Introduction to Bioidentical Hormone Replacement Therapy Enrique Jacome

Introduction to Bioidentical Hormone Replacement Therapy Enrique Jacome, MD, FAACOG Enrique Jacome, MD, FACOG

Founder & CEO • Enrique Jacome, MD, FACOG, Founder & Medical Director – Dr. Enrique G. Jacome is board certified by the American College of Obstetrics and Gynecology. He is a leading expert in Robotic Surgery, having performed close to 1, 000 robotic procedures and more than 3, 000 laparoscopic cases. As an innovator and pioneer with a unique background in hormone pellet insertion, Dr. Jacome is committed to improved the insertion technique and the pharmacokinetics related to the pellet manufacturing process. • Melissa Vinci-Rainis, CEO – With 25 years of experience, Melissa brings a proven track record as an expert in the healthcare industry. Her comprehensive knowledge of medical devices and women’s healthcare was the result of her work in the pharmaceutical industry. As CEO, Melissa directs all operations within Pellecome, including research and product development.

Management Team • • Kenneth Orbeck, DO – Medical Director, East Coast – Dr. Kenneth Orbeck practices integrative and functional medicine at his South Carolina-based bioidentical hormones practice. As a bioidentical hormones expert, Dr. Orbeck specializes in treating the underlying causes of symptoms oftentimes associated with aging, such as hot flashes, night sweats, low libido, weight gain, fatigue, mood swings and irritability. Dr. Orbeck is currently an active member of the fellowship for Anti-Aging, Regenerative and Functional Medicine (FAAFM), and the Age Management Medical Group (AMMG). Bev Blessing, MSN, PHD, FNP-BC, Chief Clinical Officer – Bev is a Family Nurse Practitioner with over 40 years of experience in clinical OBGYN and administrative medicine. Previous consultant to Health Affairs and Air Force Surgeon General. Previous CEO of University Med School and Well. Max Preventive Medicine. PHD in Health Administration focusing on mergers and acquisitions. Bev brings a wealth of experiences blending an active practice in women's health and hormone management with extensive experience in multiple aspects of health care innovation and delivery.

Management Team • • Jayson Jonsson, National Sales Director – Jayson Jonsson contributes his strategic and sales management expertise to develop highly successful sales teams and innovative lead generation programs for medical device companies. Mark Chenoweth, Sales Director – East Coast – With over 17 years of leadership experience in the aesthetic and medical device markets, Mark has lead successful sales and marketing operations through strong leadership, growth, and development initiatives. Tom Stephens, VP Regulatory, Clinical & Quality – Tom is a seasoned Regulatory, Development, and Quality professional with over 30 years in the pharmaceutical and medical device industries. His career includes positions with large industry leaders, such Glaxo. Smith. Kline and Ethicon/Johnson & Johnson, but his career focus has been to work with small start-up companies developing novel medical products in new markets. Karen Weintraub, Marketing & Customer Service – With over 20 years of experience in accounting and finance, Karen has worked for several companies extending across different industries. Her experience covers the day-to-day operations as well as budgeting and finance. Karen’s goal is to make an immediate impact, contributing to the success of the company and helping the company achieve its vision.

Pellet Therapy Pioneers in the USA J Am Assoc Gynecol Laparosc. 1999 Feb; 6(1): 39 -44. Laparoscopic Burch urethropexy in a private clinical practice. Jacome EG 1, Tutera G, Mattox FT. Pellecome™ LLC. Confidential.

