EVISTA Studies Overview Daniel Thiebaud MD, Medical Fellow, Global Osteoporosis Strategy, Eli Lilly, Australia

1. EVISTA � Studies OverviewDaniel Thiebaud MD, Medical Fellow,Global Osteoporosis Strategy, Eli Lilly, Australia

2. Concept of a SERM Concept of a SERM Selective estrogen receptor modulators (SERMs) are non-hormonal agents that bind to estrogen receptors, but produce estrogen agonist effects in some tissues while blocking the effect of estrogen in other tissues. Concept of a SERM Selective estrogen receptor modulators (SERMs) are non-hormonal agents that bind to estrogen receptors, but produce estrogen agonist effects in some tissues while blocking the effect of estrogen in other tissues.

3. Evista Update EVA : Evista versus Alendronate MORE New non vertebral fractures Clinical vertebral fractures (3 and 6 months) CORE Invasive breast cancer and overall safety RUTH � STAR timelines CHOOSE ASIA Observational study

4. Raloxifene versus Alendronate Comparison EVA Trial First ever head-to-head fracture outcome trial Compare the osteoporotic fracture risk reduction efficacy of raloxifene and alendronate Double-blind, randomized, controlled, 5-year trial with raloxifene 60 mg/d vs alendronate 10 mg/d Initially planned about 3000 postmenopausal women with osteoporosis. Enrollment terminated on Aug 2004 with 1423 patients randomized, because too slow recruitment Calcium 500 mg + vitamin D 400 IU to all patients Sites in US, Canada, and Puerto Rico

5. Baseline Characteristics

7. Multicenter, double-blind, placebo-controlled trial 25 countries, 180 centers, 3 years with 1 year extension 7705 postmenopausal women with osteoporosis Mean age 66 years Raloxifene 60 mg =Evista, 120 mg, or placebo All patients given daily elemental calcium (500 mg) and vitamin D (400-600 IU) Primary endpoints: radiographic vertebral fracture, BMD, safety Secondary endpoints: all osteoporotic fractures, cardiovascular health, breast cancer, cognitive function MORE: Multiple Outcomes of Raloxifene Evaluation The Multiple Outcomes of Raloxifene Evaluation (MORE) trial was a large, multicenter, double-blind, placebo controlled trial of postmenopausal women with osteoporosis, enrolling 7705 women at 180 sites in 25 countries.1,2 The trial consisted of a 3-year core treatment phase with a 1-year extension phase. Women were randomly assigned to receive placebo or raloxifene 60 mg/day (Evista), or raloxifene 120 mg/day. All women also received supplemental calcium (500 mg/day) and vitamin D (400 � 600 IU/day). � The primary endpoints of the MORE trial were the incidence of new vertebral fractures and bone mineral density of the lumbar spine and femoral neck. Secondary endpoints included all osteoporotic fractures, serum lipids and other markers of cardiovascular risk, cognitive function, breast cancer, and safety. Major criteria for exclusion from the study included a history of breast or endometrial cancer or the presence of abnormal uterine bleeding. � The dose of raloxifene approved for the prevention and treatment of postmenopausal osteoporosis is 60 mg/day, and effects observed with raloxifene 120 mg/day were comparable to those observed with 60 mg/day. Thus, unless noted otherwise, the data in the subsequent slides will focus on the raloxifene 60 mg/day group compared with placebo. � 1. Ettinger B et al. JAMA 1999; 282:637-45 2. Cummings SR et al., JAMA 1999;281:2189-97 MORE: Multiple Outcomes of Raloxifene Evaluation The Multiple Outcomes of Raloxifene Evaluation (MORE) trial was a large, multicenter, double-blind, placebo controlled trial of postmenopausal women with osteoporosis, enrolling 7705 women at 180 sites in 25 countries.1,2 The trial consisted of a 3-year core treatment phase with a 1-year extension phase. Women were randomly assigned to receive placebo or raloxifene 60 mg/day (Evista), or raloxifene 120 mg/day. All women also received supplemental calcium (500 mg/day) and vitamin D (400 � 600 IU/day). � The primary endpoints of the MORE trial were the incidence of new vertebral fractures and bone mineral density of the lumbar spine and femoral neck. Secondary endpoints included all osteoporotic fractures, serum lipids and other markers of cardiovascular risk, cognitive function, breast cancer, and safety. Major criteria for exclusion from the study included a history of breast or endometrial cancer or the presence of abnormal uterine bleeding. � The dose of raloxifene approved for the prevention and treatment of postmenopausal osteoporosis is 60 mg/day, and effects observed with raloxifene 120 mg/day were comparable to those observed with 60 mg/day. Thus, unless noted otherwise, the data in the subsequent slides will focus on the raloxifene 60 mg/day group compared with placebo. � 1. Ettinger B et al. JAMA 1999; 282:637-45 2. Cummings SR et al., JAMA 1999;281:2189-97

