11 Intrinsa ™ (testosterone transdermal system) Reproductive Health Drugs Advisory Committee Meeting Gaithersburg, MD December 2, 2004 Procter & Gamble Pharmaceuticals

22 Introduction to Program and Regulatory Overview Joan M. Meyer, PhD Senior Director, New Drug Development Procter & Gamble Pharmaceuticals I1C

33 What is Intrinsa?  Transdermal patch delivering 300 mcg/day testosterone when applied twice a week as continuous therapy  Proposed Indication: Treatment of hypoactive sexual desire disorder (HSDD) in surgically menopausal women receiving concomitant estrogen therapy I2C

44 HSDD is a Condition that Affects Many Women  A recognized medical condition  Associated with decreased desire, sexual activity and satisfaction  Distressing to these women  Can adversely affect a woman’s health, well-being, and relationship with spouse or partner I14C

55 Agenda IntroductionJoan M. Meyer, PhD, P&GP Clinical EfficacyJohna D. Lucas, MD, P&GP Clinical RelevanceLeonard D. DeRogatis, PhD, Johns Hopkins Clinical SafetyJohna D. Lucas, MD, P&GP Hormone DataGlenn D. Braunstein, MD, UCLA Medical NeedJan L. Shifren, MD, Harvard Long-term SafetyMichael Steinbuch, PhD, P&GP ConclusionsJoan M. Meyer, PhD, P&GP I4C

66 Additional Participants Ricardo Azziz, MD, MPH, MBAChair, Department of OB/GYN Cedars-Sinai Medical Center Vernon Chinchilli, PhDProfessor & Interim Chair, Department of Health Evaluation Sciences Penn State College of Medicine Maurie Gelfand, MDProfessor of OB/GYN McGill University Robert Reid, MDDirector of Reproductive Endocrinology Kingston General Hospital Alexander Walker, MD DrPHSenior Vice President of Epidemiology Ingenix William White, MDProfessor of Medicine University of Connecticut School of Medicine Nora Zorich, MD, PhDVice President, R&D, P&GP I5C 6

77 Intrinsa Comprehensive Clinical Development Program  3 Dermal Safety and Irritation Studies  9 Pharmacokinetic Studies Range of doses / dosing durations Established T reference range  3 Phase II Studies Dose-ranging Multiple geographies, routes of E administration  4 Phase III Studies 2 surgical menopause 2 natural menopause I6C

88 New Therapeutic Area Requires Special Studies  Instrument development and validation studies  Randomized, placebo-controlled withdrawal study  Clinical relevance study  Comprehensive safety program I7C

99 Intrinsa ™ (testosterone transdermal system) Reproductive Health Drugs Advisory Committee Meeting Gaithersburg, MD December 2, 2004 Procter & Gamble Pharmaceuticals

10 Phase III Surgical Menopause Efficacy Overview Johna D. Lucas, MA, MD, FACOG Medical Director Procter & Gamble Pharmaceuticals E1C

11 Efficacy Agenda  Instrument development & validation  Efficacy endpoints  Description of trials  Trial results E2C

12 Validated Study Instruments  Sexual Activity Log © (SAL © ) Weekly diary measuring sexual activity  Profile of Female Sexual Function © (PFSF © ) 30-day recall measuring domains of sexual function  Personal Distress Scale © (PDS © ) 30-day recall measuring distress related to lack of interest in sex McHorney CA et al. Menopause Jul-Aug;11(4): Derogatis L. et al. J Sex Marital Ther Jan-Feb;30(1):25-36 E32C

13 PFSF & PDS Development & Validation Program  Interviewed 250+ patients with HSDD  Generated 450+ items  Reduced items using psychometric criteria  Tested remaining 83 items in 3 validation trials 325 women with HSDD 255 age-matched controls E3C

14 PFSF & PDS Development & Validation Program  Chose 37 best items for final PFSF (7 domains) and 7 items for final PDS based on assessments of data quality, domain structure and item redundancy  Domains had good reliability and validity  Evaluated final version in a confirmatory validation study (n= 251) 59 surgically menopausal women with HSDD 88 naturally menopausal women with HSDD 104 age-matched controls with normal libido E4C

15 SAL Developed to Quantify Sexual Activity  Interviewed patients to understand how women quantify their sexual activity  Tested diary language to ensure universal understanding  Tested & revised SAL to minimize reporting error  Final instrument consistently well understood and shown to be valid and reliable E7C

