ProPharma Partners Consulting Presentation

ProPharma Partners International, Inc.Cyclic Mastalgia: A Large, Misunderstood Medical Condition

Analysis completed by Paulo RangelJune 2011Contacts:James Chubb, Ph.D.Founding Partnerjchubb@propharmap.com

Paulo RangelPartnerprangel@propharmap.comwww.propharmap.com1Cyclic Mastalgia: A Misunderstood and Generally Undertreated Medical ConditionOver 10 MM women in the USA suffer from moderate to severe cyclic mastalgiatheir 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 revenueWomen with CM need a better treatmentThe AnalysisThe 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)Table of ContentsThe Cyclic Mastalgia Opportunity

Cyclic Mastalgia Market SizeCyclic MastalgiaThe OpportunityWhat 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 painCaused by normal hormonal changes associated with ovulation that stimulate the proliferation of normal glandular breast tissue and results in painUsually presents a week prior to the onset of menses and dissipates with mensesBecomes more severe over timeSmith et al. "Evaluation and Management of Breast Pain." Mayo Cin. Proc. 2004;79:353-372"Breast Pain." Up-to-dateWhat is the prevalence (USA)?Women 20-45 yrs of age (USA)51,347,252 (1)Women with cyclic mastalgiaSeverity: 4+; Duration: 5-6 days4.62 MM (9%) (2)Women with cyclic mastalgiaSeverity: 4+; Duration: 7+ days5.65 MM (11%) (2)Women with moderate to severe cyclic mastalgia10.27 MM (20%)USA CensusAder et al. Prevalence and impact of cyclic mastalgia in the United States clinic-based sample. Am J Obstet Gynecol. Volume 177, Number 1Over 10 million women in the USA have moderate to severe cyclic mastalgia!How serious is cyclic mastalgia?Consequences of cyclic mastalgia are not trivial (1)10% affected sleep6-13% affected work, school and social functioning36% affected physical activity48% 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 yearsOn a monthly basis33% have pain for 7+ days93% have pain for 3+ daysSmith et al. "Evaluation and Management of Breast Pain." Mayo Can. Proc. 2004;79:353-372Primary Research8Current TreatmentPhysician recommended treatmentFirst line: NSAIDs, application of heat, dietary changesSecond line: Tamoxifen (10 mg daily)Tamoxifen is the most effective treatment for cyclic mastalgiaUse of Tamoxifen is limited because of significant side effectsThird line: Danazol (200 mg daily); limited to 6 monthsFourth line: Goserelin depot injection (3.6 mg/month)Other optionsOral contraceptivesBromocriptinePhysicians want a patient to try a treatment for 2-4 months to evaluate its effectivenessDanazol, bromocriptine, goserelin and tamoxifen are rarely used in practice because they are poorly toleratedGoyal, Amit and Mansel, Robert, "Mastalgia." Management of Breast Diseases, Chapter 4Patient with Mastalgia Reassurance/Lifestyle advicePatient requesting treatment Breast PainNSAID Oral or Topical x3 months Tamoxifen 10mg/d x3 months Danazol 200mg/d x3 months Goserelin 3.6mg/month x6 mos. Musculoskeletal painInjections of steroid or local anesthetic into tender site Oral or Topical NSAIDWorkup of any mass/cyst Persistent painPoor responsePoor responsePoor responseGood responseGoodresponseGoodresponseDischarge Tamoxifen 10mg/d x3 mo Danazol 100mg/d x3 mo Source:Goyal, Amit and Mansel, Robert, "Mastalgia." Management of Breast Diseases, Chapter 4Cardiffs Algorithm for the Management of MastalgiaHow is Cyclic Mastalgia Treated?What is the Unmet Need?Cyclic mastalgia affects a large number of women, alters their daily activity and can result in increased anxiety and depressionCurrent therapies have minimal efficacy or are limited by significant side effectsFirst line therapy (NSAIDs, hot compresses, comfortable clothing, evening primrose, etc.) is minimally effectiveStronger therapies such as Danocrine, bromocriptine and tamoxifen are rarely used because of side effectsThere are very few therapies currently in development for cyclic mastalgia

Women need an alternative to existing therapies11Comments from a Key Opinion LeaderRobert Mansel, M.D.Click on box to play video