Why Compounded Hormones? Bioidentical hormones: Regulated vs customized compounded (FDA) Prescription-regulated bioidentical hormones Customized compounded bioidentical hormones Chemically identical to human hormones US FDA oversight No FDA oversight (except 503 B) Published scientific research Minimal to no published scientific research Doses exactly reproducible Doses may be inexact and inconsistent Proven efficacy Efficacy and safety not proven in randomized control trials Pattimakiel, L. , & Tacker, H. (2011). Bioidentical hormone therapy: Clarifying the misconceptions. Cleveland Clinic Journal of Medicine, 78(12), 829 -836

Bioidentical Hormones • The B in BHRT stands for bioidentical. • Defined by Endocrine Society as compounds with EXACTLY the same chemical and molecular structure as hormones in the human body • Any modification in the compounding process can create changes in the drug structure; this is a “biosimilar” • Synthetic identical hormones [Mc. Camish Clinical Pharmacology & Therapeutics 2012 /p 409 A; Files Mayo Clin Proc 2011 /p 674 A]

Bioidentical Hormones vs Synthetics

Bioidentical Hormones vs Synthetics • Do bioidentical hormones work better than synthetics? – Meta-analysis done by Holtorf in 2009 Symptomatic Relief and QOL – Progesterone versus progestins • • 30% reduction in sleep issues 50% reduction in anxiety 60% reduction in depression 30% reduction in somatic symptoms 25% menstrual bleeding 40% reduction in cognitive difficulties 30% improvement in sexual function OVERALL 65% felt it worked better Holtorf, K. (2009). Are bioidentical hormones (estradiol, estriol, and progesterone safer or more efficacious that commonly used synthetic version in hormone replacement therapy? Postgraduate Medicine, 121(1). https: //doi. org/10. 3810/pgm. 2009. 01. 1949

Bioidentical Hormones vs Synthetics Breast Cancer Risk • Synthetic progestins increase estrogen stimulated mitotic activity and proliferation in the breast while progesterone inhibits it • WHI showed synthetic progestin increased risk for breast cancer. • Nurses’ Health Study showed a 60% increase in breast cancer when progestin was added to estrogen Holtorf, K. (2009). Are bioidentical hormones (estradiol, estriol, and progesterone safer or more efficacious that commonly used synthetic version in hormone replacement therapy? Postgraduate Medicine, 121(1). https: //doi. org/10. 3810/pgm. 2009. 01. 1949 Holtorf, H. What’s the difference between bioidentical HRT and synthetic HRT? + Which one is better? Holtorf Medical Group

Bioidentical Hormones vs Synthetics Cardiovascular Risk • From WHI study when Progestin was added to Premarin resulted in substantial increase on the risk of stroke and heart attack • Progestin reduces HDL, Increases vasoconstriction, promotes atherosclerotic plaque formation • PEPI trial showed estrogen and progesterone improved HDL over estrogen and medroxyprogesterone Holtorf, K. (2009). Are bioidentical hormones (estradiol, estriol, and progesterone safer or more efficacious that commonly used synthetic version in hormone replacement therapy? Postgraduate Medicine, 121(1). https: //doi. org/10. 3810/pgm. 2009. 01. 1949 Holtorf, H. What’s the difference between bioidentical HRT and synthetic HRT? + Which one is better? Holtorf Medical Group

Synthetic Estrogen BIOIDENTICAL • 17 -beta estradiol • Oral –Estrace NON BIOIDENTICAL • Conjugated Equine estrogen (CEE) Premarin • Equilin sulfate native to horses and estrone sulfate • Patch – Vivelle, Climara, Alora, Fempatch, Menostar • Gel – Estraderm, Estrogel, Divigel, Elestrin • Emulsion – Estrasorb • Spray – Evamist • Vaginal Cream – Estrace vaginal • Ring – Estring • • Estradiol acetate • Oral – Femtrace • Vaginal ring – Femring Estradiol hemihydrate • • Vaginal – Vagifem Estropipate Ortho E Pattimakiel, L. , & Tacker, H. (2011). Bioidentical hormone therapy: Clarifying the misconceptions. Cleveland Clinic Journal of Medicine, 78(12), 829 -836 Chart from www: menopause. org with permission of North American Menopause Society

Making Bioidentical Hormone Pellets • Testosterone pellets are made with high temperature molding without need for excipients • Smaller dose hormones such as progesterone and estradiol are made with high pressure molding. • Excipients such as stearic acid are added to address concerns regarding fragmentation. Other options include cholesterol • Purpose of stearic acid is to provide lubrication on surface and improve cohesiveness of the hormone crystalized powders • Excipients make no impact on bioidentical component of hormone because they are physiologically inert, stable, and meet regulatory requirement to not interfere with the drug. Varma, K. (2016). Excipients used in the formulation of tablets. Research and Reviews: Journal of Chemistry.

