JV- Herbal Extraction Facility- ChengDu

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2 About Us Bonatics provides a range of herbal-based skin care products to treat common skin conditions Based on Chinese herbology principles Clinically proven solutions for common skin conditions Developed by Kamedis, with over a decade of experience in formulation and development of natural based herbal products

3 JV- Herbal Extraction Facility- ChengDu Dr. Xia LongJiang Dr. Lin Shan

4 JV- Inner-Mongolia

5 Advantages Multifunctional ingredients exhibiting multiple biological activities In-depth research and comprehensive clinical trials Long term use High concentration of herbal extracts with enhanced biological activity Products vehicle especially designed to improve treatment efficacy Products manufactured under stringent quality control procedures

6 Technology Resin Column Plant Extract Unique extraction procedure using macroporous resins chromatography Resins with different porous structure parameters and polarities Biological enhanced activity achieved by increased active ingredients concentration Chromatography process removing organic salts, heavy metals and large quantities of starch Improves product stability and shelf-life Highest quality control procedures Enriched extract

7 %Active ingredients Technology Da Huang (Rhubarb) - Enrichment of Active Ingredients Before chromatography After chromatography

8 Technology Herbal extracts Enhanced Biological Activity Inhibition of pro-inflammatory cytokine secretion

9 Atopic dermatitis AD most often begins in childhood before the age of 5 (10-30%) and may persist into adulthood, or may appear during that time (1-3%) The prevalence of atopic dermatitis has increased over the last three decades Symptoms- pruritus (itching), redness, xerosis (dry skin), and lichenification (thickening of the skin) Intense itching can cause skin thickening and lead to further complications, including bacterial infection AD can affect any part of the body (hands, feet, face, neck and upper chest). In infants, AD usually manifests itself in the cheeks, the front of the knees, and the back of the elbows Symptoms might be aggravated by stress, seasonal allergies, exposure to harsh soaps and detergents, cold weather, low humidity, sweating, dust, sand, long and hot baths or showers and wool fabrics or clothing

10 Atopic dermatitis- Treatments The current treatments for AD cannot cure the skin disorder but do control the severity and duration of its symptoms. Most of the current treatment show side effects associated with long-term use. Topical Corticosteroids Topical Calcineurin Inhibitors - immunosuppressant agents Antibiotics - Concerns about resistance limit the use of antibiotics to treat only acute skin lesions Systemic Therapy Topical application of emollients and moisturizers- preserve and restore the compromised barrier function

11 Atopic dermatitis- TCM clinical trials A controlled trial of traditional Chinese medicinal plants in widespread non-exudative atopic eczema Placebo-controlled double-blind trial- a prescription formulated for widespread non-exudative atopic eczema. Forty-seven children were given active treatment and placebo in random order, each for 8 weeks, with an intervening 4-week washout period. Thirty-seven children completed the study Results: Response to active treatment was superior to response to placebo No evidence of haematological, renal or hepatic toxicity Conclusion: Wide therapeutic potential for traditional Chinese medicinal plants in atopic dermatitis and other skin diseases MARY P. SHEEHAN, M.P., and ATHERTON D.J. British Journal of Dermatology, 1992, 126 (2),

12 Atopic dermatitis- TCM clinical trials The Effectiveness of Combined Chinese Herbal Medicine and Acupuncture in the Treatment of Atopic Dermatitis Objective : To assess the effectiveness of the combination of Chinese herbal medicine and acupuncture for the treatment of atopic dermatitis Methods : 20 patients (ages 13-48) with mild-to-severe atopic dermatitis were given a combined treatment of acupuncture (twice a week) and Chinese herbal formula (3 times daily) for 12 weeks Assessments: before treatment,at weeks 3, 6, 9, and 12: changes in the Eczema Area and Severity Index (EASI), Dermatology Life Quality Index (DLQI), and patient assessment of itch measured on a visual analogue scale (VAS)

