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wyeth 2006 Analysts Meeting Presentation

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wyeth 2006 Analysts Meeting Presentation

  1. 1. Welcome Justin R. Victoria Vice President, Investor Relations
  2. 2. Forward Looking Statement The statements in these materials that are not historical facts are forward- looking statements based on current expectations of future events and are subject to risks and uncertainties that could cause actual results to differ materially from those expressed or implied by such statements. These risks and uncertainties include risks associated with the inherent uncertainty of the timing and success of product research, development and commercialization (including with respect to our pipeline products), drug pricing and payment for our products by government and third-party payers, manufacturing, data generated on the safety and efficacy of our products, economic conditions including interest and currency exchange rate fluctuations, changes in generally accepted accounting principles, the impact of competitive or generic products, trade buying patterns, global business operations, product liability and other types of litigation, the impact of legislation and regulatory compliance, intellectual property rights including the ability of any particular patent to provide market exclusivity, strategic relationships with third parties, environmental liabilities, and other risks and uncertainties, including those detailed from time to time in our periodic reports filed with the Securities and Exchange Commission, including our current reports on Form 8-K, quarterly reports on Form 10-Q and annual report on Form 10-K, particularly the discussion under the caption “Item 1A, Risk Factors.” We assume no obligation to publicly update any forward-looking statements, whether as a result of new information, future developments or otherwise.
  3. 3. Agenda J. Victoria Welcome R. Essner Introduction U. Wiinberg Enbrel® & Prevnar® E.A. Emini, Ph.D. Prevnar 13 Break J.M. Mahady New Products G. Constantine, M.D. Pristiq™ Aprela™/Viviant™ Lybrel™ J.S. Camardo, M.D. Torisel™ Tygacil® R.M. Poole, M.D., FACP Bifeprunox J.S. Camardo, M.D. Methylnaltrexone R.R. Ruffolo, Jr., Ph.D. Mid-Pipeline Review Key Registration Submissions B. Poussot Conclusion & Q&A
  4. 4. Introduction Robert Essner Chairman and Chief Executive Officer, Wyeth
  5. 5. Wyeth Past Business Performance Revenue Growth +8% $20 +10% +9% $18.8 $18.8 +4% (In Billions) $17.4 $17.4 +7% $15 $15.9 $15.9 $14.6 $14.6 $14.0 $14.0 $10 $5 $0 2001 2002 2003 2004 2005 WHI Impact
  6. 6. Wyeth Past Business Performance EPS* Growth +11% $3.00 +7% $2.92 $2.92 +10% $2.50 $2.62 $2.62 +2% +15% $2.44 $2.44 $2.00 $2.22 $2.22 $2.18 $2.18 $1.50 $1.00 $0.50 $0.00 2001 2002 2003 2004 2005 WHI Impact * Before Certain Significant Items
  7. 7. EPS Continues to Grow in 2006 EPS* Growth +12%+** +11% $3.00 +7% +10% $3.07+ $2.50 +2% +15% $2.00 July Guidance $1.50 $1.00 $0.50 $0.00 2001 2002 2003 2004 2005 2006 WHI Impact * Before Certain Significant Items ** When Adjusted for Stock Option Expensing in 2005
  8. 8. 7 New Drugs 11 Important Indications Pristiq™ Major Depressive Disorder Pristiq™ Major Depressive Disorder Vasomotor Symptoms Vasomotor Symptoms Viviant™ Prevention/Treatment Osteoporosis Viviant™ Prevention/Treatment Osteoporosis Aprela™ Menopausal Symptoms/Osteoporosis Aprela™ Menopausal Symptoms/Osteoporosis Lybrel™ Contraception Lybrel™ Contraception Torisel™ Renal Cell Cancer Torisel™ Renal Cell Cancer Mantle Cell Lymphoma Mantle Cell Lymphoma Bifeprunox Schizophrenia Bifeprunox Schizophrenia Methylnaltrexone SC – Opioid Induced Constipation Methylnaltrexone SC – Opioid Induced Constipation IV – Post Operative Ileus IV – Post Operative Ileus Tygacil®* CAP/HAP Tygacil®* CAP/HAP * Tygacil already approved, not a new drug
  9. 9. Wyeth Future Growth Prospects In-Line Product Growth Portfolio of New Product Opportunities Productivity Improvements Broad-Based Research
  10. 10. Wyeth is positioned to be a stronger company at the end of the decade and enter the next decade with great momentum.
  11. 11. Enbrel® (Etanercept) Ulf Wiinberg Senior Vice President, Wyeth President, Wyeth Pharmaceuticals - EMEA
  12. 12. Enbrel® 2005 Over 376,000 Patients Treated Worldwide EMEA $958 North America* $2,574 $3,658 2005 Worldwide Sales Asia Pac $79 Latin America $46 $ in Millions *Alliance with Amgen
  13. 13. Enbrel® Reaches Top 10 Worldwide Change vs. % Change MAT 6/06 MAT 6/06 Prior Period vs. Prior Product Rank Sales ($000) ($000) Period LIPITOR 1 $ 13,306,463 $ 593,102 5% PLAVIX 2 $ 6,353,507 $ 787,322 14% NEXIUM 3 $ 6,193,180 $ 903,461 17% SERETIDE 4 $ 5,910,049 $ 681,602 13% ZOCOR 5 $ 5,463,607 $ (221,986) -4% NORVASC 6 $ 4,940,892 $ 58,022 1% ZYPREXA 7 $ 4,620,598 $ (204,740) -4% ARANESP 8 $ 4,270,374 $ 1,093,301 34% RISPERDAL 9 $ 4,253,853 $ 447,044 12% ENBREL 10 $ 4,142,088 $ 845,371 26%
  14. 14. Enbrel® Momentum 2005 Actual Region ($ in Millions) % Growth EMEA $958 52% Latin America $46 64% AP/Japan* $79 295% Total Regional Net Sales $1,083 59% *Japan Launch March 2005
  15. 15. Enbrel® Growing From a Position of Strength Anti-TNF Biologic Sales – Ex-North America ($000) Quarterly Sales $400,000 Enbrel Remicade Humira Orencia Raptiva $350,000 $300,000 $250,000 $200,000 $150,000 $100,000 $50,000 $0 Q1'04 Q2'04 Q3'04 Q4'04 Q1'05 Q2'05 Q3'05 Q4'05 Q1'06 Q2'06 IMS, Midas Q2 2006
  16. 16. Enbrel® -- $3 Billion in 2010 Outside North America Market Factors Large available patient pool Doctors & payers inclined to early intervention with Enbrel Enbrel Geographic and medical expansion Unique mechanism of action with extensive safety/efficacy Patent protection through 2014
  17. 17. Available Patient Pool: Top 6 EU Countries Prevalence of Disease RA AS PsA PsO 1.8 Million 1.3 Million 826,000 6.0 Million Guidelines for Eligibility Current Biologic Patients 360,000 Patients
  18. 18. Japan Opportunity Japan 1 in 10 Currently Treated 140 Incremental Opportunity 120 # Patients (2005) Number of Patients (000’s) 6 100 80 ~60,000 60 110 40 49 20 28 13 4 0 Bio-Potential (M) Biologics(M) Enbrel(M) SOURCE: Wyeth Forecasting; C&MI NOTE: Slide depicts RA, PsA, AS and Psoriasis
  19. 19. Enbrel® Science 14 Years Experience #1 biologic prescribed worldwide in its class Approaching 1 million patient years of use Studied in patients 4 to 87 years of age Serious adverse event profile similar to placebo in clinical trials Unique mechanism of action
  20. 20. Enbrel® Science 14 Years of Clinical Experience Percentage of Early RA Patients With No Radiographic Progression 5 Years Sustained 73% NO further joint space narrowing NO further joint space narrowing Efficacy After 5 years 64% NO new erosions NO new erosions NO progression in 55% NO progression in Total Sharp Score Total Sharp Score n = 100 Genovese MC, Bathon JM, Fleischmann RM, et al. Longterm safety, efficacy, and radiographic outcome with etanercept treatment in patients with early rheumatoid arthritis. J Rheumotol 2005;32:1232-1242.