16 Intrinsa Surgical Menopause Study Design  2 Phase II, 2 Phase III (SM 1 & SM 2) 8-week pre-treatment baseline period 24-week randomized double-blind placebo controlled treatment period All patients on concomitant estrogen Inclusion / exclusion criteria same  All trials employed validated instruments  Open label safety: weeks 25  ongoing E10C

17 Phase III Studies  Concurrent multinational trials (US, Canada, and Australia) SM 1, 562 women, 52 sites SM 2, 532 women, 51 sites  Objective Assess efficacy / safety of transdermal testosterone in SM women with HSDD  Study population S/P hysterectomy and BSO On oral or transdermal estrogen therapy Hypoactive sexual desire disorder E14C

18 Endpoints of Phase III Program  Primary Endpoint Satisfying sexual activity  Key Endpoints Desire for sexual activity Distress associated with low desire  Other Important Endpoints E15C

19 Key Inclusion Criteria for HSDD Population  Post-operative onset of low sexual desire with significant distress  Bilateral oophorectomy and hysterectomy  6 months prior to study  years old  Stable dose of estrogen (oral or TD) for  3 months prior to study  Stable monogamous relationship for  1 year with partner present >50% of the time E16C

20 Key Exclusion Criteria for HSDD Population  Serious medical conditions  Malignancy - Breast or estrogen dependent (ever) - Other (5 years)  Depression or other psychiatric conditions  Androgen or other confounding medications  Dyspareunia  Ongoing relationship disturbances E17C

Screened 550 TTS 436 (80%) Completed 433 (79%) Completed 418 (96%) Placebo-TTS Agreed to participate 419 (97%) TTS-TTS Agreed to participate 326 (78%) Completed 315 (75%) Completed Disposition of Patients During Weeks 0-52 Surgical Menopause 1 and 2 Weeks 0-24 (24-week double-blind period) Weeks (28-week open-label safety period) 1095 (64%) Randomized 545 Placebo 8-week baseline period E18C

22 Patient Disposition at 24 Weeks SM 1SM 2 PlaceboTTSPlaceboTTS No. Randomized Completed, % Discontinued, % Adverse event 7888 Voluntary/Other E19C

23 Demographics/Baseline Characteristics SM 1SM 2 PlaceboTTSPlaceboTTS n=279n=283n=266 Age, yrs Race, % Caucasian Length of relationship, yrs Time since BSO, yrs8999 Oral/TD estrogen, %75/2574/2682/1880/20 E20C

24 HSDD Baseline Characteristics SM 1 SM 2 Mean Placebo n=279 TTS n=283 Placebo n=266 TTS n=266 Sexual desire score Personal distress score Total satisfying episodes* * 4-week frequency E21C

25 SM 1 % Increase From Baseline 33% 74% 23%51% SM 2 Testosterone Patch Increased Total Satisfying Sexual Activity at 24 Weeks E22C p= p=0.001

26 Testosterone Patch Increased Desire at 24 Weeks SM 1SM 2 p= % Increase From Baseline 29%56%18%49% E23C

27 SM 1 SM 2 % Decrease From Baseline 40% 65%48%68% p= p= Testosterone Patch Decreased Distress at 24 Weeks E24C

28 Testosterone Patch Improved All PFSF Domains at 24 Weeks Arousal PleasureOrgasm Reduced Concerns Responsiveness Self- image p=0.023 p< p= p= p= p< Placebo TTS SM 1 E25C

29 ArousalPleasureOrgasm Reduced Concerns Responsiveness Self- image p= p= p= p= p=0.002 p= Placebo TTS SM 2 Testosterone Patch Improved All PFSF Domains at 24 Weeks E26C

30 Increases in Other SAL Endpoints at 24 Weeks p= p= p= EpisodesOrgasms 4-Wk Mean Change From Baseline (SEM) SM 1 EpisodesOrgasms p= SM 2 % Increase From Baseline 9% 26% 37% 80%3% 14%23% 68% E27C

31 Testosterone Patch is Efficacious for Surgically Menopausal Women with HSDD  In surgically menopausal women with low sexual desire, Intrinsa significantly: ↑ Sexual desire ↑ Satisfying sexual activity ↓ Personal distress ↑ Arousal, orgasm, pleasure, responsiveness and sexual self image ↓ Sexual concerns ↑ Total sexual activity and number of orgasms E31C