13 Atopic dermatitis- TCM clinical trials Results : An improvement in EASI was noted in 100% of patients, when compared with the baseline (from 4.99 to 1.81; median percentage of decrease 63.5% 78.8% of patients experienced a reduction in DLQI and VAS, as compared with the baseline (decreased from 12.5 to 7.6 at the end of treatment,with 39.1% improvement) Mean VAS decreased from 6.8 to 3.7, with 44.7% improvement No adverse effects were observed Conclusions: the combination of acupuncture and Chinese herbal medicine may have a beneficial effect on patients with atopic dermatitis Fares Salameh, David Perla, Michal Solomon, Dorit Gamus, Aviv Barzilai, Shoshana Greenberger, Henri Trau. The Journal of Alternative and Complementary Medicine, 2008, 14(8):

14 Atopic dermatitis- TCM clinical trials Objective: to evaluate the effect of licorice extract as topical preparation on atopic dermatitis patients Methods: randomized double blind, placebo-controlled trial. 90 patients with mild to moderate atopic dermatitis applied Licorice gel or placebo 3 times a day for two weeks Results: significant reduction in the scores for erythema, oedema and itching when compared with baseline and placebo Conclusion: Licorice extract could be considered as an effective agent for treatment of atopic dermatitis Saeedi M, Morteza-Semnani K, Ghoreishi MR. The treatment of atopic dermatitis with licorice gel. J Dermatolog Treat Sep;14(3):153-7.

15 Atopic dermatitis- TCM clinical trials The treatment of eczema with Chinese herbs: a systematic review of randomized clinical trials Objective: systematically review the evidence for treating eczema with Chinese herbs. Methods: Extensive literature searches were carried out to identify all randomised clinical trials on the subject. Results: Only two randomized clinical trials were located. Both imply that a complex mixture of Chinese herbs is more effective than placebo in treating eczema. Yet several caveats exist, most importantly the lack of independent replication. Adverse effects have also been reported. Conclusion: At present it is unclear whether TCM herbs are effective in the treatment of eczema Armstrong NC, Ernst E. The treatment of eczema with Chinese herbs: a systematic review of randomized clinical trials. Br J Clin Pharmacol Aug;48(2):262-4.

16 Atopic dermatitis- TCM clinical trials 1. There are no reliable double- blind, placebo controlled studies of TCM 2." The mechanism of action of TCM has not been investigated

17 Atopic dermatitis- Dry Skin Line Dry Skin Line: Cleanser Body Cream Body Cream Forte Face Cream Calming Lotion Rich Gel

18 Atopic dermatitis- Body Cream Forte Body Cream Forte- an innovative herbal-based product designed to relieve atopic dermatitis symptoms related to secondary infections by stimulating betadefensin in the affected skin

19 Body Cream Forte- Herbal Extracts Antiinflammatory activity Antiallergic activity Antimicrobial (secondary infection) Itching reduction Repair of damaged skin Da Huang Huang Qin She Chuang Zi Gan Cao- Dipotassium Glycyrrhizinate Di Yu Chun Pi

20 Body Cream Forte- Herbal Extracts Known scientific activity: Di Yu (Sanguisorba officinalis, Great Burnet): Anti-allergic activity (inhibition of histamine release) Anti-inflammatory activity (inhibition of TNF-alpha, NO production) Anti-microbial activity Antioxidant (superoxide anion-scavenging effect) Chun Pi (Ailanthus altissima, Tree of Heaven): Anti-allergic activity (inhibition of histamine release) Potent anti-inflammatory properties (down regulation of T(H)2 cytokines, such as IL-4 and IL-13)

21 Atopic dermatitis- Pathogenesis Defective barrier function of the stratum corneum (defective lipid production, particularly ceramides) - Infection- reduced antimicrobial barrier - Increased transepidermal water loss (TEWL)- increased skin dryness Inflammation- elevation of TH2 cells, results in increased production of pro-inflammatory molecules and inhibition of the innate immune system (antimicrobial peptides- defensin)