  21. 21. Trend Towards Earlier Treatment Recent- Severely- Moderately- Onset RA Advanced RA Advanced RA
  22. 22. Value: Favorable Cost-Benefit NICE Guidance 2006 The National Institute for Health and Clinical Excellence (NICE, UK) recommends the use of ENBREL® for the treatment of plaque psoriasis BEFORE the use of Raptiva ENBREL had a more favorable economic profile in the treatment of patients with psoriatic arthritis than Remicade
  23. 23. Convenience Pre-filled Syringe 25mg/50mg Autoinjector Patient Services NEW! The flexibility of 3 administration options
  24. 24. Enbrel® Growth-2010 Wyeth-Only Territories – 24% CAGR 2005 2010 $1 Billion $3 Billion Asia Asia Latin Pacific Pacific America $79 15% Latin $46 America 5% Europe Europe Europe Europe $958 80% $958 80% $ in Millions % of Revenue by Region
  25. 25. Grange Castle … Wyeth’s Commitment to Biotech Growth 4 Integrated Manufacturing Facilities Drug Substance Vaccine Conjugation Fill / Finish Syringe Line MNTX
  26. 26. Prevnar® Pneumococcal 7-valent Conjugate Vaccine (Diphtheria CRM Protein) 197
  27. 27. Prevnar® – Strong Growth Momentum June 2006 YTD Δ vs 1H05 Region North America $565 million +13% EMEA $285 million +94% Latin America $45 million +70% Asia Pacific $55 million +41% TOTAL $950 million +33%
  28. 28. Global Vaccine Sales by Product 2005 Audited Sales 1st and Only Blockbuster Vaccine $1,200 Prevnar® $1,000 Audited Annual Sales ($MM) $800 Varivax Combined audited sales $600 Engerix B of these four vaccine products MMRII $400 does not equal Prevnar’s sales Vaxigrip $200 $0 Source: IMS MIDAS Data, ATC2-J7, April 2006.
  29. 29. Growing Prevnar® to $3 Billion in 2010 Accelerating momentum in 2006 New launches New national immunization programs in developed markets Emerging countries – private and national programs Increased compliance and catch-up opportunities $3 Billion Prevnar Sales (Infant Vaccination)
  30. 30. Major Pneumococcal Diseases Pneumonia Otitis Media Meningitis Bacteremia
  31. 31. The Face of Pneumococcal Disease .5M Adults die every year 1M Infants die every year
  32. 32. Disease Burden in Children DTP/Polio S. Pneumo 20% 28% Measles Hib 21% 15% Rotavirus 15% Other 1% #1 Cause of Vaccine-Preventable Death in Children WHO 2004 Global Immunization Data
  33. 33. Impact on Pneumococcal Disease Since the launch of Prevnar ® … Tens of millions of children immunized Millions of cases of disease averted Tens of thousands of lives saved …many more children and adults will benefit as we expand the use of Prevnar across the globe
  34. 34. Increasing Impact of Prevnar® in U.S. …in children … and adults (>50 Years of Age) Average Incidence of Vaccine Serotype 90 35 Prelicensure Prelicensure 80 30 (1998-1999) (1998-1999) IPD per 100,000 Population Estimated Cases/100,000 70 Postlicensure Postlicensure 25 60 (2003) (2002-2003) 55% 20 50 40 Reduction 15 94% 30 10 Reduction 20 5 10 0 0 Average for 2003 Average for 2003 1998 and 1999 1998 and 1999 MMWR. 2005;Vol: 54(No. 36):893-897.