32 Intrinsa ™ (testosterone transdermal system) Reproductive Health Drugs Advisory Committee Meeting Gaithersburg, MD December 2, 2004 Procter & Gamble Pharmaceuticals

33 Clinical Relevance of Treatment Effects Leonard R. DeRogatis, PhD Director Johns Hopkins Center for Sexual Health and Medicine C1C

34 Clinical Relevance of Treatment Effects  Evidence from Phase III Study All endpoints derived from concerns and experiences of HSDD patients Decrease in personal distress is a direct marker of relevant treatment impact Improvement of sexual function across all relevant domains  Evidence from Clinical Relevance Study C2C

35 Anchoring Technique for Examining Clinical Relevance  Well-established through broad use  Readily understood  Patient-based. Uses direct questions concerning patient benefit  Patient perceptions of benefit are tied to study endpoints through statistical analyses (ROC)  Results define meaningful change (MCID) which helps establish clinical relevance C3C

36

37 Anchoring Model of Clinical Relevance PATIENTPERCEPTIONROCANALYSIS MCID RESPONDERS Meaningful Benefit Desire Satisfying Activity Distress ∆ PFSF ∆ PDS Yes / No % % % Clinical Relevance Study Phase III Studies ∆ SAL C5C

38 Clinical Relevance Study Design  132 women from Phase III trials  First, open-ended questions about experience in clinical study  Then, specific questions about benefits, if any  Question for anchoring analyses “Overall, considering everything we have talked about today, would you say that you experienced a meaningful benefit from the study patches?” C6C

39 Clinical Relevance Study Responders by Treatment C7C TTSPLp-value 52%31%p=0.025 Self-identified Responders

40 Clinical Relevance Study Mean Changes from Baseline Reported overall meaningful benefit Reported no overall meaningful benefit Satisfying Sexual Activity Desire Distress C13C

41 ROC Discrimination Change > 1 AUC = 0.77 True positive rate False positive rate Satisfying Sexual Activity C8C

42 Clinical Relevance Results PATIENTPERCEPTIONROCANALYSIS MCID RESPONDERS Meaningful Benefit Desire Satisfying Activity Distress ≥ 8.9 ≤ - 20 Yes TTS PL 50 vs 34 % 51 vs 39 % 52 vs 31 % p = N = 132 All p < N =1095 Clinical Relevance Study Phase III Studies > 144 vs 30 % TTS PL C9C

43 Interest in Continuing Treatment C10C

44 Summary  Significantly more TTS patients than placebo patients experienced meaningful benefit  Anchoring using MCID values confirms similar proportions of responders in Phase 3 trials  Consistent results across all endpoints sexual desire satisfying sexual activity personal distress C11C

45 Conclusion  Consistent pattern of outcomes shows strong evidence of a clinically meaningful benefit, which translates into observable clinical relevance. C12C

46 Intrinsa ™ (testosterone transdermal system) Reproductive Health Drugs Advisory Committee Meeting Gaithersburg, MD December 2, 2004 Procter & Gamble Pharmaceuticals

47 Phase III Surgical Menopause Safety Overview Johna D. Lucas, MA, MD, FACOG Medical Director Procter & Gamble Pharmaceuticals S1C

48 Safety Focus Areas for Testosterone Therapy in Women  Androgenic skin changes  Weight  Blood Pressure  Liver Dysfunction  Polycythemia  Cardiovascular Disease  Breast Cancer  Other Adverse Events Noted on Male Product Labels S2C

49 Phase III Trial Design 0-6 Months 7-12 Months SM 1 SM 2 NM 1 NM 2 = primary safety data= additional safety data DB OL S3C n = 532 n = 562 DB = Double BlindOL = Open Label

50 Exposure to Testosterone Patch Phase II & III Studies Number of Patients Surgical Menopause Natural Menopause Total Exposure* ICH Guideline Minimum ≥ 300 mcg/day 300 mcg/day At least 1 dose ≈ 6 months ≈ 12 months ≈ 18 months1270 Total patient months S4C *exposure as of 6/04

