42x90 PowerPoint Presentation RESEARCH POSTER PRESENTATION DESIGN © 2019 www.PosterPresentations.com Introduction Mechanism of Action • Cysteamine is an aminothiol naturally present in human body cells as an antioxidant resulting from the degradation of Coenzyme A.1 • Cysteamine hydrochloride is known for its potent depigmenting effect since 1960's when Chavin tested it through injecting cysteamine into the black goldfish skin.2 Other in vitro and animal in vivo studies showed the higher depigmenting efficacy of this cysteamine compared to hydroquinone.3-5 • However, rapid oxidation and very offensive odor made it difficult for topical use.6 • An innovative technology has now been released to stabilize and deodorize cysteamine. Cysteamine thus became utilizable for the first time in a topical product.7 • Stabilized cysteamine has demonstrated significant effectiveness for the treatment of melasma by two double-blind randomized and vehicle control clinical studies, showing both greater reduction in mMASI score and melanin index compared to placebo.7- 8 References 1. Gallego-Villar (2017). Cysteamine revisited: repair of arginine to cysteine mutations. J. Inherit. Metab. Dis., 40(4), 555-567. 2. Chavin, W.; Schlesinger, W. (1966). Some potent melanin depigmentary agents in the black goldfish. Die Naturwissenschaften 53(16): 413–414. 3. Frenk E, Pathak MA, Szabo G, Fitzpatrick TB. (1968). Selective action of mercaptoethylamines on melanocytes in mammalian skin: experimental depigmentation. Arch Dermatol 97:465–77. 4. Bleehen, S. S., Pathak, M. A., Hori, Y., & Fitzpatrick, T. B. (1968). Depigmentation of skin with 4-isopropylcatechol, mercaptoamines, and other compounds. J Invest Dermatol, 50(2), 103-117. 5. Qiu L, Zhang M, Sturm RA, Gardiner B, Tonks I, Kay G, Parsons PG. (2000) Inhibition of melanin synthesis by cysteamine in human melanoma cells. J Invest Dermatol. 114(1):21-7. 6. Atallah, C., Charcosset, C., & Greige-Gerges, H. (2020). Challenges for cysteamine stabilization, quantification, and biological effects improvement. J Pharm Anal. 7. Mansouri, P.; Farshi, S.; Hashemi, Z.; Kasraee, B. (2015).Evaluation of the efficacy of cysteamine 5% cream in the treatment of epidermal melasma: a randomized double-blind placebo-controlled trial. Br J Dermatol. 173 (1): 209–217. 8. Farshi, and al. (2017).Efficacy of cysteamine cream in the treatment of epidermal melasma, evaluating by Dermacatch as a new measurement method: a randomized double-blind placebo-controlled study. J Dermatol Treat, 1–8. 9. Wood, J. M., & Schallreuter, K. U. (1991). Studies on the reactions between human tyrosinase, superoxide anion, hydrogen peroxide and thiols. Biochim Biophys Acta, 1074(3), 378-385. 10. Sakurai, H.; Yokoyama, A.; Tanaka, H. (1971). Studies on the sulfur-containing chelating agents. XXXI. Catalytic effect of copper (II) ion to formation of mixed disulfide. Chem. Pharm. Bull. 19, 1416–1423 11. Bottu, G. (1989). The effect of quenchers on the chemiluminescence of luminol and lucigenin. J Biolumin Chemilumin. 12. Crinelli, Rita, et al. (2019). Boosting GSH Using the Co-Drug Approach: I-152, a Conjugate of N-acetyl-cysteine and β- mercaptoethylamine. Nutrients 11.6 1291. 13. Publication pending 14. Karrabi, M., and al. (2020). Clinical evaluation of efficacy, safety and tolerability of cysteamine 5% cream in comparison with modified Kligman’s formula in subjects with epidermal melasma: A randomized, double‐blind clinical trial study. Skin Res and Technology 15. Karrabi, M., and al. (2020). Clinical evaluation of efficacy and tolerability of cysteamine 5% cream in comparison with tranexamic acid mesotherapy in subjects with melasma: a single-blind, randomized clinical trial study. Arch of Dermatol Res. 16. Nguyen, J & Rodrigues, M. (2021). Evaluation of the efficacy of cysteamine cream compared to hydroquinone in the treatment of melasma: A randomised, double‐blinded trial. Aus J Dermatol, 62(1), e41-e46. Seemal R. Desai, MD FAAD Director and Founder: Innovative Dermatology Clinical Assistant Professor of Dermatology: University of Texas Southwestern Cysteamine: Clinical efficacy, safety and tolerability versus best-in-class treatments for melasma Cysteamine has a broad action in the regulation of melanogenesis: • Enzymatic effect: inhibition of tyrosinase and peroxidase, essential enzymes in the melanogenesis pathway leading to the conversion of tyrosine into dopaquinone, and to the polymerization of indoles into melanin.9 • Chemical effect: chelation of mineral ions, preventing Fenton-type reactions.10 • Antioxidant & Quencher of free radicals: suppression of all the oxidation steps in the melanogenesis process & prevention of photo-oxidation (ie darkening of melanin precursors in the epidermis). 