  35. 35. Significant Future Growth Potential Double sales over the next 5 years $4 $3 B + $3 New Launches New Launches NIPs NIPs Sales ($B) Emerging Markets Emerging Markets Compliance/ Compliance/ $2 Catch-up Catch-up $1.5 B $1 $0 2005A 2010F Source: Wyeth internal sales data, 2006
  36. 36. Prevnar® Launched in 70 Countries Additional 13 launches by 2008
  37. 37. National Immunization Programs: Developed Countries Current NIPs Potential NIPs United States Austria Taiwan Australia Belgium New Zealand Canada Denmark Portugal France Finland Saudi Arabia Germany Hong Kong Singapore Greece Iceland South Korea Luxembourg Ireland Spain Netherlands Italy Sweden Norway Japan Qatar Switzerland United Kingdom Total Birth Cohort ~7 Million Total Birth Cohort ~4 Million
  38. 38. Emerging Market Opportunities Private Markets Private to Potential NIPs Chile Peru Argentina China Philippines Brazil Ecuador Romania Colombia Hungary Russia Czech Republic India South Africa Mexico* Indonesia Thailand Poland Malaysia Uruguay Turkey Pakistan Venezuela Total Birth Cohort ~10 Million Total Birth Cohort ~58 Million * Mexico announced initiation of national program in 3Q06
  39. 39. Growth in NIP Countries Increase compliance with country-recommended regimens (U.S. example) 2002 public/private market compliance ~40% (3 doses or more) 2005 public/private market compliance ~83% (3 doses or more) Target DTaP “Gold Standard” compliance ~90% Each compliance % point increase ~$10 million/year Catch-up opportunities U.K. program 1.7 million doses in 2006/2007
  40. 40. Growing Prevnar® to $3 Billion in 2010 Accelerating momentum in 2006 New launches New national immunization programs in developed markets Emerging countries – private and national programs Increased compliance and catch-up opportunities $3 Billion Prevnar Sales (Infant Vaccination)
  41. 41. The Future of Pneumococcal Vaccines: Leading the Way Toward Extended Serotype Coverage With Pneumococcal 13-Valent Conjugate Vaccine New advances in vaccine development Potential 10 valent competitive candidate Prevnar 13 in Phase 3 development Increase pneumococcal serotype coverage (13 serotypes) Expand use to adults (> $1.5 billion)
  42. 42. 13-Valent Pneumococcal Polysaccharide Conjugate Vaccine (13v PnC) Emilio A. Emini, Ph.D., F.A.A.M. Executive Vice President Vaccine Research and Development
  43. 43. 13v PnC Infant Product Profile The most complete vaccine available for the global prevention of pneumococcal disease and otitis media Phase 2 proof of concept achieved Licensing criteria agreed upon Status Worldwide phase 3 studies ongoing Submission – Early 2009 Peak Sales > $3 Billion
  44. 44. 13v PnC Provides Superior Coverage in the U.S. 7v vs 10v vs 13v Serotype Coverage Comparison – U.S. 7v Pre-Prevnar® (1998) 81% Source: CDC ABC Surveillance
  45. 45. Estimated Invasive Pneumococcal Disease Rates Due to Vaccine Serotypes (Children <5 Years of Age) 90 Estimated Cases/100,000 Prelicensure 80 (1998-1999) 70 Postlicensure 60 (2003) 50 94% 40 Reduction 30 20 10 0 Average for 1998 and 2003 1999 Active Bacterial Core Surveillance, Emerging Infections Program Network. Prevnar® was licensed in the United States in February 2000.
  46. 46. Estimated Invasive Pneumococcal Disease Rates For All Serotypes (Children <5 Years of Age) 120 Estimated Cases/100,000 Prelicensure 100 (1998-1999) Postlicensure 80 (2003) 60 75% Reduction 40 20 0 Average for 1998 and 2003 1999 Active Bacterial Core Surveillance, Emerging Infections Program Network. Prevnar® was licensed in the United States in February 2000.
  47. 47. 13v PnC Provides Superior Coverage in the U.S. 7v vs 10v vs 13v Serotype Coverage Comparison – U.S. 7v Pre-Prevnar® (1998) 81% Post-Prevnar (2003) 17% Prevnar has greatly reduced serious disease caused by the 7 vaccine-associated serotypes Source: CDC ABC Surveillance
  48. 48. 13v PnC Provides Superior Coverage in the U.S. 7v vs 10v vs 13v Serotype Coverage Comparison – U.S. 7v 10v Pre-Prevnar® (1998) 81% Post-Prevnar (2003) 17% 22% Prevnar has greatly reduced serious disease caused by the 7 vaccine-associated serotypes A 10v vaccine provides only marginal additional coverage Source: CDC ABC Surveillance
  49. 49. 13v PnC Provides Superior Coverage in the U.S. 7v vs 10v vs 13v Serotype Coverage Comparison – U.S. 7v 10v 13v Pre-Prevnar® (1998) 81% Post-Prevnar (2003) 17% 22% 60% Prevnar has greatly reduced serious disease caused by the 7 vaccine-associated serotypes A 10v vaccine provides only marginal additional coverage 13v PnC will provide substantial coverage Source: CDC ABC Surveillance
  50. 50. 13v PnC Also Provides Superior Coverage in Other Countries 7v vs 10v vs 13v Serotype Coverage Comparison 7v 10v 13v France pp 44% 49% 70% Germany pp 52% 68% 81% Spain pp 31% 48% 83% Norway 63% 67% 83% Mexico 53% 59% 74% pp = Post-Prevnar®
  51. 51. Serotype Coverage Prevnar® (7v) and 13v PnC 13v PnC 3 6B 1 6B 4 4 19A Prevnar 9V 18C 9V 18C 14 14 5 7F 19F 23F 6A 19F 23F
  52. 52. Serotype Coverage Prevnar® (7v) and 13v PnC 13v PnC 3 GSK 10v 6B 1 6B 4 4 19A Prevnar 9V 18C 9V 18C 14 14 5 7F 19F 23F 6A 19F 23F
  53. 53. Incidence of Invasive Pneumococcal Disease Due to Serotype 19A in the U.S. (Children <5 Years of Age) 7 Rate (Cases/100,000 Population) 6 5 4 3 2 1 0 July 1999 – July 2000 – July 2001 – July 2002 – July 2003 – June 2000 June 2001 June 2002 June 2003 June 2004 Time Pai R. JID. 2005;192:1988-95.