8. Incidence Rates for Vertebral, Wrist and Hip Fractures in Women After 50 The incidence of all osteoporotic fractures increases with age.1 Shortly after menopause, the incidence of wrist fracture begins to increase and continues to do so until of age of 65, when it plateaus. The incidence of hip fracture increases more slowly with age until later in life when the incidence begins to increase exponentially. Vertebral fracture, the most common fracture, occurs earlier after menopause than hip fracture, and continues to rise with age. � Approximately 1.5 million osteoporotic fractures occur in the United States annually, comprised of 250,000 wrist fractures, 250,000 hip fractures, 700,000 vertebral fractures, and 300,000 fractures at other sites.2 Thus, most common osteoporotic fractures are vertebral fractures. � Wasnich RD: Primer on the Metabolic Bone Diseases and Metabolism. 4th edition, 1999 2. Riggs and Melton, New Eng J Med 1986;314:1676-86Incidence Rates for Vertebral, Wrist and Hip Fractures in Women After 50 The incidence of all osteoporotic fractures increases with age.1 Shortly after menopause, the incidence of wrist fracture begins to increase and continues to do so until of age of 65, when it plateaus. The incidence of hip fracture increases more slowly with age until later in life when the incidence begins to increase exponentially. Vertebral fracture, the most common fracture, occurs earlier after menopause than hip fracture, and continues to rise with age. � Approximately 1.5 million osteoporotic fractures occur in the United States annually, comprised of 250,000 wrist fractures, 250,000 hip fractures, 700,000 vertebral fractures, and 300,000 fractures at other sites.2 Thus, most common osteoporotic fractures are vertebral fractures. � Wasnich RD: Primer on the Metabolic Bone Diseases and Metabolism. 4th edition, 1999 2. Riggs and Melton, New Eng J Med 1986;314:1676-86

13. Women with severe osteoporosis Does raloxifene prevent multiple new vertebral fractures ? Does raloxifene prevent the first severe vertebral fracture? Does raloxifene prevent subsequent fracture (also non vertebral) when a severe fracture is present?

14. Effect of Raloxifene on the Risk of 2 or More New Vertebral Fractures in Women without Existing Fractures: MORE Trial � 3 Years Multiple vertebral fractures, leading to spinal deformity and chronic back pain, account for much of the morbidity and long term disability associated with spinal osteoporosis. Fourteen women in the placebo group (1.0%) and 1 in the raloxifene group (0.1%) had 2 or more new vertebral fractures at 3 years. Raloxifene 60 mg/day reduced the cumulative risk of multiple vertebral fractures by 93%1, consistent with the hypothesis that preventing the first vertebral fracture substantially reduces the risk of having subsequent vertebral fractures. � 1. Lufkin E et al. North American Menopause Society 12th Annual Meeting Program and Abstract Book, P21, p70, October 4-6, 2001 Effect of Raloxifene on the Risk of 2 or More New Vertebral Fractures in Women without Existing Fractures: MORE Trial � 3 Years Multiple vertebral fractures, leading to spinal deformity and chronic back pain, account for much of the morbidity and long term disability associated with spinal osteoporosis. Fourteen women in the placebo group (1.0%) and 1 in the raloxifene group (0.1%) had 2 or more new vertebral fractures at 3 years. Raloxifene 60 mg/day reduced the cumulative risk of multiple vertebral fractures by 93%1, consistent with the hypothesis that preventing the first vertebral fracture substantially reduces the risk of having subsequent vertebral fractures. � 1. Lufkin E et al. North American Menopause Society 12th Annual Meeting Program and Abstract Book, P21, p70, October 4-6, 2001

15. Semiquantitative Evaluation of Vertebral Fracture Severity Semiquantitative Evaluation of Vertebral Fracture Severity A semiquantitative scale was used to grade both baseline and incident vertebral fractures in this study. Radiologists who were blinded to treatment assignment called vertebrae �normal� or reported the presence of a �mild�, �moderate� or �severe� deformity using this scale. Mild, moderate and severe deformities correspond to vertebrae which have lost approximately 20%, 25% or 40% or greater of their height. In this study a new fracture was reported if a vertebrae that had a score of 0 (normal) at baseline was determined to have a score of 1 (mild) , 2 (moderate) or 3 (severe) at follow-up. Semiquantitative Evaluation of Vertebral Fracture Severity A semiquantitative scale was used to grade both baseline and incident vertebral fractures in this study. Radiologists who were blinded to treatment assignment called vertebrae �normal� or reported the presence of a �mild�, �moderate� or �severe� deformity using this scale. Mild, moderate and severe deformities correspond to vertebrae which have lost approximately 20%, 25% or 40% or greater of their height. In this study a new fracture was reported if a vertebrae that had a score of 0 (normal) at baseline was determined to have a score of 1 (mild) , 2 (moderate) or 3 (severe) at follow-up.