Cyclic Mastalgia is a Compelling Target MarketCyclic 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 needMore than 10 MM women have moderate to severe cyclic mastalgiaCM affects sleep, physical and sexual activity and often leads to anxiety and depressionWomen indicated in primary research that they have had cyclic mastalgia for a median of 13.5 years; it is persistent and long-livedCurrent 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 eventsCyclic Mastalgia Market SizeUse of the patient flow chartPatient Flow Model1Total Prevalent Patients2Patients Seeking Treatment4Treatment Rate5Market Penetration6Doses/Per Patient/Per Year7Price8Gross Revenue3Diagnosis RateTo 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 researchThe patient flow is used to estimate the revenue potential for a productEach box should be supported by primary and/or secondary market researchIn 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. 15Cyclic Mastalgia Patient Flow (USA)Total PopulationDiagnosis RatePrevalence (USA)(women 20-45 yrs)51,347,252Severity 4+ &Duration 5-6 days4.62 MM (9%)Severity 4+ &Duration 7+ days5.65 MM (11%)Patients Seeking Treatment 6.0 MM (58%)Diagnosis Rate4.17 MM (70%)> 10 MM target patients in the USA16Cyclic Mastalgia: Prevalence1Total Prevalent PatientsIn 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 byVAS of 4 cm or more (scale of 1-10)Pain duration of 7 or more days per monthAn additional 9% of premenopausal women haveVAS 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 pain21% described severe breast painAder et al. Prevalence and impact of cyclic mastalgia in the United States clinic-based sample. Am J Obstet Gynecol. Volume 177, Number 1Smith et al. "Evaluation and Management of Breast Pain." Mayo Clin. Proc. 2004;79:353-37217Cyclic Mastalgia: Patients Seeking TreatmentMinor 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 analgesicsOTC analgesics demonstrate only minimal benefitReasons for seeking treatment (2)Concerns about cancer may prompt a woman to seek treatmentWomen 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;79:353-372Primary Research2Patients Seeking Treatment18Cyclic 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/Gyn44% - General Practitioner25% - Nurse practitioner20% - Professional at women's health or breast care center

Ob/Gyn providers are the key target to drive sales in this market

2Patients Seeking TreatmentPrimary ResearchCyclic Mastalgia: Diagnosis Rate3Diagnosis RateDiagnosis approach (1)History. Identify and characterize breast-related symptomsPhysical examination. Determine area of pain; physical abnormalities (mass, nipple discharge, etc.) have precedenceMammogram. Rule out any underlying problem (e.g., breast cancer) it is rare that pain alone is an indication of breast cancerProspective assessment with a daily breast pain diary to document the occurrence and severity of painDiagnosis based on recall of symptoms is 65% sensitiveDiagnosis 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;79:353-37220Patient Flow Diagram for a Particular Product Opportunity

Various drivers of gross revenue are determined on a product-by-product basisTotal PopulationTreatment RateGross RevenueMarket PenetrationDoses/Per Patient/YearPricePrevalence (USA)(women 20-45 yrs)51,347,252Penetration RateAnnual Doses per PatientPriceGross RevenueSeverity 4+ &Duration 5-6 days4.62 MM (9%)Severity 4+ &Duration 7+ days5.65 MM (11%)Patients Seeking Treatment 6.0 MM (58%)Diagnosis Rate4.17 MM (70%)Treatment Rate21Expanded Summary of CM Treatment OptionsProductCommentsConservative (1)Support garments (well-fitting brassiere); warm compresses or ice packsEvening 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 mastalgiaUncontrolled, 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 groupTopical treatment was applied 3 times per day (every 8 hours) for 6 monthsTamoxifen (3)Success rate is 71-96%, but there are significant side effects which limit its useDanazolA synthetic testosterone that binds to progesterone and androgen receptors, exhibits a wide spectrum of systemic adverse effects including the potential of teratogenicitySevere 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 womenAdverse events significant hot flashes, headache, fatigue, nausea, depressionUsed only of all other pharmacologic treatments do not workBromocriptineDopamine agonist. Has demonstrated efficacy, but very significant side effects.Severe side effects in 35% of cases (5)"Breast Pain." Up-to-dateSmith et al. "Evaluation and Management of Breast Pain." Mayo Clin. Proc. 2004;79:353-372Colak et al. "Efficacy of Topical Nonsteroidal Anti-inflammatory Drugs in Mastalgia Treatment." J. Am Coll Surg; Vol. 196, No. 4, April 2003Danocrin Prescribing InformationGateley et al. Drug treatments for mastalgia. J of the Royal Society of Medicine. Vol. 85 January 1992ProPharma Partners International, Inc.Contacts:James Chubb, Ph.D.Founding Partnerjchubb@propharmap.com

Paulo RangelPartnerprangel@propharmap.comwww.propharmap.com23