  54. 54. Comparison of Prevnar® and 13v PnC in a Phase 2 Infant Trial: Percentage of Children Achieving a Protective Level of Functional Antibody Following the Primary Immunization Series 100 75 Percentage 50 25 0 4 6B 9V 14 18C 19F 23F 1 3 5 6A 7F 19A Serotype 7v 13v
  55. 55. The Infant Vaccine Phase 3 Program Objectives: Demonstrate the immunological non-inferiority of 13v PnC to 7-valent Prevnar® in young infants Demonstrate that 13v PnC does not interfere with immune responses elicited by concomitantly administered childhood vaccines Demonstrate immunological consistency across multiple production batches of the vaccine Demonstrate the vaccine’s safety and tolerability The program will involve approximately 4,000 children
  56. 56. 13v PnC Adult Product Profile The vaccine of choice for adults 50 years of age and older for the prevention of pneumococcal disease Proof of concept achieved Licensing criteria agreed upon Status Worldwide phase 3 clinical studies to begin in late 2006 Submission 2009 Peak Sales > $1.5 Billion
  57. 57. The Need for an Improved Pneumococcal Vaccine for Adults Current vaccine is a 23-valent free polysaccharide vaccine (23v Ps) indicated for adults 65 years and older Antibody titers and efficacy decline after 5 years1 23v Ps induces immunological hyporesponsiveness to either another dose of 23v Ps2 or to a dose of conjugate vaccine3 Re-vaccinations with 23v Ps cause more severe adverse events4 Therefore, 23v Ps is generally given only once, which provides only a narrow window of protection during a prolonged period of risk5 Effectiveness is very low in immunocompromised patients Shapiro, et al., NEJM 1991; 1 Torling, et al., Vaccine 2003; 2 deRoux, et al., IDSA 2005; 3 Jackson, et al., JAMA 1999; Vaccine 2005; 4 ACIP recommendation: MMWR 1997. 5
  58. 58. There Remains a Substantial Invasive Pneumococcal Disease Burden in the U.S. (2004 Rates With 60% Uptake of 23v Ps Vaccine) 75 Cases of Invasive Pneumococcal Disease Cases per 100,000 50 25 0 18 to 34 35 to 49 50 to 64 65 to 79 80+ Age Group Years Estimated # of Deaths 1800 Deaths 1200 600 0 18 to 34 35 to 49 50 to 64 65 to 79 80+ Age Group Years CDC, ABC Surveillance 2004 (provisional)
  59. 59. 13v PnC Will Offer Additional Benefits Over 23v Ps Vaccine Conjugate vaccine antibody responses are superior to 23v Ps antibody responses Conjugate vaccine does not induce immunological hyporesponsiveness Therefore, 13v PnC can be used to extend the age range of protection against pneumococcal disease (50 years of age and older) and provide long-term protection by repeat dosing
  60. 60. Immunological Hyporesponsiveness of the 23-Valent Polysaccharide Vaccine Relative Antibody Response Immune response depressed after 2nd dose Pre-dose 1 Post-dose 1 1 year Pre-dose 2 Post-dose 2 (4-7 years) Torling, et.al (2003) Vaccine 22:96-103.
  61. 61. Randomized Trial of 7-valent Prevnar® (7v PnC) and 23v Ps Vaccine in Naïve Elderly 70+ Years of Age Year 1 Year 2 7v PnC 7v PnC n = 43 23v Ps n = 110 n = 38 23v Ps 7v PnC n = 78 n = 109
  62. 62. Is the Antibody Response to 7v PnC Equivalent/ Superior to the 23v Ps Response? Year 1 Year 2 7v PnC 7v PnC 23v Ps 23v Ps 7v PnC
  63. 63. 7v PnC Functional Antibody Response is Equivalent or Superior to 23v Ps Response 3000 * 7v PnC 23v Ps 2500 2000 OPA GMT * 1500 * * 1000 500 0 4 6B 9V 14 18C 19F 23F Serotype 7v PnC n = 110 23v Ps n = 104-107 * Statistically significant
  64. 64. Does Prior 23v Ps Immunization Affect the Response to Subsequent 7v PnC Immunization? Year 1 Year 2 7v PnC 7v PnC 23v Ps 23v Ps 7v PnC
  65. 65. Prior 23v Ps Blunts the Response to Subsequent 7v PnC (Hyporesponsiveness) 18 7v PnC 23v PS 7v PnC 15 ELISA GMC (μg/ml) * 12 * 9 * * 6 * * 3 0 4 6B 9V 14 18C 19F 23F Serotype 7v PnC n = 61 23v Ps 7v PnC n = 62 * Statistically significant
  66. 66. Does Prior 7v PnC Immunization Blunt the Response to a Second Dose of 7v PnC? Year 1 Year 2 7v PnC 7v PnC 23v Ps 23v Ps 7v PnC
  67. 67. Prior 7v PnC Does Not Blunt the Response to a Second Dose of 7v PnC 18 7v PnC 7v PnC 7v PnC 15 EL ISA G MC (μ g /m l) 12 9 6 3 0 4 6B 9V 14 18C 19F 23F Serotype 7v PnC n = 61 23v Ps 7v PnC n = 31
  68. 68. Does Prior 7v PnC Immunization Affect the Response to Subsequent 23v Ps Immunization? Year 1 Year 2 7v PnC 7v PnC 23v Ps 23v Ps 7v PnC
  69. 69. Prior 7v PnC Does Not Blunt the Response to Subsequent 23v Ps 18 23v Ps 7v PnC 23v Ps ELISA GMC (μg/ml) 15 12 9 6 3 0 4 6B 9V 14 18C 19F 23F Serotype 23v Ps n = 62 7v PnC 23v Ps n = 30
  70. 70. Conclusions Conjugate vaccine can be used repeatedly without inducing hyporesponsiveness Free polysaccharide vaccine can be administered after conjugate vaccine without hyporesponsiveness Conjugate vaccine should be given first, if both vaccines are used to maximize serotype coverage
  71. 71. Impact of Extending The Age Range of Protection with 13v PnC Preventable Invasive Deaths Disease Preventable/ Cases Year 23v Ps alone in the U.S. in the U.S. 2979 489 13v PnC alone Conjugate with re-vaccination 5544 895 13v PnC + 23v Ps 6110 988 50 yr 65 yr 70 yr
  72. 72. The Adult Vaccine Phase 3 Program Objectives: Demonstrate immunological non-inferiority of 13v PnC to the 23-valent polysaccharide vaccine in vaccine-naïve adults >50 years of age Demonstrate that 13v PnC can enhance the anti- polysaccharide responses in adults previously immunized with the 23-valent vaccine, and that initial immunization with 13v PnC does not cause immunological hyporesponsiveness Demonstrate that 13v PnC does not interfere with the immune response to concomitantly administered influenzavirus vaccine Demonstrate the vaccine’s safety and tolerability The program will involve approximately 3,200 adults