16. raloxifene 60 mg/day decreased the risk of at least 1 new moderate/severe vertebral fracture by 61% in women without prevalent vertebral fractures and by 37% in women with prevalent vertebral fractures. Both of these risk reductions were statistically significant compared to placebo.raloxifene 60 mg/day decreased the risk of at least 1 new moderate/severe vertebral fracture by 61% in women without prevalent vertebral fractures and by 37% in women with prevalent vertebral fractures. Both of these risk reductions were statistically significant compared to placebo.

17. Reduction of 47% of at Least 1 New Nonvertebral* Fracture in Women With Baseline SQ Grade 3MORE Trial - 3 Years

18. Raloxifene prevents Non Vertebral Fracture in Women with 2 Prevalent Vertebral Fractures(n= 1369, mean age 69y MORE Trial - 3 Years � pooled raloxifene In the small subgroup of women with SQ grade 3 prevalent vertebral fractures, raloxifene 60 mg/d significantly decreased the relative risk of new vertebral fractures by 27% compared with placebo. The corresponding number-needed-to-treat to prevent 1 new vertebral fracture (NNT) was 10. In addition, raloxifene 60 mg/d significantly decreased the relative risk of new nonvertebral fractures by 47% compared with placebo. The corresponding number-needed-to-treat to prevent 1 new nonvertebral fracture was 18. NNT (Number-needed-to-treat) = number of women needed to be treated to prevent a fracture event.In the small subgroup of women with SQ grade 3 prevalent vertebral fractures, raloxifene 60 mg/d significantly decreased the relative risk of new vertebral fractures by 27% compared with placebo. The corresponding number-needed-to-treat to prevent 1 new vertebral fracture (NNT) was 10. In addition, raloxifene 60 mg/d significantly decreased the relative risk of new nonvertebral fractures by 47% compared with placebo. The corresponding number-needed-to-treat to prevent 1 new nonvertebral fracture was 18. NNT (Number-needed-to-treat) = number of women needed to be treated to prevent a fracture event.

19. This figure depicts the reduction in vertebral fracture risk expressed as relative risks and 95% confidence intervals for the approved antiresorptive therapies for postmenopausal osteoporosis studied in large prospective, randomized, placebo-controlled trials. The therapies studied include raloxifene, alendronate, risedronate, and nasal spray calcitonin. The change in LS BMD compared to placebo and the prevalent vertebral fracture status is noted in the middle column. The change in LS BMD varied from 0.7% with salmon calcitonin nasal spray to 6.8% with alendronate. BMD changes with raloxifene and risedronate were in between these values. Despite the range of BMD changes, the reduction in the risk of new vertebral fractures was similar for all of these agents, as shown by the overlapping confidence intervals. This figure depicts the reduction in vertebral fracture risk expressed as relative risks and 95% confidence intervals for the approved antiresorptive therapies for postmenopausal osteoporosis studied in large prospective, randomized, placebo-controlled trials. The therapies studied include raloxifene, alendronate, risedronate, and nasal spray calcitonin. The change in LS BMD compared to placebo and the prevalent vertebral fracture status is noted in the middle column. The change in LS BMD varied from 0.7% with salmon calcitonin nasal spray to 6.8% with alendronate. BMD changes with raloxifene and risedronate were in between these values. Despite the range of BMD changes, the reduction in the risk of new vertebral fractures was similar for all of these agents, as shown by the overlapping confidence intervals.