Menopause Population • 6000 women reach menopause every day • 27 million women between ages 45 -64 suffer menopausal symptoms • Represents 20% of the workforce • Anticipated to grow 4. 2% annually over the next 5 years (through 2023)

Prescriptions for Hormones Compounded vs FDA approved • Management of hormone insufficiency is changing • Trend to transition to Bio-Identical Hormones • The Rose study showed 2. 5 million US women >40 may use compounded hormone therapy annually accounting for 28 -68% of hormone therapy prescriptions. • Reported sales $1. 3 -1. 6 Billion Menopause, 2016. Apr, 23(4): 359 -67

Menopause Market Size • Menopausal Market expected to reach US $10. 6 billion in 2024 • Estrogen Leads Hormonal Products in Revenue and Prescription Volume • Breakdown: – 74. 4% Compounded bioidentical hormone drugs – 12. 9% FDA approved bio-identical separate hormone drugs – 12. 7% FDA approved synthetic, combination HRT Global Industry Analysis (2018). New studies reestablishing safety of HRT & Launch of safer drugs to drive growth of the global HRT Market amidst challenges posed by widespread off-label prescriptions.

Global Market

Low Testosterone • • • Low testosterone affects 40% of men aged 45 and older Rates increased with rising rates of diabetes, obesity, COPD, chronic kidney disease, HIV, and opioid dependence. Population based studies show hypogonadism in men 47 -60 ranges from 2. 1% to 12. 8%. It rises to 38. 7% in primary care/ screening studies. Incidence with comorbidities went as high at 78. 8% Although treatment is increasing, it continues to be only 10 -12% of men with hypogonadism get treated. Bayer Research News 2015. Testosterone Deficiency – Prevalence and Treatments Rates.

Future Testosterone Market • By 2020, there will be nearly 55 million Americans 65 + • Older Population, increased incidence of Low Testosterone, and also growing awareness of Testosterone replacement therapy will expand market further

Low Testosterone Market Size By 2022, annual revenue generated from testosterone drug sales in the United States is expected to reach 3. 4 billion U. S. dollars, slightly slower growth than anticipated due to mixed influences • Patent expirations and increased price competition • Increased stringency with regulatory agencies • Inconsistencies in research reports • More consumer directed advertising, favorable reimbursements, and insurance coverage • Increase in diabetes and resultant low T • Improved availability of options / therapies Global Industry Analysts (2017). The global market for testosterone replacement therapy is projected to reach US$ 3. 4 billion by 2022.

Problem • Limited insurance coverage on hormone therapy • Expensive even when covered

Medical Specialists Treating Hormone Deficiency Primary Care – Family Practice Endocrinology Obstetrics and Gynecology Internal Medicine Sports Medicine Urology Gerontology / Aging Adolescent Pediatrics Naturopaths and Alternative / Complimentary Medicine Pharmacists

Pellecome Objectives • Founded by Dr. Enrique Jacome who has over 30 years of experience in hormone management and over 30, 000 insertions. • Our goal was to completely re-design the surgical device and refine the surgical technique. • Additionally we sought to improve the manufacturing process in such a way that it would meet or exceed FDA expectations for standardization • Train and educate medical personnel on the use of implants as an option for long lasting hormone replacement therapy • Become the largest distributor of FDA approved manufactured pellets around the globe