51 Safety Evaluations  Adverse Events (AEs) Overall Serious AEs Withdrawals due to AEs  Androgenic Assessments and Adverse Events  Adverse Events of Special Interest  Weight and Vital Signs  Laboratory Evaluations Liver Function Cardiovascular Risk Factor Assessments Hematology  Breast Cancer S5C

52 Overall Adverse Event Summary 24 Weeks SM 1SM 2 % of Patients Placebo N=279 TTS N=283 Placebo N=266 TTS N=266 Patients with AEs Serious AEs / Deaths2.5/0 2.3/11.9/0 Withdrawals due to AEs Most Common AEs Application-site reaction Upper respiratory infection Headache S6C

53 S7C Androgenic Effects at 24 Weeks  Acne  Hirsutism  Alopecia  Clitoromegaly  Voice deepening 94% of events were mild 78% of these patients had only one event Time to event similar to placebo

54 Acne Assessments & AEs 24 Weeks SM 1SM 2 % of Patients Placebo N=279 TTS N=283 Placebo N=266 TTS N=266 Acne: Clinical Assessments (Change from baseline) <0< 3  Acne: AEs Acne Scale: Palatsi S8C

55 Facial Hair Assessments & AEs 24 Weeks SM 1SM 2 % of Patients Placebo N=279 TTS N=283 Placebo N=266 TTS N=266 Facial Hair Clinical Assessments (Change from baseline ) Chin <  Upper lip <  Hirsutism: AEs Hirsutism Scale: Facial measures of Ferriman-Gallwey/Lorenzo S9C

56 Other Androgenic AEs 24 Weeks SM 1SM 2 % of Patients Placebo N=279 TTS N=283 Placebo N=266 TTS N=266 Alopecia Voice Deepening Clitoromegaly S10C

57 SM 1SM 2 % of Patients Placebo N=279 TTS N=283 Placebo N=266 TTS N=266 Acne Alopecia Hirsutism Voice Deepening Clitoromegaly Androgenic AE Withdrawals 24 Weeks S11C

58 AEs of Special Interest 24 Weeks SM 1SM 2 % of Patients Placebo N=279 TTS N=283 Placebo N=266 TTS N=266 Breast Tenderness Hot Flushes Weight Gain S12C

59 Weight and Blood Pressure 24 Weeks SM 1SM 2 Baseline  from Baseline Placebo N=279 TTS N=283 Placebo N=266 TTS N=266 Weight (kg) Systolic BP (mmHg) Diastolic BP (mmHg) S13C

60 Other Adverse Events 24 Weeks SM 1SM 2 % of Patients Placebo N=279 TTS N=283 Placebo N=266 TTS N=266 Anxiety Edema Aggression Abnormal LFTs S16C

61 Liver Function Test AEs 24 Weeks S17C  Isolated bilirubin elevations (n=2)  Mild transaminase elevations (n=3) 2 resolved on testosterone 1 remained just above ULN on testosterone (52 weeks) and repeat after discontinuation  Moderate transaminase elevation (n=1) Resolved on testosterone after concomitant drug discontinued

62 Liver Function Tests 24 Weeks SM 1SM 2 Mean Baseline/  from Baseline Placebo N=279 TTS N=283 Placebo N=266 TTS N=266 Alk phos (U/L) ALT SGPT (U/L) AST SGOT (U/L) Bilirubin (mg/dL) S18C

63 Hematology 24 Weeks SM 1SM 2 Mean Baseline  from Baseline Placebo N=279 TTS N=283 Placebo N=266 TTS N=266 Hematocrit (%) Hemoglobin (g/dL) Platelet count (x1000/mcL) S32C

64 Hemoglobin Changes With Testosterone Therapy 24 weeks (SM 1 and SM 2) Hemoglobin - 24 wk (g/dL) Baseline Value (g/dL) Treatment Group - TTS S34C

65 Carbohydrate Metabolism 24 Weeks SM 1SM 2 Mean Baseline/ ∆ from Baseline Placebo N=279 TTS N=283 Placebo N=266 TTS N=266 Glucose (mg/dL) HbA 1C (%) Insulin (  IU/mL) S22C

66 Serum Lipids 24 Weeks SM 1SM 2 Mean Baseline  from Baseline Placebo N=279 TTS N=283 Placebo N=266 TTS N=266 T Chol (mg/dL) HDL (mg/dL) LDL (mg/dL) Trig (mg/dL) S26C

