (Source: Autophagy and ageing: keeping that old broom working. Trends in Genetics 24, 2008) Process of Autophagy Identification & Collection of Cellular Components for Degredation OUR VISION To become the global leader in the cosmetics and pharmaceutical industries through providing the innovative active ingredients that actively induce autophagy in various cells. Completion of Autophagosome Fusion of Autophagosome with Lysosome Isolation Membrane Formation OUR MISSION To secure a world-class technical leadership in the development of autophagy-based peptides and non-peptide active ingredients. To provide the best value, top quality innovations to our customers in the cosmetics and pharmaceutical industries. OUR VALUES Professionalism through intensive research Passion for bettering human life and beauty Innovation through challenge Responsibility to our customers, partners, and shareholders Formation of Autolysosome & Degredation of Contents Incospharm was founded in 2011 and is continually developing peptides for anti-wrinkle, moisturising, anti-oxidant, and brightening of the skin. AQUATIDE has significant activity of cellular autophagy induction, enabling and maintaining healthier skin. Active ingredients for sensitive and troubled skin where ageing process is faster than normal skin are also under development for cosmetics or pharmaceutical applications. Incospharm has partnered with Arysta Health and Nutrition Sciences (Tokyo, Japan) for global sales and marketing since its foundation. 3 4

3 AQUATIDE 5000 Catalog Number ICP0005 Ingredients for Cosmetic and Pharmaceutical s Increases skin hydration Normalizes TEWL Natural moisturizing factor (NMF) in the stratum corneum has a high moisture retaining efficacy, and plays a major role in the skin barrier function. Skin Hydration TEWL Pyrrolidone carboxylic acid (PCA) is one of the major NMFs found in human skin. Aquatide, PCA-mimetic peptide, increases moisturisation, activates autophagy, reduces Trans Epidermal Water Loss (TEWL) and improves the skin barrier function. Autophagy and AQUATIDE 5000 Autophagy is the natural destructive mechanism that allows the orderly degradation and recycling of cellular components. Increased autophagy delays ageing and extends longevity. Sirtuin1 (SIRT1) is a deacetylase, functioning in the regulation of metabolism, cell survival and organismal lifespan. Active SIRT1 regulates the autophagy during cell stress, including calorie restriction and oxidative stress. Resveratrol AQUATIDE 5000 Sirt-1 mtor Vehicle 2% AQUATIDE 5000 AQUATIDE 5000 shows water retaining activity and increases skin hydration Increases ceramide contents Reduces ACNE symptoms Vehicle 2% AQUATIDE 5000 AQUATIDE 5000 enhances skin barrier function AQUATIDE 5000, the first known peptide-derived SIRT1 activator, activates SIRT1 by direct interaction. SIRT1 has been known as longevity protein that increases lifespan of various organisms. Through this interaction AQUATIDE 5000 increases a deacetylation of SIRT1 target protein FoxO1, resulting in the cell protective autophagy. Autophagy LONGEVITY S6K Ageing 4E-BP Activity and Efficacy Activates Autophagy Activates SIRT1 AQUATIDE 5000 increases synthesis of long and very long chain ceramides in the skin AQUATIDE 5000 has strong anti-inflammatory activity, and reduces average 65% of ACNE symptoms AQUATIDE 5000 AQUATIDE 5000 Hexacarboxymethyldipeptide % Aquatide 2% 1,2-Hexanediol 97.5% Water Activates autophagy Increases water retaining activity Increases ROS scavenging activity Sensitive skin care Anti-oxidant Anti-inflammation 1~2% for cream, lotion and essence formulation 0.1~1% for masksheet AQUATIDE 5000 treatment increases autophagic LC3 puncta formation (green dots) AQUATIDE 5000 activates SIRT1 enzymatic activity Patent No KP: USP: 9,359,401 JP:

4 AQUATIDE- TripleShield Catalog Number ICP2001 Ingredients for Cosmetic and Pharmaceutical s 1 st Shield: Repelling by silver oxide and sialyllactose to protect against heavy metals and viral infection 2 nd Shield: Elimination by Aquatide to enhance skin barrier function and autophagosis of PAHs 3 rd Shield: Homeostasis by Aquatide to suppress inflammation and allergic reactions Our skin is facing many kinds of stress such as ageing, mycrobacterium and virus attack, UV and infrared light as well as recently issued environmental stress such as pollen, PM2.5, PM10 including its harmful component polycyclic aromatic hydrocarbons (PAHs) and heavy metals. These environmental stressors cause the cellular damage, inflammation and pigmentation on skin cells. nd 2 Shield - Enhances Barrier Function, Elimination of Radicals and PAHs Reduces Radical formation Induces Filaggrin Expression Filaggrin Aquatide-TripleShield has been developed specifically for troubled or sensitive skin. Aquatide-TripleShield contains three active ingredients, Aquatide, Silver Oxide and Sialyllactose, that protects the skin from the environmental stressor - PM10, PM2.5, heavy metals, PAHs and pollen - and improves skin resistance and moisture barrier, enhances antioxidant. AQUATIDE shows higher ROS scavenging activity compared to ascorbic acid Aquatide AQUATIDE increases filaggrin expression in keratinocytes Activity and Efficacy st 1 Shield - Repels Heavy Metals and Viral Infection rd 3 Shield - Increases Homeostasis to Suppress Inflammation Pollen, PM2.5 and its major harmful component PAH, especially benzo[a]pyrene increase PGE2 production through COX2 induction and show a sign of inflammatory symptoms. Reduces PGE2 secretion Protects skin from irritancy Vehicle formulation PM2.5 Pollen { Dust Virus etc. Heavy metals PAHs Aquatide-TripleShield formulation PM2.5 Pollen UV O 3 Dust Virus etc. Heavy metals PAH AQUATIDE reduces LPS/PM2.5-mediated PGE2 secretion. Aquatide-TripleShield reduces pollutants-mediated inflammation and irritancy. Healthy skin Damaged skin Damaged skin + Modified from Journal of Dermatological Science 75(2014) Aquatide-TripleShield Silver Oxide prevents heavy metals ion accumulation and penetration through repulsive force Sialyllactose prevents virus infection and activates innate immunity Hexacarboxymethyl Dipeptide-12 (and) Sialyllactose (and) Silver Oxide 0.05% Aquatide 0.095% Calcium sodium borosilicate 0.05% Sialyllactose 0.005% Silver oxide % Water 5~20% for cream, lotion and essence formulation 1~5% for masksheet Anti-pollution Increases water retaining activity Increases ROS scavenging activity Enhances innate immune response Sensitive skin care Anti-oxidant Anti-inflammation Patent No Patent application in process 7 8

