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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 Slide 2 Cyclic Mastalgia: A Misunderstood and Generally Undertreated Medical Condition Slide 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) Slide 4 Table of Contents The Cyclic Mastalgia Opportunity Cyclic Mastalgia Market Size Slide 5 Cyclic Mastalgia The Opportunity Slide 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 (1)Smith et al. "Evaluation and Management of Breast Pain." Mayo Cin. Proc. 2004;79:353-372 (2)"Breast Pain." Up-to-date Slide 7 What is the prevalence (USA)? Women 20-45 yrs of age (USA) 51,347,252 (1) Women with cyclic mastalgia Severity: 4+; Duration: 5-6 days 4.62 MM (9%) (2) Women with cyclic mastalgia Severity: 4+; Duration: 7+ days 5.65 MM (11%) (2) Women with moderate to severe cyclic mastalgia 10.27 MM (20%) (1)USA Census (2)Ader et al. Prevalence and impact of cyclic mastalgia in the United States clinic-based sample. Am J Obstet Gynecol. Volume 177, Number 1 Over 10 million women in the USA have moderate to severe cyclic mastalgia! Slide 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 (1)Smith et al. "Evaluation and Management of Breast Pain." Mayo Can. Proc. 2004;79:353-372 (2)Primary Research Slide 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 Slide 10 Patient with Mastalgia Reassurance/Lifestyle advice Patient requesting treatment Breast Pain NSAID Oral or Topical x3 months Tamoxifen 10mg/d x3 months Danazol 200mg/d x3 months Goserelin 3.6mg/month x6 mos. Musculoskeletal pain Injections of steroid or local anesthetic into tender site Oral or Topical NSAID Workup of any mass/cyst Persistent pain Poor response Good response Good response Good response Discharge Tamoxifen 10mg/d x3 mo Danazol 100mg/d x3 mo Source:Goyal, Amit and Mansel, Robert, "Mastalgia." Management of Breast Diseases, Chapter 4 Cardiffs Algorithm for the Management of Mastalgia How is Cyclic Mastalgia Treated? Slide 11 What is the Unmet Need? 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 Women need an alternative to existing therapies Slide 12 Comments from a Key Opinion Leader Robert Mansel, M.D. Click on box to play video Slide 13 Cyclic Mastalgia is a Compelling Target Market 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] Available therapies are marginally effective and/or associated with adverse events Slide 14 Cyclic Mastalgia Market Size Use of the patient flow chart Slide 15 Patient Flow Model 1 Total Prevalent Patients 2 Patients Seeking Treatment 4 Treatment Rate 5 Market Penetration 6 Doses/Per Patient/Per Year 7 Price 8 Gross Revenue 3 Diagnosis Rate 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. 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. Slide 16 Cyclic Mastalgia Patient Flow (USA) Total Population Diagnosis Rate Prevalence (USA) (women 20-45 yrs) 51,347,252 Severity 4+ & Duration 5-6 days 4.62 MM (9%) Severity 4+ & Duration 7+ days 5.65 MM (11%) Patients Seeking Treatment 6.0 MM (58%) Diagnosis Rate 4.17 MM (70%) > 10 MM target patients in the USA Slide 17 Cyclic Mastalgia: Prevalence 1 Total Prevalent Patients 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 (1)Ader et al. Prevalence and impact of cyclic mastalgia in the United States clinic-based sample. Am J Obstet Gynecol. Volume 177, Number 1 (2)Smith et al. "Evaluation and Management of Breast Pain." Mayo Clin. Proc. 2004;79:353-372 Slide 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) (1)Smith et al. "Evaluation and Management of Breast Pain." Mayo Clin. Proc. 2004;79:353-372 (2)Primary Research 2 Patients Seeking Treatment Slide 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 2 Patients Seeking Treatment (1)Primary Research Slide 20 Cyclic Mastalgia: Diagnosis Rate 3 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% (1)Smith et al. "Evaluation and Management of Breast Pain." Mayo Clin. Proc. 2004;79:353-372 Slide 21 Patient Flow Diagram for a Particular Product Opportunity Various drivers of gross revenue are determined on a product-by-product basis Total Population Treatment Rate Gross Revenue Market Penetration Doses/Per Patient/Year Price Prevalence (USA) (women 20-45 yrs) 51,347,252 Penetration Rate Annual Doses per Patient Price Gross Revenue Severity 4+ & Duration 5-6 days 4.62 MM (9%) Severity 4+ & Duration 7+ days 5.65 MM (11%) Patients Seeking Treatment 6.0 MM (58%) Diagnosis Rate 4.17 MM (70%) Treatment Rate Slide 22 Expanded Summary of CM Treatment Options ProductComments Conservative (1) Support garments (well-fitting brassiere); warm compresses or ice packs Evening primrose (2) Data is conflicting; efficacy is not clear. Prescription license revoked in the UK in 2002. Acetaminophen; NSAIDs (1) Acetaminophen, NSAIDs or both may be tried early (usually first line therapy) Pain may be dulled but not eliminated (from primary research) Topical NSAIDs (3) Not in widespread use for cyclic mastalgia Uncontrolled, non-blinded study at one center in Turkey measured VAS scores at the start and at 6 months; demonstrated a statistically significant drop in pain in the treatment group vs the placebo group Topical treatment was applied 3 times per day (every 8 hours) for 6 months Tamoxifen (3) Success rate is 71-96%, but there are significant side effects which limit its use Danazol A synthetic testosterone that binds to progesterone and androgen receptors, exhibits a wide spectrum of systemic adverse effects including the potential of teratogenicity Severe side effects in 30% of cases (5) Indicated for the short-term treatment (up to 6 months) of severe benign (fibrocystic) breast disease or mastalgia associated with severe symptomatic benign breast disease, in patients refractory to other treatments (4) Gonadotropin releasing hormone agonists (2) Demonstrated efficacy in an uncontrolled study with 21 women Adverse events significant hot flashes, headache, fatigue, nausea, depression Used only of all other pharmacologic treatments do not work Bromocriptine Dopamine agonist. Has demonstrated efficacy, but very significant side effects. Severe side effects in 35% of cases (5) (1)"Breast Pain." Up-to-date (2)Smith et al. "Evaluation and Management of Breast Pain." Mayo Clin. Proc. 2004;79:353-372 (3)Colak et al. "Efficacy of Topical Nonsteroidal Anti-inflammatory Drugs in Mastalgia Treatment." J. Am Coll Surg; Vol. 196, No. 4, April 2003 (4)Danocrin Prescribing Information (5)Gateley et al. Drug treatments for mastalgia. J of the Royal Society of Medicine. Vol. 85 January 1992 Slide 23 ProPharma Partners International, Inc. Contacts:James Chubb, Ph.D. Founding Partner jchubb@propharmap.com Paulo Rangel Partner prangel@propharmap.com www.propharmap.com