67 Coagulation Evaluations SM 1 24 Weeks Placebo N=279 TTS N=283 Baseline ∆ from Baseline Baseline ∆ from Baseline PT (sec) APTT (sec) Fibrinogen (mg/dL) PAI activity (U/ml) PAI antigen (ng/mL) tPA antigen (ng/mL) ATIII (functional) S31C

68 Evaluation of Patients with Cardiac Risk Factors  At least three of the following: BMI >30 kg/m 2 Triglycerides ≥ 150 mg/dL HDL < 50 mg/dL Blood Pressure ≥ 130/85 mmHg Fasting Glucose ≥ 110 mg/dL S30C

69 Overall AE Summary SM Open-Label Weeks S36C SM 1 and SM 2 Integrated TTS Exposure % of Patients 6 mos P  TTS N= mos TTS  TTS N= mos P  TTS  TTS N= mos TTS  TTS  TTS N=154 Patients with AEs Serious AEs Withdrawals due to AEs Androgenic AE withdrawals Weeks 53-78Weeks 25-52

70 Adverse Event Summary Natural Menopause Trials NM 1 24 Weeks NM 2 52 Weeks Interim data 1:2 Randomization % of Patients Placebo N=273 TTS N=276 Placebo N=117 TTS N=241 Patients with AEs Serious AEs/Deaths1.5/02.5/0.76.8/03.3/0 Withdrawals Most common AEs Application site reactions Upper respiratory infections Breakthrough Bleeding S37C

71 Androgenic Adverse Events Natural Menopause Trials NM 1 24 Weeks NM 2 52 Weeks Interim data 1:2 Randomization % of patients Placebo N=273 TTS N=276 Placebo N=117 TTS N=241 Acne Alopecia Hirsutism Voice Deepening Clitoromegaly S38C

72 NM 1 24 Weeks NM 2 52 Weeks Interim data 1:2 Randomization % of patients Placebo N=273 TTS N=276 Placebo N=117 TTS N=241 Acne Alopecia Hirsutism Voice Deepening Clitoromegaly Androgenic AE Withdrawals Natural Menopause Trials S39C

73 Reported Cases of Breast Cancer Patient numbers Observed Cases Surgical Menopause Phase II Placebo1591 TTS3640 Surgical Menopause Phase III Placebo  TTS 5452 Placebo  TTS  TTS TTS  TTS Natural Menopause Phase III Placebo3900 TTS5170 S40C

74 Breast Cancer Cases Case #1 (placebo)  50 year old diagnosed with invasive ductal carcinoma diagnosed during the initial placebo period Case #2 (placebo  TTS)  63 year old diagnosed with invasive metastatic adenocarcinoma diagnosed after 5 weeks of TTS treatment (axillary mass, normal mammogram) S41C

75 Breast Cancer Cases Case #3 (placebo  TTS  TTS)  56 year old diagnosed with tubulolobular carcinoma after 37 weeks TTS treatment (area noted on baseline mammogram) Case #4 (placebo  TTS)  50 year old diagnosed with DCIS after 24 weeks TTS treatment (new mammographic finding) S42C

76 Breast Cancer Summary  Total number of observed cases is within range expected based on the number and risk profile of women  Observed cases in patients with least exposure S43C

77 Safety Data Summary  Overall AEs, serious AEs, and withdrawals due to AEs similar for TTS and placebo  Androgenic effects are infrequent, generally mild, and rarely led to withdrawal  No changes in lab values except small change in red cell mass S44C

78 Favorable Safety Profile  Testosterone patch was well tolerated  No serious safety concerns identified  Androgenic adverse events Generally mild Low withdrawal rate Easily self monitored S45C

79 Intrinsa ™ (testosterone transdermal system) Reproductive Health Drugs Advisory Committee Meeting Gaithersburg, MD December 2, 2004 Procter & Gamble Pharmaceuticals

80 Phase III Surgical Menopause Hormone Data Glenn D. Braunstein, MD Professor, Department of Medicine The David Geffen School of Medicine at UCLA Chairman, Department of Medicine Cedars-Sinai Medical Center H1C

81 Hormone Data Agenda  How testosterone circulates in the blood and its availability to tissues  Impact of Intrinsa on serum testosterone and SHBG  Correlation of testosterone with efficacy & safety  Endometrial and breast safety H2C