22 Atopic dermatitis

23 Atopic dermatitis secondary infections AD is often complicated by secondary infections of skin lesions by bacterial, viral and fungal pathogens A correlation between the severity of the eczema and colonization with Staphylococcus aureus has been demonstrated The skin lesions of % of patients with eczema and AD are colonized with S. aureus The density of S. aureus can reach up to 10 7 colony-forming units/ cm 2 without clinical signs of infection Beta-defensins are a class of small cationic peptides produced by keratinocytes in the skin, display an intrinsic antimicrobial activity and also regulate inflammatory and immune responses AD lesions demonstrated deficiently low expression of inflammation induced antimicrobial peptides

24 Body Cream Forte Research Stimulation Body Cream Forte Inhibition The product activity is based on two principles: Herbal extracts that stimulate human -defensin (hbd-3) expression Herbal extracts that down-regulate IL-13 expression ( -defensin inhibitor)

25 Body Cream Forte- Research

26 Body Cream Forte- Research Screening of 500 herbal extracts: - 6 Herbal extracts were found to stimulate Beta-defensin - 10 Herbal extracts were found to inhibit IL-13 Excluded- Herbal extracts that have a potential toxicity, herbal extracts that are not known for human application Herbal extracts were optimized using a macro-porous resin chromatography process Synergistic activity between herbal extracts was measured Clinical study

27 hbd3 Expression level Body Cream Forte- Research Extract optimizationelevated biological activity Synergistic effect of herbal extracts 계열 Control Ailanthi radicis cortex (ARC)1% ARC+No % ARC+No % Test composition ARC+No % ARC+No % IL-13 inhibition by herbal extracts (0.3%) before and after resin chromatography Synergism between (1%) Ailanthi radicis cortex (Chun Pi) and (0.33%) Radix Sanguisorbae (Di Yu)

28 Body Cream Forte- in-vitro studies Identification of herbal extracts that stimulate human β-defensins and inhibit Th2 cytokines, abnormally expressed in atopic dermatitis Di Yu- Sanguisorba officinalis Chun Pi- Ailanthus altissima In vitro effects of Sanguisorba officinalis and Ailanthus altissima. A. inhibition of IL-13 release in KU812 cells (ELISA). Release in the presence of Dexamethasone is used as positive control. B. RT PCR on HaCaT cells- Green: hbd-3 expression in cells treated with 0.3% of herbal extract. Blue: hbd-3 expression in untreated cells. Red: GADPH expression (reference).

29 Body Cream Forte- Clinical trial SCORAD- Scoring atopic dermatitis A Extent (max score: 100) B- Intensity - 6 symptoms (erythema, oedema, oozing, excoriation, lichenification, dryness)- 0-3 (max score: 18) C- Subjective symptoms (itching, loss of sleep) (max score:20) A/5 + 7*B/2 + C Mild<25; Moderate 25-50; Severe> 50

30 Body Cream Forte- Clinical Data Assessment of skin condition in 30 atopic dermatitis patients, following treatment with Body Cream Forte for 3 weeks Dermatest, Germany Change in SCORAD** Change in SCORAD** in severe and non-severe AD 0% -10% -20% -30% -40% -50% Day 7 Day 14 Day 21-3% -26% * -46% * 0% -10% -20% -30% -40% -50% Day 7 Day 14 Day 21 non-severe, N=22 severe, N=8 Significant reduction of 46% in SCORAD Equal efficacy in severe and non- severe atopic dermatitis *p<0.01 vs. baseline **Compared to baseline

31 Body Cream Forte- Clinical Data Dermatest, Germany Intensity change** of individual symptoms after 3 weeks of treatment Patients who showed improvement in the symptoms of atopic dermatitis after 3 weeks of treatment 0% -20% Erythema Oedema Oozing ExcoriationLichenifiction Dryness N=20 N=11 N=18 N=20 N=20 N=20 100% 80% 60% 83% 71% 93% 70% 77% 90% -40% -60% -80% -100% -44% -70% -92% * -76% -69% -44% * * * * * 40% 20% 0% N=20 N=11 N=18 N=20 N=20 N=20 Erythema Oedema Oozing ExcoriationLichenifiction Dryness * p<0.001 vs. baseline ** Compared to baseline Reduction in symptoms related to 2ry infections: Oozing reduction of 92% in 93% of patients Lichenification reduction of 69% in 77% of patients Oedema reduction of 70% in 71% of patients