  73. 73. New Product Opportunities Joe Mahady Senior Vice President, Wyeth President, Wyeth Pharmaceuticals, The Americas and Global Businesses
  74. 74. SNRI Profile Makes Effexor XR® the #1 Antidepressant in the World $4,000 Zoloft $3,000 US Sales Dollars (000s) Lexapro $2,000 Wellbutrin Paxil $1,000 Cymbalta $0 2001 2002 2003 2004 2005 2006 Rolling MATs Ending June 2006 Source: IMS Monthly Midas (Aug 06); Constant US$ (Mil)
  75. 75. Pristiq™ (DVS-233) (Desvenlafaxine Succinate)
  76. 76. Pristiq™ Proven SNRI Pharmacological Impact for Management of Depression Similar to Effexor XR® in terms of efficacy, safety and tolerability Very low potential for drug-drug interaction Well-established QTc safety profile
  77. 77. Pristiq™ Differentiation With FDA-approval, the first non-hormonal treatment of moderate- to-severe vasomotor symptoms (VMS) associated with menopause
  78. 78. WHI Trial Reduced Prescription of Hormone Products 120,000 Hormone Prescriptions (000) New Prescriptions 100,000 Total Prescriptions 80,000 Women's Health Initiative: Initial Results Released 60,000 40,000 20,000 0 MAT MAT MAT MAT MAT MAT MAT MAT 3/99 3/00 3/01 3/02 3/03 3/04 3/05 3/06 Source: IMS NPA Data (May 06)
  79. 79. A Small Percentage of the 23 Million Symptomatic Women Use Available Treatments Menopausal Women Hysterectomized Women Experiencing Hot Flushes Experiencing Hot Flushes 10% Use 30% Use Hormone Estrogen Therapy Therapy 15 Million Women 8 Million Women Sources: Wyeth /ICR Patient Study Dec 2005, projected to total population using U.S. census data
  80. 80. Pristiq™ (Desvenlafaxine Succinate) With FDA-approval, the first non-hormonal treatment of moderate- to-severe vasomotor symptoms (VMS) associated with menopause
  81. 81. Transition Through Menopause Can Be Associated With New Onset or Recurrence of a Major Depressive Episode Estrogen fluctuation or decline may diminish serotonin and norepinephrine functioning Dual reuptake inhibitor may be a better fit for depression associated with menopause
  82. 82. Women Represent Over 70% of Patients Treated with an Antidepressant Treated Patients by Gender Female Female 71% <40 Years 19% Male Female >40 Years 29% 52% Source: SDI Longitudinal Patient Data, April 2006 (USA)
  83. 83. Initially Approached Two Distinct Products Product A Product B Depression Vasomotor Symptoms
  84. 84. Pristiq™, A Single Product With Two Indications Pristiq Vasomotor Symptoms Depression Positioning Positioning First Line Treatment of First FDA-Approved Major Depressive Disorder Non-Hormonal Treatment of Associated With Menopause Moderate-to-Severe VMS
  85. 85. Pristiq™ Pristiq Can become the first and only SNRI proven to effectively address the distinctive symptoms and therapeutic needs of women with: Depression associated with menopause Vasomotor symptoms Fibromyalgia
  86. 86. Providing Specific Benefits for Over 35 Million Women U.S. Prevalence Major Vasomotor Depression symptoms Fibromyalgia 23 Million2 4 Million3 12 Million1 Women Women Women 1 National Institute of Mental Health. “What To Do When A Friend is Depressed…” Bethesda (MD): National Institute of Mental Health, National Institutes of Health, U.S. Department of Health and Human Services; 2001. 2 Wyeth /ICR Patient Study Dec 2005, projected to total population using U.S. census data 3 Patient Base by Decision Resources, August 2005 2006 Syndicated Depression Omnibus shows VMS and depression overlap of ~3M women, 2005 Depression Consumer Landscape Study shows fibromyalgia and depression overlap of ~1M women
  87. 87. Pristiq™ (Desvenlafaxine Succinate) Ginger Constantine, M.D. Vice President and Therapeutic Area Director Woman’s Health and Bone Repair Clinical Research & Development, Wyeth Pharmaceuticals
  88. 88. Pristiq™ Modulates Serotonin and Norepinephrine May be Integral in Modulation of Depression, Thermoregulatory Dysfunction, Pain Being Developed for Female Predominant Conditions Major Depression Vasomotor Symptoms Fibromyalgia
  89. 89. Estrogen: Complex Regulatory Effects on Serotonin and Norepinephrine Pathways Estrogen influences serotonin and norepinephrine: Neuronal firing Release rates Affects specific receptors Increases synthesis and decreases breakdown Norepinephrine stimulation of serotonin neurons may offset estrogen loss
  90. 90. Menopause and Depression Are Linked Postmenopause Depressed Mood Premenopause Irritability 0% 20% 40% 60% 80% 100% % Women With Symptom Maartens LW, et al Fam Pract.;18:189-94,2001.
  91. 91. Risk of Depressive Episode Greater During Perimenopause 7 Risk of Depressive Onset (%) 6 5 4 3 2 1 0 Premenopause Perimenopause Schmidt, et al. Am J Psychiatry. 2004.
  92. 92. Remission of Depression: Differential Response With Age SSRIs and SNRIs Pooled Analysis of 32 Depression Studies 50 Placebo SSRIs* Effexor®/Effexor XR® Remission Rate, Week 8 (%) †‡ †‡ P≤0.05 40 † 36% 30 30% 20 10 0 <40 <40 >55 <40 >55 >55 (n=263) (n=108) (n=1041) (n=367) (n=1007) (n=355) Age *SSRIs=fluoxetine, fluvoxamine, paroxetine, sertraline, and citalopram. †P≤0.05 drug vs. placebo. ‡P≤0.05 vs. SSRIs. Younger women = age ≤40; older women = age >55. Cohen LS, et al. Poster presented at ACNP Annual Meeting; San Juan, Puerto Rico; December 2004.