82 How Testosterone Circulates in the Blood SHBG Bound 65-80% Albumin Bound 18-35% Free 1-2% H3C

83 Reference Range for Testosterone Levels  No accepted reference range available for women  Testosterone levels in women vary widely  Range determined based on 161 pre- menopausal women aged Time H4C

84 Placebo TTS Intrinsa Increased Median Free T Levels to Within Reference Range (Combined SM 1 & SM 2) Study Visit (Weeks) Whiskers describe the 10th and 90th percentiles; dots represent the median values Dashed lines denote reference ranges in premenopausal women H6C

85 PlaceboTTS Intrinsa Increased Median Bioavailable T to Within Reference Range (Combined SM 1 & SM 2) Study Visit (Weeks) Whiskers describe the 10th and 90th percentiles; dots represent the median values Dashed lines denote reference ranges in premenopausal women H7C

86 PlaceboTTS Total Testosterone Levels Did Not Exhibit Continued Accumulation (Combined SM 1 & SM 2) Study Visit (Weeks) Whiskers describe the 10th and 90th percentiles; dots represent the median values Dashed lines denote reference ranges in premenopausal women H8C

87 Placebo TTS Serum SHBG Stable Over One Year (Combined SM 1 & SM 2) Study Visit (Weeks) Whiskers describe the 10th and 90th percentiles; dots represent the median values Dashed lines denote reference ranges in premenopausal women H9C

88  s in Free T Are Correlated With  s in Efficacy H13C Phase II (pooled) Phase III (pooled)NM1 Total Satisfying Activity0.21*0.17*0.21* Desire0.28*0.22*0.19* Personal Distress-0.25*-0.16*-0.15* Spearman correlation coefficient *p < 0.05

89 Investigating Hormones and Safety  Effect on estrogens and estrogen responsive tissues  Reported and observed androgenic effects  Clinical laboratory measurements H14C

90 PlaceboTTS No Change in Serum Estradiol Concentrations With Intrinsa (Combined SM 1 & SM 2) Study Visit (Weeks) Whiskers describe the 10th and 90th percentiles; dots represent the median values H15C

91 No Evidence of Significant Effects on Breast and Endometrium  Karolinska Study – 6 months Mammographic breast density not different from placebo Breast epithelial proliferation not different from placebo Significant decrease in stromal cell proliferation with TTS  Natural Menopause Study – 12 months no increase in endometrial hyperplasia  No Intrinsa-related estrogen side effects in safety database H16C

92 Relationship between Maximum Free T and Androgenic Effects  Pooled Phase II and Phase III studies  Trend test examined incidence of androgenic AEs vs. maximum free T  Facial hair the only AE that was statistically associated with free T  Facial hair also associated with increases in objective assessment scores H17C

93

94 Relationship Between Free T and Important Laboratory Parameters  Examined laboratory parameters related to liver function, lipids, carbohydrate metabolism, hematology, and clotting factors  Changes for patients within the highest decile of free T compared to placebo were small and clinically insignificant H22C

95 Intrinsa Hormone Summary  Surgically menopausal women with HSDD had low baseline T  TTS increased free, bioavailable & total T  No evidence of T accumulation over 12 months  No changes in estradiol, estrone & SHBG  Higher exposure to free and total T not associated with clinically significant lab changes H18C

96 Intrinsa Hormone Summary  Median free and bioavailable T levels raised into pre-menopausal reference range  Changes in T levels correlated with increase in satisfying sexual events, increase in desire, and decrease in personal distress  Available one year data showed: No evidence of safety concerns with increased T Higher free T associated with small increases in facial hair in pooled trials H19C

97 Intrinsa ™ (testosterone transdermal system) Reproductive Health Drugs Advisory Committee Meeting Gaithersburg, MD December 2, 2004 Procter & Gamble Pharmaceuticals

98 Hypoactive Sexual Desire Disorder in Menopausal Women Jan L. Shifren, MD Assistant Professor of Obstetrics, Gynecology, and Reproductive Biology Harvard Medical School Director of the Menopause Program, Vincent Ob/Gyn Service Massachusetts General Hospital D1C

99 Women’s International Study of Health and Sexuality (WISHeS)  Self-report mail survey on general, menopausal, & sexual health  2467 US & 2050 EU women, ages  520 surgically & naturally menopausal women in US with partners  Three validated instruments: SF-36 Profile of Female Sexual Function (PFSF) Personal Distress Scale (PDS) Leiblum SR, et al., International Society for the Study of Women’s Sexual Health, Oct , 2002, Vancouver, Canada Leiblum SR, et al. Menopause. 2002;9:474. D4C

