A New Cosmeceutical for Estrogen Deficient Skin Diane S. Berson - PowerPoint PPT Presentation

A New Cosmeceutical for Estrogen Deficient Skin Diane S. Berson M.D. Weill Cornell Medicine New York, New York

Disclosures • Allergan • Aclaris • Galderma • P & G • Ortho Derm • Dermira • Almirall • Sienna • Ferndale • Revance • J & J • Sonoma • L’Oreal

Estrogen receptors and the skin 1‐2 Estrogen receptors (ERs) in skin cells • ER  and ER  Two pathways : (keratinocytes, fibroblasts, and 1. Genomic cells of epidermal appendages) (DNA related) • ER  more widespread 2. Non‐genomic • ER expression highest on face, scalp and vagina • Estrogen increases ER expression Reference: 1. Hall G, Phillips TJ . J Am Acad Dermatol. 2005;53:555‐68. 2. Thornton MJ Dermo‐Endocrinology . 2013;5:2, 264‐270

ER signaling results in visible effects on skin The image part with relationship ID rId2 was not found in the file. Estrogen has been shown to 1‐4 : ↑ moisture retention ↑ skin rigidity, elasticity, wound healing ( hyaluronic acid, mucopolysaccharides, sebum production) ↑ hydration, epidermal thickness, blood flow ↑ thickness of cutaneous layers (epidermis: keratinocyte proliferation, dermis: fibroblast proliferation) ↑ extracellular matrix components ↓ wrinkling (collagen, elastin, fibrillin) Estrogen is an essential component to skin Evidence of estrogen’s effect on skin comes functioning, health and wellness primarily from studies of the application of exogenous estrogen to post‐menopausal women References: 1 . Hall G, Phillips TJ . J Am Acad Dermatol. 2005;53:555‐68. 2. Wolff EF, Narayan D, Taylor HS. Fertil Steril . 2005;84:285‐8. 3. Svoboda RM, Del Rosso JQ, Zeichner JA, Draelos ZD. Skin. 2018;2:308‐16. 4. Draelos ZD. Fertil Steril. 2005;84(2):291‐2.

The picture of Estrogen Deficient Skin (EDS) 1‐3 What the Patient experiences Histological Changes • Significant decrease in Collagen I & III • Dryness and type 1 procollagen • Pruritis • Decrease in glycoaminoglycan content • Increased wrinkles • Decrease in TGF‐β1 expression • Thinning • Reduced expression of IGF‐1 receptors • Atrophy and production of IGF‐1 • Impaired wound healing • Reduced ROS defense activity References: 1 . Hall G, Phillips TJ . J Am Acad Dermatol. 2005;53:555‐68. 2. Thornton MJ Dermo‐Endocrinology . 2013;5:2, 264‐270 3. Rzepecki AK, Murase J, Juran R, Fabi S, McLellan B. “Estrogen Deficient Skin: The Role of Topical Therapy”. International Journal of Women’s Dermatology, 2019, in press.

Significant collagen loss after onset of menopause 1 References: 1. Archer DF. Gynecol Endocrinol . 2012;28(suppl 2):2‐6. 2. Hall G, Phillips TJ . J Am Acad Dermatol. 2005;53:555‐68. 3. Shu YY, Maibach HI. Am J Clin Dermatol . 2011;12:297‐311.

EDS a serious condition for dermatology Patient Education needed • Women generally don’t relate skin changes to menopause • Some associated “Dryness” • Virtually none are aware of collagen loss associated with EDS 2 • When informed of 30% loss statistic, menopausal women increased skin concerns to level of “hot flashes” • Dermatologists rarely discuss with patients Reference: 1. The menopause. Women’s Health Concern website. www.womens‐health‐concern.org/help‐and‐advice/factsheets/menopause/. Accessed September 11, 2018. 2 . AK Rzepecki, J Murase, R Juran, S Fabi, B McLellan, International Journal of Women’s Dermatology, 2019, in press

Importance is growing • Mean life expectancy, now 76.8, has increased 30 years since 1900 1 • Onset of menopause has been delayed by only 5 years in the same time so women spend more of life in menopause 3 • ~6,000 women enter menopause daily 2 • ~46 million women over 55 by 2020 2 References: 1. Ten great public health achievements. United States, 2001‐2010. MMWR . 2011;60:619‐23. 2 . 2011 Women’s Health Stats & Facts. American Congress of Obstetricians and Gynecologists (ACOG). 3 . From Menarche to Menopause: Trends among US Women Born from 1912 to 1969 . Hazel B. Nichols Amy Trentham‐Dietz John M. Hampton Linda Titus‐ErnstoffKathleen M. Egan Walter C. Willett Polly A. Newcomb, American Journal of Epidemiology, Volume 164, Issue 10, 15 November 2006, Pages 1003–1011, https://doi.org/10.1093/aje/kwj282, Published: 8/23/2006. 4. Life expectancy in the USA, 1900‐98,. www.demog.berkeley.edu/~andrew/1918/figure2.html,. 5. Life expectancy in the USA, 1900‐98. men and women. Year. M. F. 1900. 46.3. 48.3. 1901. 47.6. 50.6. 1902. 49.8. 53.4. 1903. 49.1. 52.0. 1904. 46.2. 49.1. 1905.