  93. 93. Pristiq™ (Desvenlafaxine Succinate) Efficacy on Major Depressive Disorders Men & Women
  94. 94. Pristiq™: Effective in Treating Major Depressive Disorder Efficacy demonstrated at: 100, 200, and 400 mg in short–term studies 200 and 400 mg in a 6-month relapse prevention study
  95. 95. Pristiq™: Effective in MDD 100 mg - 400 mg/Day Placebo-Controlled Studies Study Placebo Pristiq 100 mg * 306 Pristiq 200 mg Pristiq 400 mg * Fixed Dose Placebo 308 Pristiq 200 mg* Pristiq 400 mg * 0 -3 -6 -9 -12 -15 HAM-D Δ from Baseline * Statistically significant - p <.05 vs placebo
  96. 96. Pristiq™: Effective in MDD 100 mg - 400 mg/Day Placebo-Controlled Studies Study Placebo Pristiq 100 mg * 306 Pristiq 200 mg Pristiq 400 mg* Fixed Dose Placebo Pristiq 200 mg * 308 Pristiq 400 mg * 0 -3 -6 -9 -12 -15 Placebo 304 Pristiq 200-400 mg Flexible Dose Placebo 320 Pristiq 200-400 mg 0 -3 -6 -9 -12 -15 HAM-D Δ from Baseline * Statistically significant - p <.05 vs placebo
  97. 97. Pristiq™: Effective in MDD 100 mg - 400 mg/Day Placebo-Controlled Studies Study Placebo Pristiq 100 mg * 306 Pristiq 200 mg Pristiq 400 mg * Fixed Dose Placebo Pristiq 200 mg* 308 Pristiq 400 mg * Placebo 304 Pristiq 200-400 mg Flexible Dose Placebo 320 Pristiq 200-400 mg Placebo 309 Pristiq 200-400 mg Effexor XR® 75-150 mg Effexor XR® Comparator Placebo 317 Pristiq 200-400 mg Effexor XR® 150-225 mg * 0 -3 -6 -9 -12 -15 HAM-D Δ from Baseline * Statistically significant - p <.05 vs placebo
  98. 98. Primary Efficacy Variable (HAM-D17) Mixed Effects Model – Week 8 Study Placebo Pristiq 100 mg * 306 Pristiq 200 mg * Pristiq 400 mg * Fixed Dose Placebo Pristiq 200 mg * 308 Pristiq 400 mg * Placebo 304 Pristiq 200-400 mg Flexible Dose Placebo 320 Pristiq 200-400 mg * Placebo Pristiq 200-400 mg * 309 Effexor XR® 75-150 mg Effexor XR® Comparator Placebo 317 Pristiq 200-400 mg Effexor XR® 150-225 mg * 0 -3 -6 -9 -12 -15 -20 HAM-D Δ from Baseline * p-value vs placebo ≤ 0.05
  99. 99. Pristiq™ and Effexor XR® Comparative Studies in MDD Two Effexor XR trials of identical design Low dose Effexor XR (Study 309) Titration with Effexor XR (not Pristiq) High dose Effexor XR (Study 317) Titration with Effexor XR and Pristiq Flexible dose Pristiq, 200/400mg, placebo Study design: Comparisons vs placebo Post-hoc analysis: Allows Pristiq/ Effexor XR comparison
  100. 100. Pristiq™/Effexor XR® Comparable MDD Efficacy Pooled Post-Hoc Analysis 0 -2 -4 Change from Baseline Ham-D17 Total -6 Pristiq 200-400 mg -8 * * Placebo -10 * Effexor XR * 75-150 mg -12 * ** Effexor XR 150-225 mg * -14 * * * -16 1 2 3 4 5 6 7 8 Week * P < 0.05 vs placebo DVS 309-EU and 317-US: Pooled Analysis Ham-D17 Total Score (Mixed Effect Model, ITT)
  101. 101. Pristiq™ MDD: Relapse Prevention Clinically Important Result Primary Efficacy Analysis 1.0 Pristiq 200 mg Pristiq 400 mg 0.8 Sustained Remission Possibility 0.6 Placebo 0.4 0.2 0.0 0 50 100 150 Days on Double-Blind
  102. 102. Pristiq™ (Desvenlafaxine Succinate) Efficacy on Vasomotor Symptoms
  103. 103. The Majority of Women Will Suffer Hot Flushes 70 Hot Flush 60 50 % of Women 40 30 20 10 0 38 44 46 50 52 54 56 58 60 62 66 72 Age in Years Source: Rodstrom K. et al. Menopause 2002 9(3): 156-161
  104. 104. Pristiq™: Effective in Treating VMS Associated With Menopause Efficacy demonstrated at 100 mg, 150 mg in 2 placebo-controlled studies Primary efficacy – number and severity of VMS Secondary efficacy – responder analysis, onset of action, number of awakenings at night due to VMS
  105. 105. Pristiq™: Effective in Reducing Number of Moderate and Severe VMS Study 315 Study 319 13 13 12 12 11 11 10 10 # of Flushes 9 # of Flushes 9 8 8 Placebo Placebo 7 7 6 6 Pristiq 150 mg 5 5 Pristiq 100 mg Pristiq 4 4 100 mg Pristiq 150 mg 3 3 2 2 0 1 2 3 4 5 6 7 8 9 10 11 12 01 23 45 678 9 10 11 12 Weeks Weeks 100 mg dose: p-value versus placebo < 0.05 at all time points 150 mg dose: p-value versus placebo < 0.05 at all time points
  106. 106. Pristiq™: Reduction in Average Daily Number and Severity Score of Hot Flushes Study 315, 100 mg Study 319, 100 mg n=145 n=162 Time Point p-Value vs p-Value vs p-Value vs p-Value vs Placebo Placebo Placebo Placebo Number Severity Number Severity Week 1 <0.001 <0.001 <0.001 <0.001 Week 2 <0.001 0.001 <0.001 <0.001 Week 3 <0.001 0.003 <0.001 <0.001 Week 4 0.013 0.054 <0.001 <0.001 Week 5 0.020 0.019 <0.001 0.004 Week 6 0.026 0.048 <0.001 0.002 Week 7 0.019 0.042 <0.001 0.003 Week 8 0.018 0.029 0.001 0.005 Week 9 0.008 0.011 0.001 0.004 Week 10 0.013 0.018 <0.001 0.001 Week 11 0.013 0.004 0.002 0.002 Week 12 0.005 0.002 0.002 0.002 ITT LOCF
  107. 107. High Responder Rate in VMS 60% Study 315 Study 319 % Subjects With > 75 % Reduction in Hot Flushes * * * * 40% 20% 0% Pristiq Pristiq Placebo Placebo Pristiq™ Pristiq 100 mg 150 mg 100 mg 150 mg * p-value versus placebo <0.05
  108. 108. Rapid Onset of Action Time (Days) to Reach a 50% Reduction in Number of VMS 30 Study 315 Study 319 25 Time in Days 20 15 10 * * * * 5 0 Pristiq Pristiq Placebo Placebo Pristiq™ Pristiq 100 mg 150 mg 100 mg 150 mg * p-value versus placebo <0.001
  109. 109. Reduces Nighttime Awakenings Due to VMS Pristiq Pristiq Placebo Placebo Pristiq™ Pristiq 100 mg 150 mg 100 mg 150 mg 0.00 Reduction in Number of Nighttime -1.00 Awakenings -2.00 * ** * * Study 315 Study 319 -3.00 * p-value versus placebo <0.05; ** p-value versus placebo <0.001