100 Menopausal Women with HSDD Report Decreased Sexual Activity Leiblum SR, et al., American Society of Reproductive Medicine, Oct 16-19, 2004, Philadelphia, PA No. of events in past 30 days woman initiates partner initiates HSDDNormal desire * *Statistically significant different from HSDD (p<0.0001) D2

101 Women with Low Desire Are Significantly Less Satisfied with Their Sex Lives Desire Domain Score (PFSF) Satisfaction With Sex Life r=0.49 p< Leiblum SR, et al., Second International Consultation on Erectile and Sexual Dysfunctions, June 2003, Paris, Fr D7C

102 Women Less Satisfied with Their Sex Lives Are Less Satisfied with Their Relationship or Marriage Completely Dissatisfied Somewhat Dissatisfied Neither Satisfied or Dissatisfied Somewhat Satisfied Completely Satisfied Satisfaction with Sex Life Relationship Satisfaction r=0.56 p< D8C Leiblum SR, et al., Second International Consultation on Erectile and Sexual Dysfunctions, June 2003, Paris, Fr

103 Greater Percentage of HSDD Menopausal Women Report Negative Feelings Due to Their Condition N=343N=73 Normal Desire (%) Hypoactive Sexual Desire Disorder (%) I felt ______ because of my lack of interest in sex 449*Ashamed 456*Low self-esteem 889*I was letting my partner down 1088*Unhappy 579*Frustrated 570*Troubled 874*Hopeless 664*Less feminine 459*Like a sexual failure * p< Leiblum SR, et al., International Society for the Study of Women’s Sexual Health, Oct 28-31, 2004, Atlanta, GA D9C

104 Menopausal Women with HSDD Have Diminished Health Status as Measured by the SF-36 *p<0.001 Leiblum SR, et al., International Society for the Study of Women’s Sexual Health, Oct 28-31, 2004, Atlanta, GA Physical Function Role Physical Bodily Pain General Health Vitality Social Function Role Emotional Mental Health Mean HSDDNormal Desire * * * * * * * D10C

105 Focus on Physiology Socio-Cultural Influences Psychology Interpersonal Relationships Physiology Medical & neurological problems Gynecological & urogenital problems Estrogen deficiency Androgen insufficiency D22C

Premenopausal Menopausal Testosterone pg/mL Judd et al. Am J Obstet Gynecol. 1974;118:794. *p<0.001 * * Testosterone Levels Decrease After Oophorectomy Baseline After Oophorectomy D23C

107 Physician Response to Lack of Treatment Options  In 2003, 21% of the total prescriptions for branded male testosterone products were written for women* Represents 145,000 prescriptions  In , there were 1,315,000 prescriptions written for compounded or generic testosterone products for women* *National Disease and Therapeutic Index, IMS Health, 2003 D18C

108 Improvement in TTS-treated Patients at 24 Weeks (SM 1 & SM 2) EndpointBaseline Change from Baseline Satisfying Sexual Activity (4 wk) Desire Distress D24C

109 Conclusion  HSDD has a significant impact on women’s lives  Intrinsa presents a meaningful treatment option for women with HSDD, since it improves sexual desire and activity, and reduces distress  Intrinsa offers an important treatment option for physicians who have no approved therapies for HSDD D20C

110 Intrinsa ™ (testosterone transdermal system) Reproductive Health Drugs Advisory Committee Meeting Gaithersburg, MD December 2, 2004 Procter & Gamble Pharmaceuticals

111 Intrinsa Long-term Safety Plan Michael Steinbuch, PhD Director, Pharmacovigilance and Epidemiology Procter & Gamble Pharmaceuticals LT1C

112 No Safety Signals Observed in Intrinsa Trials  Phase II/III Studies found no safety signal 18 months in SM women 12 months in NM women LT2C

113 Phase IV Safety Study Options  Observational studies  Randomized controlled trials (RCTs)  Patient registries LT3C

114 Observational Studies  Advantages Ideal for rapid signal detection Real world setting Large numbers of patients Ability to adjust for confounding variables Evaluate all patients exposed to Intrinsa LT4C