11 • Cascade reaction: increase of intracellular glutathione, amplifying natural depigmenting effects.12 • Keratolytic effect: by breaking keratin disulfide bonds, it enhances the removal of melanin contained in the superficial epidermis layers and accelerates the epidermal turnover for generation of new non-pigmented skin layers.13 5% Stabilized Cysteamine (ST-CYS-5%) versus modified Kligman’s formula (mKF)14 Material and methods Double-blinded, Investigator-driven, randomized 50 female with melasma, 20-50 years old, assigned in 2 groups: •ST-CYS-5% 15min application + moisturizer + sunscreen (daily, 16weeks) •mKF overnight application (4% hydroquinone, 0.05% retinoic acid and 0.1% betamethasone) + moisturizer + sunscreen (daily, 16 weeks) Evaluation of mMASI score; Investigator Global Assesment & Patient questionnaires Evaluation at baseline, 8 weeks and 16 weeks Efficacity Results At both week 8 and week 16, ST-CYS-5% produced significantly greater reductions from baseline in modified Melasma Area Severity Index (mMASI) (32.3%, 51.3%), compared to mKF (23.7%, 42.3%; P = .005 and .001, respectively). Investigator global assessment and patient self-assessment scores were similar for both treatments at each time-point. Safety & Tolerability results In all and at 16 weeks, 64% of patients treated with ST-CYS-5% reported no skin irritation, whereas only 8% of patients treated with mKF reported no skin irritation. 5% Stabilized Cysteamine (ST-CYS-5%) versus Tranexamic Acid mesotherapy (TXA)15 Material and methods Single-blinded, Investigator-driven, Randomized 54 female with melasma, 18-50 years old, assigned in 2 groups: •ST-CYS-5% 30min application (daily, 16weeks) •TXA 0.05ml (4mg/mL) administered mesotherapy (every 4 weeks for 8 weeks) Evaluation of mMASI score and Melanin Index Evaluation at baseline, 8 weeks and 16 weeks for group ST-CYS-5% Evaluation at baseline, 4 weeks and 8 weeks for group TXA Efficacity Results The degree of improvement of mMASI reduction was 45.9% for ST-CYS-5% after 16 weeks and 47.1% for multiple sessions of TXA mesotherapy. No patient in either group had recurrence of melasma in the follow-up period. In both group and at both visits, Melanin index measured by Dermacatch was equally reduced (p>0.1). Safety & Tolerability results Complications were significantly more frequent in the TXA group. -27.4% -45.9% -32.6% -47.1% -50.0% -40.0% -30.0% -20.0% -10.0% 0.0% Stabilized Cysteamine (Cyspera® Scientis SA) TXA mesotherapy 5% Stabilized Cysteamine (ST-CYS-5%) versus Hydroquinone 5% (HQ)16 Material and methods Double-blinded, Investigator-driven, Randomized 20 female with melasma, >18 years old, assigned in 2 groups : •ST-CYS-5% 15min application + moisturizer + sunscreen (daily, 16weeks) •Moisturizer + HQ4% + sunscreens (daily 16weeks) Evaluation of mMASI score & Quality of Life (QoL) questionnaire Evaluation at baseline, 8 weeks and 16 weeks Efficacity Results Various limitations for this study due to large number of drop out in both groups and small number of volunteer initially recruited (n= 9 in HQ group, n=5 in ST-CYS group) At week 16, ST-CYS-5% was shown to be slightly superior in MASI score reduction compared to HQ4% when analyzed as per protocol (-39.1% versus -33%, p=0.96) At week 16, QoL was slightly improved in both group, but not in a significant way Conclusion : Stabilized topical cysteamine was proven to be significatively more effective for the treatment of melasma and better tolerated than the modified Kligman’s formula. When compared to Hydroquinone and physician administered mesotherapy tranexamic acid (TXA), stabilized cysteamine was shown to be as effective and better tolerated. According to these results, cysteamine can be considered the first line non-hydroquinone treatment for melasma. Comparison of Evolution in mMASI Score versus baseline -60.0% -50.0% -40.0% -30.0% -20.0% -10.0% 0.0% -32.3% -51.3% -23.7% - 42.3% Stabilized Cysteamine (Cyspera® Scientis SA) modified Kligman Formula Visit 1 (8 weeks) Visit 2 (16 weeks) Sig. superior mMASI score reduction at 2 and 4 months None Mild Moderate Severe Comparison of the severity of adverse events observed after 16weeks (irritation) Stabilized Cysteamine Modified Kligman Formula 92% irritation with mKF incl. 12% severe cases Comparison of Evolution in mMASI Score versus baseline Visit 1 (8 weeks for ST-CYS, 4weeks for TXA) Visit 2 (16 weeks for ST-CYS, 8 weeks for TXA) Comparable mMASI score reduction None Mild Moderate Severe Stabilized Cysteamine (Cyspera® Scientis SA) TXA Mesotherapy Comparison of the severity of adverse events observed at end of treatment (irritation) -19.7% -39.1%-39.2% -33.0% -50.0% -40.0% -30.0% -20.0% -10.0% 0.0% Stabilized Cysteamine (Cyspera® Scientis SA) Hydroquinone 4% Visit 1 (8 weeks) Visit 2 (16 weeks) 100% of patients shows signs of irritation * (p value = 0.005) *** (p value = 0.001) *** (p value < 0.001) *** (p value < 0.001) Comparable mMASI score reduction