ProPharma Partners International, Inc .

1. ProPharma Partners International, Inc. Cyclic Mastalgia: A Large, Misunderstood Medical Condition Analysis completed by Paulo Rangel June 2011 Contacts: James Chubb, Ph.D. Founding Partner jchubb@propharmap.com Paulo Rangel Partner prangel@propharmap.com www.propharmap.com

2. Cyclic Mastalgia: A Misunderstood and Generally Undertreated Medical Condition • Over 10 MM women in the USA suffer from moderate to severe cyclic mastalgia …their sleep, work, physical and sexual activity are all affected • Many providers and pharmaceutical companies view CM as a “lifestyle” condition and fail to place sufficient importance on the condition… …women who suffer from CM are of a different opinion • First line therapy is NSAIDs, hot compresses and comfortable clothing, which are all marginally effective • The successful drug may achieve $500 MM in USA revenue… …Women with CM need a better treatment

3. The Analysis The objective of this analysis is to convey the potential for the cyclic mastalgia market The condition, current treatments and the unmet need are described Further analysis has been completed for a specific drug candidate (not included here)

4. Table of Contents The Cyclic Mastalgia Opportunity Cyclic Mastalgia Market Size

5. Cyclic Mastalgia The Opportunity

6. What is Cyclic Mastalgia? • Breast pain can be classified as cyclic mastalgia, noncyclic mastalgia and extramammary pain (non-breast) (1) • Cyclic mastalgia is the most common form of breast pain and has a clear association with the menstrual cycle. It most commonly affects premenopausal women between the ages of 20 and 45. (2) • Cyclic mastalgia description (2) • Most often bilateral and diffuse pain • Caused by normal hormonal changes associated with ovulation that stimulate the proliferation of normal glandular breast tissue and results in pain • Usually presents a week prior to the onset of menses and dissipates with menses • Becomes more severe over time • Smith et al. "Evaluation and Management of Breast Pain." Mayo Cin. Proc. 2004;79:353-372 • "Breast Pain." Up-to-date

7. What is the prevalence (USA)? Over 10 million women in the USA have moderate to severe cyclic mastalgia! • USA Census • Ader et al. “Prevalence and impact of cyclic mastalgia in the United States clinic-based sample.” Am J Obstet Gynecol. Volume 177, Number 1

8. How serious is cyclic mastalgia? • Consequences of cyclic mastalgia are not trivial (1) • 10% affected sleep • 6-13% affected work, school and social functioning • 36% affected physical activity • 48% affected sexual activity • Women also experience increased anxiety and depression (1) • Women interviewed reported (2) • An average pain score of 5.3 (scale of 1-10) • Median time with cyclic mastalgia of 13.5 years • On a monthly basis • 33% have pain for 7+ days • 93% have pain for 3+ days • Smith et al. "Evaluation and Management of Breast Pain." Mayo Can. Proc. 2004;79:353-372 • Primary Research

9. Current Treatment • Physician recommended treatment • First line: NSAIDs, application of heat, dietary changes • Second line: Tamoxifen (10 mg daily) • Tamoxifen is the most effective treatment for cyclic mastalgia • Use of Tamoxifen is limited because of significant side effects • Third line: Danazol (200 mg daily); limited to 6 months • Fourth line: Goserelin depot injection (3.6 mg/month) • Other options • Oral contraceptives • Bromocriptine • Physicians want a patient to try a treatment for 2-4 months to evaluate its effectiveness • Danazol, bromocriptine, goserelin and tamoxifen are rarely used in practice because they are poorly tolerated Goyal, Amit and Mansel, Robert, "Mastalgia." Management of Breast Diseases, Chapter 4

10. How is Cyclic Mastalgia Treated? Workup of any mass/cyst Patient with Mastalgia Patient requesting treatment Reassurance/Lifestyle advice Breast Pain Musculoskeletal pain Cardiff’s Algorithm for the Management of Mastalgia Oral or Topical NSAID Good response NSAID Oral or Topical x3 months Discharge Persistent pain Injections of steroid or local anesthetic into tender site Poor response Good response Tamoxifen 10mg/d x3 mo Tamoxifen 10mg/d x3 months Poor response Good response Danazol 200mg/d x3 months Danazol 100mg/d x3 mo Poor response Goserelin 3.6mg/month x6 mos. Source: Goyal, Amit and Mansel, Robert, "Mastalgia." Management of Breast Diseases, Chapter 4

11. What is the Unmet Need? Women need an alternative to existing therapies • Cyclic mastalgia affects a large number of women, alters their daily activity and can result in increased anxiety and depression • Current therapies have minimal efficacy or are limited by significant side effects • First line therapy (NSAIDs, hot compresses, comfortable clothing, evening primrose, etc.) is minimally effective • Stronger therapies such as Danocrine, bromocriptine and tamoxifen are rarely used because of side effects • There are very few therapies currently in development for cyclic mastalgia

12. Comments from a Key Opinion LeaderRobert Mansel, M.D. Click on box to play video

13. Cyclic Mastalgia is a Compelling Target Market Available therapies are marginally effective and/or associated with adverse events • Cyclic mastalgia is poorly understood and often minimized by health care providers • It is the most common form of breast pain and represents a clear, unmet need • More than 10 MM women have moderate to severe cyclic mastalgia • CM affects sleep, physical and sexual activity and often leads to anxiety and depression • Women indicated in primary research that they have had cyclic mastalgia for a median of 13.5 years; it is persistent and long-lived • Current therapeutics are marginally effective or have significant side effects that limit their use • An effective and well tolerated therapy could achieve sales of $250-500 MM in the United States alone [based on a broader analysis]

14. Cyclic Mastalgia Market Size Use of the patient flow chart

15. Patient Flow Model To estimate the revenue potential of a product in cyclic mastalgia, a patient flow model is utilized. For a particular drug candidate, boxes 4-8 need to be determined based on primary and/or secondary market research • The patient flow is used to estimate the revenue potential for a product • Each box should be supported by primary and/or secondary market research • In some cases, no data sources may not be available. In such instances, team estimates are relied upon. • Due to these limitations, quantitative outputs should be considered directional only.