  110. 110. Improves Mood in Non-Depressed Postmenopausal Women Week 12 Data Total Mood Tension Score Anger Hostility Anxiety Depression Fatigue 0 POMS, Change From Baseline * -5 * * * * * -10 -15 * -20 * Placebo Pristiq™ 100 mg Pristiq 150 mg -25 * p-value versus placebo <0.05; Data on File (Pooled data from Studies 315 and 319)
  111. 111. Pristiq™ (Desvenlafaxine Succinate) Safety/Tolerability Profile
  112. 112. Safety and Tolerability Profile of Pristiq™ (Adverse Reactions ≥ 5%) Consistent With the SNRI Class Asthenia Nervousness Hypertension Somnolence Anorexia Tremor Constipation Sweating Dry Mouth Abnormal Vision Nausea Mydriasis Vomiting Abnormal Ejaculation/Orgasm Dizziness Impotence (Male) Insomnia Most common adverse drug reactions (>5%), pooled data VMS+MDD
  113. 113. Pristiq™/Effexor XR® Comparator Studies Combined Data, Adverse Events >5% Adverse Event Placebo Pristiq Effexor XR Effexor XR (%) (n=245) 200-400mg 75-150mg 150-225mg (n=231) (n=127) (n=117) Asthenia 4% 9% 8% 6% Hypertension 3% 5% 3% 6% Tachycardia <1% 6% 0% 4% Insomnia 9% 13% 11% 13% Anorexia 1% 10% 5% 15% Somnolence 7% 13% 9% 19% Dry Mouth 4% 20% 13% 26% Nausea 12% 38% 21% 29% Vomiting 1% 7% 2% 3% Sweating 4% 19% 9% 18% Impotence† <1% 9% 6% 11% † Men only
  114. 114. MDD Program: Most Nausea Occurred During Week One MDD Pooled Fixed Dose Studies 50% Incidence of Nausea Placebo (n=323) 40% Pristiq™ 100 mg (n=118) Pristiq 200 mg (n=307) Pristiq 400 mg (n=317) 30% 20% 10% 0% 1 2 3 4 6 8 8 Week of Treatment Wyeth data on file (MDD001 DAR)
  115. 115. MDD Program: Incidence of Discontinuation for Nausea By Week 50 Placebo 40 Pristiq™ 100 mg % Subjects 30 Pristiq 200 mg Pristiq 400 mg 20 10 0 Week 1 Week 2 Week 3 Week 4 Subjects in DVS SR Flexible Dose studies (309 and 317 @ 200-400 mg/day) are not included in this display
  116. 116. VMS Program: Most Nausea Occurred During Week One and Was Dose Dependent VMS Pooled Studies 50% Placebo (n=323) Incidence of Nausea 40% Pristiq™ 50mg (n=149) Pristiq 100mg (n=495) 30% Pristiq 150mg (n=336) Pristiq 200mg (n=409) 20% 10% 0% 1 2 3 4 5-8 >12 12 Weeks of Treatment Wyeth data on file
  117. 117. Pristiq™ – Additional Features No prolongation of QT interval From thorough QTc study Blood pressure, pulse rate increases consistent with SNRIs 100 mg/day: No consistent increase/decrease Pristiq very low drug-drug interactions
  118. 118. Pristiq™ Phase 3 Summary Efficacy MDD improved Ham-D17 – 100, 200 and 400 mg VMS reduced number/severity hot flushes – 100, 150 mg Sleep, mood, awakenings due to hot flushes reduced Total mood score improved Satisfaction score positive – 100, 150 mg Safety Early discontinuation rate below 10% at end of week 1 Tolerability profile improved after week 1 Predominant symptoms – nausea, dizziness, insomnia, somnolence Median duration of nausea: 3-4 days
  119. 119. Pristiq™ Low-Dose Program MDD 3 ongoing low-dose studies 50, 100 mg, placebo (2 studies U.S., EU) 50, 100 mg, placebo, duloxetine 1 low-dose study to support registration in Asia Low-dose drug-drug interaction studies underway VMS Titration study – 25, 50, 100 mg (ongoing)
  120. 120. Conclusion Pristiq™ provides a unique therapy for women transitioning through menopause and beyond MDD Effective antidepressant in men/women May provide better efficacy in women than SSRIs VMS – non-hormonal vasomotor symptom relief associated with menopause Fibromyalgia – clinical program ongoing
  121. 121. Pristiq™ (Desvenlafaxine Succinate)
  122. 122. Pristiq™ Will Broaden the Reach of Our SNRI Franchise Major Major Depressive Depressive Disorder Disorder Generalized Generalized Anxiety Anxiety Disorder Disorder Social Social Anxiety Anxiety Disorder Green = Effexor XR® Disorder Panic Panic Disorder Disorder
  123. 123. Pristiq™ Will Broaden the Reach of Our SNRI Franchise Major Vasomotor Major Vasomotor Fibromyalgia Fibromyalgia Depressive Symptoms of Depressive Symptoms of Syndrome Syndrome Disorder Menopause Disorder Menopause Generalized Generalized Anxiety Anxiety Disorder Disorder Social Social Anxiety Anxiety Disorder Green = Effexor XR® Disorder Blue = Pristiq™ Panic Panic Disorder Disorder Red = Effexor/Pristiq
  124. 124. Pristiq™ Product Profile for Major Depression or VMS Can become the first and only SNRI proven to effectively address the distinctive symptoms and therapeutic needs of women with depression associated with menopause or vasomotor symptoms MDD NDA Dec 2005 Status VMS NDA June 2006 Peak Sales > $2 Billion
  125. 125. Viviant™/Aprela™ (Bazedoxifene) and (Bazedoxifene/Conjugated Estrogens) Alliance with Ligand Pharmaceuticals
  126. 126. Initial Target Profile Viviant™ (Bazedoxifene) Effective osteoporosis agent Less potential to exacerbate hot flushes Safe for breast and uterus Minimal metabolic disturbances
  127. 127. Evolving Target Profile Viviant™ (Bazedoxifene) Effective osteoporosis agent Less potential to exacerbate hot flushes Safe for breast and uterus Minimal metabolic disturbances
  128. 128. The Number of Women at Risk for Osteoporosis Is Projected to Increase From 30 to 41 Million by 2020 45 41 Million Osteoporosis Osteopenia 40 # of Women in Millions 35 30 Million 30 30 25 Increase 20 22 15 10 11 5 8 0 2002 2020 Source: National Osteoporosis Foundation