32 Body Cream Forte- Clinical Data Change** in average itching level after 3 weeks of treatment Dermatest, Germany 0% Day 7 Day 14 Day 21-10% -20% -14% -30% -40% -50% -30% * -60% -70% -60% * Significant reduction of 60% in itching level *p<0.001 vs. baseline **Compared to baseline (n = 19)

33 Body Cream Forte- Clinical Data Significant reduction of 16% in TEWL Significant increase of 32% in skin hydration

34 Body Cream Forte- Clinical Data Significant improvement in atopic dermatitis symptoms Significant improvement in symptoms related to secondary infections No additional treatment needed No cases of exacerbation/secondary infections following treatment No adverse events observed

35 Body Cream Forte Innovation award-2011siif (Seoul International Invention Fair) ESDR Poster presentation Patent: Plant extracts for the treatment and prevention of infections PCT/IL2011/ Ongoing clinical trial- Children with moderate- severe atopic dermatitis (Israel, Spain)

36 Bonatics vs. Competitors Clinical trials Atopic Dermatitis treatments - Barrier Repair Creams Source Treatment Co. N Method m=sugarman%2c%20 parish Treatment Duration (d) % Change Severity % Change Itch Emollient 15 EASI/VA (vehicle) 22 S Atopiclair Sinclair Atopiclair Sinclair Epiceram PuraCap 13 EASI/VA S Aquaphor Eucerin Atopiclair Sinclair 63 VAS Epiceram Fluticasone Propionate 0.05% cream (steroid) Body Cream Forte PuraCap Perrigo Kamedis 59 children 62 children 30 adults SCORAD SCORAD

37 Bonatics vs. Competitors Clinical trials Atopic Dermatitis treatments - Topical Calcineurin Inhibitors - nonsteroidal immunosuppressive agents Source Treatment Co. N Method ubmed/ ubmed/ Pimecrolimus ELIDEL Tacrolimus PROTOPIC Tacrolimus PROTOPIC Pimecrolimus ELIDEL Novartis 217 Astellas Pharma Astellas Pharma Treatment Duration (d) % Change Severity EASI EASI Novartis Vehicle ubmed/ Pimecrolimus 1.0% Betamethasone -17- valerate cream (steroid) Novartis 45 EASI Body Cream Forte Kamedi s 30 adults SCORAD 21-46

38 Dry Skin Line Fragrance Free, Steroid Free, Paraben Free, SLS Free Product Skin type Treatment Principles Instruction for use Intended use Main Active ingredients Body Cream Itchy, Dry & Irritated Skin (mildmoderate AD) Relief for itchy, dry, red and irritated skin Highly nourishing and moisturizing Soothing and hydrating Apply 1-3 times a day. For children aged 6 months to 3 years, apply once a day. Da Huang, She Chuang Zi, Huang Qin, Dipotassium Glycyrhizate, Ceramides & Cholesterol & Phytosphingosine, Hyaluronic Acid Body Cream Forte Face Cream Extremely Itchy, Dry& Irritated skin (moderatesevere AD) Itchy, Dry & Red Skin Soothes severely irritated and itchy skin Protects and replenishes the skin s moisture barrier Highly nourishing and moisturizing Relief for itchy, dry, red and irritated skin Highly nourishing and moisturizing Soothing and hydrating Apply 1-3 times a day. For children aged 6 months to 3 years, apply once a day. Apply to clean skin. Use 1-3 times a day on dry, red, irritated and itchy skin. During the day, use under sunscreen. For children aged 6 months to 3 years, apply once a day Suitable for adults and children aged 6 months and older. Da Huang, She Chuang Zi, Huang Qin, Di Yu, Chun Pi, Dipotassium Glycyrhizate, Ceramides & Cholesterol & Phytosphingosine, Hyaluronic Acid Da Huang, She Chuang Zi, Huang Qin, Dipotassium Glycyrhizate, Ceramides & Cholesterol & Phytosphingosine, Hydroxyphenyl Propamidobenzoic Acid, Bisabolol, Hyaluronic Acid Cleanser Itchy, Dry & Red Skin Rapid and gentle relief Cleanses and moisturizes the skin Soothes the skin Use 1-3 times a day as a daily soap for shower and bath. For children aged 6 months to 3 years, use once a day Wu Huan Zi, Da Feng Zi, Ma Chi Xian, Allantoin