5 Biotide2000 Catalog Number ICP1003 Ingredients for Cosmetic and Pharmaceutical s is a conjugate of hexapeptide-2 and biotin. Hexapeptide-2 plays an important role in increasing muscle mass, and rejuvenating connective tissues by stimulating the growth hormone secretion. Biotin, known as vitamin B7, also plays an important role in the epidermal metabolism and turn over to keep healthy skin conditions. Reduces Fine wrinkle Before 4 weeks 9 weeks Before 5 weeks Aged dermis contains low quantity of collagen, which weakens dermal strength and appears fine wrinkle on all face. Biotide 2000 directly stimulates the collagen production in the fibroblast cells, and also increases the mass of healthy fibroblasts consisting dermis layer of the skin. Activity and Efficacy Increases collagen expression in 3D skin model Control (200uM) Fine wrinkles is reduced after 4-5 weeks of application, and its reduction is significant after 9 weeks of application. Action mechanism of Paracrine factors transcription Type1 collagen transcription FGF2 FGF5 ILs Keratinocyte increases collagen expression (Masson s Trichrome staining and ELISA) and enlarges dermis layer Induces expression of cell communicating proteins Increases Collagen synthesis Fibroblast CollagenⅩⅦ Fibrils of type1 collagen Collagen-17 stimulates not only collagen gene expression in fibroblast cells, but also keratinocyte cells to secret Laminin-5 paracrine factors (FGF2, FGF5 and Interleukins), which activate dermal fibroblast cells to synthesise collagen actively. Integrin α6 ß-actin Laminin-5 Integrin-α6 Biotinoyl hexapeptide-2 amide 0.2% Biotide 2.0% 1,2-Hexanediol 97.8% Water 2~5% for cream. cream, lotion and essence formulation 0.1~1% for masksheets Anti-wrinkle Patent No USP:9,180,082 EP: increases expression of Collagen-17, Laminin-5 and Integrin-α6 9 10

6 rhegf Catalog Number ICP0206 Pineapple Ceramide Catalog Number ICP0102 EGF (Epidermal Growth Factor) stimulates the growth and differentiation of the fibroblasts and epithelial cells, and plays a role in the development and regeneration of various tissues. Activity Increases BALB/3T3 proliferation rhegf NIBSC EGF Control 1ng/ml 5ng/ml 10ng/ml Incospharm s rhegf has 10X higher BALB/3T3 proliferation activity than EGF standard from The National Institute for Biological Standards and Control (NIBSC) rh-oligopeptide-1 Purity 95% 10 ppm Endotoxin 10EU/mg Bioactivity 1.0x107IU/mg Anti-wrinkle Reduces pore size Eliminates scars and speckles Improves texture and condition of skin Prevents hair loss Treats burns, wound healing Pineapple Ceramide contains the highest content of glucose linked ceramide- glucoceramide. Glucoceramide reduces melanin contents, induces hyaluronic acid synthase-3 and aquaporin-3 expressions. Therefore, glucoceramide treatment contributes skin lightening, moisturising and smoothing effect. Activity Maintains healthy skin structure control HAS3 Filaggrin Laminin5 Collagen-1 Aquaporin-3 19% 22% 57% 75% 117% Ananas Sativus(pineapple) Fruit Extract Cyclodextrin (80%) Ananas Sativus Fruit Extract (20%) 0.1 ~ 0.5% Skin lightening Moisturising Texture improvement Pineapple Ceramide increases expression of skin barrier related proteins and improves healthy skin structure Bioredoxyl Catalog Number ICP0101 Wasabi Flavone Catalog Number ICP0103 Thioredoxin (TRX) controls REDOX (Oxidation-Reduction) reaction, and moderate bio-stress depending system like inflammation and immunological reaction. Bioredoxyl containing high concentration of TRX improves atopic dermatitis and skin ageing symptoms-melanin accumulation, skin redness after sunburn and wrinkle. Rice Ferment Filtrate (SAKE) Rice Ferment Filtrate (SAKE) - TRX content : over 1,000ppm 0.1 ~ 0.2% Wasabi Flavone helps to keep healthy skin function through increasing collagen production, and helps to introduce matured collagen with enhancing its triple helix structure that is closely related to anti-ageing and deep wrinkle reduction. Wasabia Japonica Leaf Extract 1,3-Butylene glycol (98.8%) Wasabia Japonica Leaf Extract (1.2%) 0.5 ~ 1% Efficacy Reduces UV-mediated redness Moderate hyper immune-response Anti-oxidation Anti-inflammation Reduces atopic dermatitis symptoms Efficacy Reduces wrinkle depth Maturation of collagen Anti-wrinkle Bioredoxyl reduces UV irradiation-mediated redness Day0 Day56 Bioredoxyl improves skin conditions against atopic and dry skin on adults and children Wasabi Flavone reduces deep wrinkles after 12 weeks 11 12