  129. 129. The Majority of Women Who Stopped Taking ET/HT Did Not Switch to Prescription Osteoporosis Brands 18 16.0 Million Osteo Brands 16 Est. Patients in Millions Oral ET/HT 14 4.4 11.2 Million 12 + 1.0M 10 5.4 8 6 11.6 - 5.8M 4 5.8 2 0 Pre-WHI Post-WHI Jan-Jun 2002 Jan-Jun 2004 Source: Patient estimates derived using IMS National Prescription Audit data
  130. 130. Viviant™ (Bazedoxifene) With FDA-approval, the first new SERM in nearly 10 years providing physicians a new option for patients at risk of osteoporosis and fracture
  131. 131. New Paradigm for Menopause Select Estrogen “Targets” Patient Benefits Prevent osteoporosis Relief of vasomotor Vasomotor symptoms Improved vulvovaginal Breast atrophy Neutral on breast Bone Amenorrhea Endometrium Endometrial protection Vagina without progestin Improved quality of life
  132. 132. Aprela™ (Bazedoxifene/Conjugated Estrogens) The First TSEC or Tissue Selective Estrogen Complex
  133. 133. Aprela™ (Bazedoxifene/Conjugated Estrogens) Wyeth’s analysis suggest that Viviant’s unique characteristics make it the only SERM that could be combined into such an estrogen complex
  134. 134. Aprela™: The Most Comprehensive Medicine for Menopause TSEC Vasomotor Vasomotor Breast Breast Bone Bone Endometrium Endometrium Vagina Vagina
  135. 135. Aprela™ and Viviant™ (Bazedoxifene/Conjugated Estrogens) and (Bazedoxifene) Ginger Constantine, M.D. Vice President and Therapeutic Area Director Woman’s Health and Bone Repair Clinical Research & Development, Wyeth Pharmaceuticals
  136. 136. Climacteric Complaints Related to the Menopause Occurs in ~50% of Women Flushing Irritability Night sweats Lack of self-confidence Waking at night Insomnia Tiredness Painful intercourse Depressed mood Vaginal dryness
  137. 137. Menopause Specific Quality-of-Life (MenQOL) Vasomotor Menopausal Stage Domain Score Premenopause 1.53 Postmenopause 3.20 p-Value <0.0001 Adapted from Blumel JE, et al. Maturitas 34:17-23, 2000
  138. 138. The Majority of Women Will Suffer Hot Flushes 70% Hot Flush 60% 50% % of Women 40% 30% 20% 10% 0% 38 44 46 50 52 54 56 58 60 62 66 72 Age in Years Source: Rodstrom K et al. Menopause 9(3): 156-161, 2002
  139. 139. Osteoporosis Osteoporotic fracture: Profound effect on health ↑ Mortality following hip fracture ↑ Disability ↓ Quality-of-Life (QOL) Huge economic impact U.S. costs ~ $17.9 billion/year Increase in hip fractures after discontinuing HT following WHI† Abstract: RM Dell, MD et al; Presented: AAOS Annual Mtg March 22-26, 2006 †
  140. 140. Osteoporosis
  141. 141. Architectural Change One Year Postmenopause Baseline 1 Year Borah, et al; Dufresne, et al; Abstracts presented: OI World Congress on Osteoporosis, 2002.
  142. 142. Aprela™ (Bazedoxifene/Conjugated Estrogens) Tissue Selective Estrogen Complex (TSEC) A New Paradigm for Menopausal Therapy
  143. 143. Clinical Rationale for a Tissue Selective Estrogen Complex (TSEC) Current HT and SERMs have clinical drawbacks TSEC may provide improved clinical benefits with fewer potential side effects Program initiated in 1999 Maintain Leadership in Menopausal Health
  144. 144. Women’s Health Initiative Estrogen Alone Arm Cumulative Hazard for Total Breast Cancers 0.04 HR, 0.82 (95% CI, 0.65-1.04) Log-Rank p =.10 0.03 Cumulative Hazard 0.02 0.01 CEE Alone Placebo 0.00 0 1 2 3 4 5 6 7 8 9 Time, years Adapted from Stefanick, M. L. et al. JAMA 2006;295:1647-1657.
  145. 145. Optimal Targeted Response of Tissue Selective Estrogens Complex (TSEC) Target TSEC Increased Bone Mass Improved Hot Flush Vaginal Health Prevent Endometrial Hyperplasia Decreased Breast Tenderness The Most Comprehensive Medicine for Menopause
  146. 146. Tissue Selective Estrogen Continuum Defines Activity Full Full TSEC Antagonist Agonist Aprela™ Estrogen Receptor Anti-Estrogens Bazedoxifene 17β-Estradiol Raloxifene
  147. 147. Tissue Selective Estrogen Continuum Defines Activity Endometrial Antagonist Agonist Stimulation Viviant™ Tamoxifen 17β-Estradiol Raloxifene Lasofoxifene Viviant’s Endometrial Profile Permits TSEC Benefits M.B. Taylor, North American Menopause Society, October 2004
  148. 148. Raloxifene and 17ß-Estradiol NAMS Abstract Pilot Study on the Endometrial Effects of Combined Raloxifene and Oral 17-beta Estradiol in Postmenopausal Women M.B. Taylor, MD1, Y. Qu, Ph.D.1, S. Siddhanti, PhD1, L. Plouffe Jr, MD1. Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN. Results….. By 52 weeks, ET (endometrial thickness) was significantly increased in the RLX+E group compared with baseline and the RLX group (p<0.05). Two women (4%) in RLX+E group and none in the RLX group had endometrial hyperplasia in the exit endometrial biopsy. Abstract Presented: NAMS 15th Annual Meeting, Washington, DC; October 2004
  149. 149. Aprela™ (Bazedoxifene/CE) A New Paradigm Relieve vasomotor symptoms Prevent osteoporosis Improve vulvovaginal atrophy (VVA) Excellent amenorrhea No increased breast tenderness vs placebo Provide endometrial protection Improve quality-of-life
  150. 150. Aprela™ Effectively Treats Vasomotor Symptoms Number of Moderate-to-Severe Symptoms Phase 3 Study 0 Placebo A djuste d M e a n C ha nge -2 Fro m B a se line Raloxifene -4 -6 Aprela 20/0.625 -8 Aprela 20/0.45 -10 0 1 2 3 4 5 6 7 8 9 10 11 12 Week Statistically significant at all end points vs placebo and 8 – 12 weeks vs raloxifene Data on file: Ph 3 BZA/CE analysis 3115A1-303 study

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