115 FDA Feedback  Issues raised by FDA Inability to capture medical claims data on women over 65 Inadequate statistical power to detect possible safety signal  P&G response Women over 65 represent 2% to 3% of potential Intrinsa users Study will have adequate power LT5C

116 Ingenix ® LabRx  Comprehensive longitudinal database Hospital, physician, pharmacy, laboratory  Open formulary (United Healthcare)  Validation of endpoints (85% abstraction rate)  Timely claims processing (90% within 4 mos)  Stable patient population (85% retention/yr)  Experienced research staff  Proven track record LT6C

117 Examples of Analysis Based on Ingenix Data at 2 Years Post-launch  FDA-accepted protocols for cardiovascular outcomes in: Oral contraceptive users Oral anti-diabetic therapies  Other outcomes in current, FDA-accepted Ingenix ® postmarketing safety studies Allergic reactions Vascular insufficiency of the intestine GI surgery Pregnancy and pregnancy outcome LT7C

118 Intrinsa Observational Study  Objective: Compare event rates in Intrinsa users vs nonusers  Design: Prospective cohort with 3:1 matching over a 5 year duration  Exclusion criteria: None  Endpoints: Cardiovascular disease (CVD) CHD (fatal, nonfatal MI) Stroke (fatal, nonfatal) Venous thromboembolic disease (DVT, PE) Composite CVD endpoint Breast cancer LT8C

119 Ingenix Patient Population 10,000,000 patients 135,000 menopausal women taking estrogen Estimated 5,500 Intrinsa users 19,000 potential users of Intrinsa 600,000 menopausal women LT9C

120 Power Considerations for Cardiovascular Events  Assumptions: 5500 new treated patients per year 0.15% event rate per year* 50% discontinuation per year 15% disenrollment per year alpha=0.05, one-sided test * JAMA. 2004;291: LT10C

121 Power for Signal Detection Year from launch RR Person- years for Intrinsa Power % % % % % LT11C

122 Robustness of Observational Study  Collaborative protocol development External experts and FDA  Blinded medical expert panel will adjudicate endpoints  Independent safety review board will analyze, interpret and report results to FDA and P&GP  First data at 18 months post-launch LT12C

123 Phase IV Safety Study Options  Observational studies  Randomized controlled trials (RCTs)  Patient registries LT13C

124 Randomized Controlled Trial Option  Advantages Ideal for hypothesis testing and determination of cause/effect Random allocation minimizes confounding  Disadvantages Not real world (i.e., inclusion/exclusion criteria) Recruitment and retention Timeliness LT14C

125 Patient Registry Option  Advantages Signal detection Large number of exposed patients Real world setting Recruitment ease  Disadvantages No comparison group LT15C

126 Summary  P&GP is committed to continued monitoring of long-term safety of Intrinsa  Ingenix ® LabRx is one of the largest and most comprehensive insurance claims databases  Novel approach Implementation at launch External expert design Independent safety review board execute, analyze and report to FDA  Optimal study design for timely signal detection LT16C

127 Intrinsa ™ (testosterone transdermal system) Reproductive Health Drugs Advisory Committee Meeting Gaithersburg, MD December 2, 2004 Procter & Gamble Pharmaceuticals

128 Closing Remarks Joan M. Meyer, Ph.D. Senior Director, New Drug Development Procter & Gamble Pharmaceuticals W1C

129 1) Do the efficacy data represent a clinically meaningful benefit? Yes  We assessed three related, but independent endpoints  Efficacy assessments were patient-centered  The results were statistically significant and highly consistent across all studies and endpoints  The randomized withdrawal trial reinforced the pharmacologic effect of the drug

130 2) Is the patient exposure adequate to demonstrate long-term safety? Yes Number of Patients Surgical Menopause Natural Menopause Total Exposure ICH Guideline Minimum ≥ 300 mcg/day 300 mcg/day At least 1 dose ≈ 6 months ≈ 12 months ≈ 18 months1270 Total patient months

131 3) Are there safety concerns or unanswered questions that need to be studied?  It is not uncommon to have unanswered questions at approval  Points to consider: No safety signals have been seen Androgens and estrogens have been used for years in women We have proposed a rigorous independent post- marketing safety study to supplement traditional PV Labeling will reflect current knowledge

132 4) Are the efficacy and safety data adequate to support approval of TTS? Yes