16. Cyclic Mastalgia Patient Flow (USA) Prevalence (USA) (women 20-45 yrs) 51,347,252 Total Population Severity 4+ & Duration 5-6 days 4.62 MM (9%) Severity 4+ & Duration 7+ days 5.65 MM (11%) > 10 MM target patients in the USA Diagnosis Rate Patients Seeking Treatment 6.0 MM (58%) Diagnosis Rate 4.17 MM (70%)

17. Cyclic Mastalgia: Prevalence • In a study that included 632 premenstrual women attending an Ob/Gyn clinic in the USA, 67% experienced premenstrual discomfort in the past 6 months (1) • 11% of premenopausal women have “clinical mastalgia” as defined by… • VAS of 4 cm or more (scale of 1-10) • Pain duration of 7 or more days per month • An additional 9% of premenopausal women have • VAS of 4 cm or more (scale of 1-10) • Pain duration of 5-6 days per month • 20% of premenopausal women with cyclic mastalgia experience moderate to severe pain symptoms (1) • In a survey of working women in South Wales…(2) • 45% described mild breast pain • 21% described severe breast pain • Ader et al. “Prevalence and impact of cyclic mastalgia in the United States clinic-based sample.” Am J Obstet Gynecol. Volume 177, Number 1 • Smith et al. "Evaluation and Management of Breast Pain." Mayo Clin. Proc. 2004;79:353-372

18. Cyclic Mastalgia: Patients Seeking Treatment • Minor breast discomfort and swelling within a few days of the onset of menses is normal (1) • Women will usually start by treating themselves (2) • Most often, women start with over-the-counter analgesics • OTC analgesics demonstrate only minimal benefit • Reasons for seeking treatment (2) • Concerns about cancer may prompt a woman to seek treatment • Women may mention their breast pain during a scheduled visit, but 1-2 years may pass before she mentions the pain to her doctor • Primary research indicated that 58% of women with moderate to severe cyclic mastalgia had discussed their pain with a professional (2) • Smith et al. "Evaluation and Management of Breast Pain." Mayo Clin. Proc. 2004;79:353-372 • Primary Research

19. Cyclic Mastalgia: Patients Seeking Treatment (2) • 58% of women had discussed their pain with a professional • Type of health care professional (numbers indicate that some women spoke with more than one type of health care professional) • 86% - Ob/Gyn • 44% - General Practitioner • 25% - Nurse practitioner • 20% - Professional at women's health or breast care center • Ob/Gyn providers are the key target to drive sales in this market • Primary Research

20. Cyclic Mastalgia: Diagnosis Rate • Diagnosis approach (1) • History. Identify and characterize breast-related symptoms • Physical examination. Determine area of pain; physical abnormalities (mass, nipple discharge, etc.) have precedence • Mammogram. Rule out any underlying problem (e.g., breast cancer) – it is rare that pain alone is an indication of breast cancer • Prospective assessment with a daily breast pain diary to document the occurrence and severity of pain • Diagnosis based on recall of symptoms is 65% sensitive • Diagnosis based on a prospective breast pain diary is 69% specific • Based on the literature, the diagnosis rate is 70% • Smith et al. "Evaluation and Management of Breast Pain." Mayo Clin. Proc. 2004;79:353-372

21. Patient Flow Diagram for a Particular Product OpportunityVarious drivers of gross revenue are determined on a product-by-product basis Prevalence (USA) (women 20-45 yrs) 51,347,252 Total Population Severity 4+ & Duration 5-6 days 4.62 MM (9%) Severity 4+ & Duration 7+ days 5.65 MM (11%) Treatment Rate Patients Seeking Treatment 6.0 MM (58%) Diagnosis Rate 4.17 MM (70%) Treatment Rate Market Penetration Penetration Rate Annual Doses per Patient Doses/Per Patient/Year Price Price Gross Revenue Gross Revenue

22. Expanded Summary of CM Treatment Options • "Breast Pain." Up-to-date • Smith et al. "Evaluation and Management of Breast Pain." Mayo Clin. Proc. 2004;79:353-372 • Colak et al. "Efficacy of Topical Nonsteroidal Anti-inflammatory Drugs in Mastalgia Treatment." J. Am Coll Surg; Vol. 196, No. 4, April 2003 • Danocrin Prescribing Information • Gateley et al. “Drug treatments for mastalgia.” J of the Royal Society of Medicine. Vol. 85 January 1992

23. ProPharma Partners International, Inc. Contacts: James Chubb, Ph.D. Founding Partner jchubb@propharmap.com Paulo Rangel Partner prangel@propharmap.com www.propharmap.com