Addressing EDS with HRT 1‐2 • Indicated to treat postmenopausal symptoms, eg hot flashes, etc. • Multiple documented ancillary benefits for the skin • Studies show improvement in moisture, thickness and signs of aging • One double‐blind placebo controlled study showed no statistical difference in dryness, itching, bruising or thinning • An open‐label study showed no significant difference in histology, including collagen content or skin thickness • Declining use due to fears of coronary artery disease, stroke, hyperplasia or cancer of the endometrium, breast & ovaries • Women turning to bioidentical HRT • No controlled studies Reference: 1. Svoboda RM, Del Rosso JQ, Zeichner JA, Draelos ZD. S kin . 2018;2:308-16. 2. Hall G, Phillips TJ . J Am Acad Dermatol. 2005;53:555‐68 .

Addressing EDS with topical estrogen 1‐2 • Topical estradiol & estradiol valerate • Indicated for VVA; use for EDS is off‐label • 23+ studies evaluating effect on EDS • Concentrations of 0.01% ‐ 0.062% • Documented benefits for the skin including skin thickness, dryness, wrinkles, etc • Risks of telangiectasias, irritation and tenderness • Some evidence of systemic absorption and, therefore, the associated risks (coronary artery disease, stroke, cancer, etc) Reference: 1. Svoboda RM, Del Rosso JQ, Zeichner JA, Draelos ZD. Skin . 2018;2:308‐16. 2. AK Rzepecki, J Murase, R Juran, S Fabi, B McLellan, International Journal of Women’s Dermatology, 2019, in press

Addressing EDS with SERMs 1 • Selective estrogen receptor modulators (SERMs) • Phytoestrogens (soy, isoflavones, genistein) • Lack evidence of ER activation • Most positive effects were increased hydration & improvement in wrinkles • Most data regarding increased collagen and improved epidermal thickness as not significant • Effects most likely due to vehicle or antioxidant activity Reference: 1. Svoboda RM, Del Rosso JQ, Zeichner JA, Draelos ZD. Skin . 2018;2:308‐16. 2. AK Rzepecki, J Murase, R Juran, S Fabi, B McLellan, International Journal of Women’s Dermatology, 2019, in press

Need for an EDS solution 1 Ideal solution: A product that has estrogen’s beneficial cutaneous effects without the potential for effects elsewhere in the body Reference: 1. Svoboda RM, Del Rosso JQ, Zeichner JA, Draelos ZD. Skin . 2018;2:308‐16.

MEP Technology Synthetic estrogenic sterol ester OH O CH 3 CH 3 • 1% ERβ binding affinity of estradiol • No “off target” activity: rapidly converted O by hydrolytic enzymes to inactivated hydrolysis carboxylic enzymes H O A new class of cosmeceutical agent Methyl Estradiolpropanoate (MEP): Non‐hormonal Estrogen Methyl 3‐((8R,9S,13S,14S,16R,17S)3,17‐dihydroxy‐ Receptor Agonist (NERA) 13‐methyl‐7,8,9,11,12,13,14,15,16,17‐decahydro‐ 6H‐cyclopenta[a]phenanthren‐16‐yl)propanoate

MEP Technology Non‐hormonal estrogen receptor agonist (NERA) • Unlike estradiol, MEP is not a hormone • None of the potential risks • Unlike SERMs, MEP is an agonist, not a modulator • Mode of action is known and demonstrably effective

Promising preclinical data for MEP precursor Epithelium Epithelium Epithelium Epithelium Epithelium Epithelium Vehicle Control | Rat 27316 Estradiol 10 µg/kg | Rat 27337 “Compound C” 100 µg/kg | Rat 27314 “Compound C” is a molecule Preclinical findings: of similar structure to MEP • Produced the same healthy thickening response of the and used for clinical proof of epithelium and vaginal wall subtypes as estradiol concept studies NOTE: MEP has not been and will not be tested on animals.

Promising preclinical data for MEP precursor, cont. Endometrium Vehicle Control | Rat 27316 Estradiol 10 µg/kg | Rat 27337 “Compound C” 100 µg/kg | Rat 27314 “Compound C” is a molecule Preclinical findings: of similar structure to MEP • No undesired effect on the uterus at supra‐therapeutic doses and used for clinical proof of • Subcutaneous dosing indicated potential for large safety concept studies margin compared to estradiol NOTE: MEP has not been and will not be tested on animals.

Clinical Study A Double‐Blind Randomized Pilot Study Evaluating the Safety and Efficacy of Topical MEP in the Facial Appearance Improvement of Estrogen Deficient Females Zoe Diana Draelos, MD PUBLISHED NOVEMBER 2018 The image part with relationship ID rId2 was not found in the file.

Safety study design • Randomized, placebo‐controlled • N=60 (40 active; 20 placebo) • Ages 53‐80; all amenorreic for 3+ years • Applied twice daily to face for 12 weeks • Blood samples at baseline and week 12 • Evaluated* for presence of MEP and inactive metabolite (alkyl carboxylate E161,0,8) • Investigator and subjects evaluated tolerability * MicroConstants, Inc. San Diego, CA.