39 Dry Skin Line Fragrance Free, Steroid Free, Paraben Free, SLS Free Product Skin type Treatment Principles Instruction for use Intended use Main Active ingredients Calming Moisturizer Rich Hydrating Gel Local Treatment of Itchy & Irritated Skin. Calming the Skin after Stings Extra Dry & Cracked Skin Areas (Hands and Feet) Calms irritation caused by insect bites Immediate relief for red, irritated and itchy skin Treats extra dry and chapped skin areas Moisturizes and nourishes severely dry skin Calms redness and irritation Apply to clean skin. Use 1-3 times a day on irritated and itchy skin. For best results, two applications, minutes apart, are recommended. For children aged 6 months to 3 years, apply once a day. Apply 1-3 times a day to extra dry and chapped skin areas. For children aged 6 months to 3 years, apply once a day. Suitable for adults and children aged 6 months and older. Da Huang, She Chuang Zi, Huang Qin, Dipotassium Glycyrhizate, Hydroxyphenyl Propamidobenzoic Acid, Bisabolol, Hyaluronic Acid Da Huang, She Chuang Zi, Huang Qin, Dipotassium Glycyrhizate, Hyaluronic Acid

40 Dry Skin Line Product Skin barrier (lipids) ingredients Moisturizing ingredients Calming ingredients Anti-Inflammatory ingredients Body Cream Body Cream FORTE Face Cream Rich Hydrating Gel Calming Moisturizer Cleanser

41 Personal clinical experience 1.5 years of clinical application Clear indications, wide applications Well tolerated by patients Easy applications Good patient feedback Modern packaging

42 Atopic dermatitis- Dry Skin Line

43 Indications Erythema: Forte Regular Itching: Calming lotion Dry skin: Rich gel Facial lesions: Face/Forte All atopies: Wash

44 Atopic dermatitis- Dry Skin Line A 2-year-old boy had been suffering from atopic dermatitis of the facial skin for several months, demonstrating visible redness of the cheeks and persistent itching. During treatment with Dry Skin Cleanser and Dry Skin Face Cream, all the symptoms of itchiness and redness gradually disappeared. After four months, the boy made a full recovery with no signs of skin irritation, and the atopic skin infection has not recurred, even after two years of monitoring (Israel, TCM Clinic).

45 Atopic dermatitis- Dry Skin Line The patient, a 26-year-old female, had suffered from atopic dermatitis for more than 20 years. Her symptoms mainly included erythema in the joint creases and on the knees and cheeks, with severe lichenification and itching. She had previously been treated with a variety of products, including steroid-based creams, to no avail. Treatment with Dry Skin Body Cream delivered rapid relief from itching. After two weeks, the symptoms disappeared completely (Israel, TCM Clinic).

46 Atopic dermatitis- Dry Skin Line The patient, a 10-year-old girl, had been suffering from atopic dermatitis on her hands, legs, and face since the age of 3. Following treatment with Dry Skin Body Cream, a significant improvement began in the condition of her skin. After 45 days, the symptoms had been completely eradicated, and there was no need for further treatment (Israel, TCM Clinic).

47 Atopic dermatitis- Dry Skin Line The patient, a 1-year-old baby, was suffering from the symptoms of atopic dermatitis on his arms and legs. Dry Skin Body Cream was applied 1-2 times a day to the affected areas of the body, and after only 4 days the symptoms had almost completely disappeared (Spain, distributer).

48 Calming

49 Forte Regular

50 Face/Forte

51 Other indications Heat in the skin Sunburn: Rich gel Sun allergy: Regular Rash: Regular/Calming Urticaria: Calming

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