21. Number Needed to Treat (NNT) to Prevent 1 Vertebral Fracture

23. Raloxifene Clinical ProfileRaloxifene Clinical Profile

24. Completed and Ongoing Large-Scale Raloxifene Clinical Trials This slide summarizes the number of women who have been and are currently being studied in large-scale clinical trials of raloxifene. Approximately 1700 women without osteoporosis and 7700 women with osteoporosis have been studied in osteoporosis prevention and treatment trials, respectively. The MORE trial has ended. However, approximately 4000 women originally enrolled in MORE continue to receive raloxifene treatment and will be followed for an additional 4 years as part of the CORE (Continuing Outcomes Relevant to Evista) trial. The RUTH trial completed enrollment in August 2000 with 10,101 women enrolled, with first results available 2005-2006. The STAR trial will eventually enroll approximately 19,000 women; over 15,000 women have been enrolled in STAR as of January 2003. In addition to these ongoing clinical trials, there have been an estimated 2 million patient-years of therapy with raloxifene worldwide since EVISTA was introduced to the market in January of 1998. STAR: Enrollment as of 3/1/04 was 18,005 EVA: 757 Enrolled as of 1/28/04 Completed and Ongoing Large-Scale Raloxifene Clinical Trials This slide summarizes the number of women who have been and are currently being studied in large-scale clinical trials of raloxifene. Approximately 1700 women without osteoporosis and 7700 women with osteoporosis have been studied in osteoporosis prevention and treatment trials, respectively. The MORE trial has ended. However, approximately 4000 women originally enrolled in MORE continue to receive raloxifene treatment and will be followed for an additional 4 years as part of the CORE (Continuing Outcomes Relevant to Evista) trial. The RUTH trial completed enrollment in August 2000 with 10,101 women enrolled, with first results available 2005-2006. The STAR trial will eventually enroll approximately 19,000 women; over 15,000 women have been enrolled in STAR as of January 2003. In addition to these ongoing clinical trials, there have been an estimated 2 million patient-years of therapy with raloxifene worldwide since EVISTA was introduced to the market in January of 1998. STAR: Enrollment as of 3/1/04 was 18,005 EVA: 757 Enrolled as of 1/28/04

25. Cardiovascular Effects Cardiovascular Effects

26. Effect of Raloxifene on All Breast Cancer MORE Trial - 4 Years Effect of Raloxifene on All Breast Cancer Incidence: MORE Trial � 4 Years This slide shows the data for breast cancer incidence in the MORE trial through 4 years of treatment, representing a total of 77 cases of breast cancer. The number of breast cancer cases observed in the raloxifene groups (in yellow) continues to be less than those observed in the placebo group (shown in white). After 4 years of follow-up, the incidence of breast cancer (invasive or non-invasive) in the raloxifene groups was reduced by 62% relative to placebo. The rates of breast cancer in the placebo and raloxifene groups were 5.3 per 1000 and 1.9 per 1000 women-years, respectively. Importantly, the rate of breast cancer in the placebo group is comparable to the expected rate of breast cancer in the general population for white women over age 65.1 Mandatory mammograms were performed at baseline and in years 2, 3 and 4. Mammograms were optional in year 1, when 48% of women elected to have the procedure. 1. Rios et al. SEER Cancer Statistics Review 1973-1996. NCI, 1999.� NOTE: Breast cancer incidence was a secondary endpoint of the MORE trial. Except for Mexico, Philippines, Turkey, Venezuela, raloxifene is not approved for the reduction in risk of breast cancer. Effect of Raloxifene on All Breast Cancer Incidence: MORE Trial � 4 Years This slide shows the data for breast cancer incidence in the MORE trial through 4 years of treatment, representing a total of 77 cases of breast cancer. The number of breast cancer cases observed in the raloxifene groups (in yellow) continues to be less than those observed in the placebo group (shown in white). After 4 years of follow-up, the incidence of breast cancer (invasive or non-invasive) in the raloxifene groups was reduced by 62% relative to placebo. The rates of breast cancer in the placebo and raloxifene groups were 5.3 per 1000 and 1.9 per 1000 women-years, respectively. Importantly, the rate of breast cancer in the placebo group is comparable to the expected rate of breast cancer in the general population for white women over age 65.1 Mandatory mammograms were performed at baseline and in years 2, 3 and 4. Mammograms were optional in year 1, when 48% of women elected to have the procedure. 1. Rios et al. SEER Cancer Statistics Review 1973-1996. NCI, 1999.� NOTE: Breast cancer incidence was a secondary endpoint of the MORE trial. Except for Mexico, Philippines, Turkey, Venezuela, raloxifene is not approved for the reduction in risk of breast cancer.

28. CORE Study Objectives Because of the favorable results of the MORE trial, a decision was made to enroll as many women as possible into the CORE trial where the primary objective was the incidence of invasive breast cancer over an additional 4-year�period beginning January 1, 1999. A secondary objective was to determine the effect of Raloxifene on the incidence of invasive estrogen receptor positive breast cancer and to evaluate the tolerability of Raloxifene over an 8-year period. Because of the favorable results of the MORE trial, a decision was made to enroll as many women as possible into the CORE trial where the primary objective was the incidence of invasive breast cancer over an additional 4-year�period beginning January 1, 1999. A secondary objective was to determine the effect of Raloxifene on the incidence of invasive estrogen receptor positive breast cancer and to evaluate the tolerability of Raloxifene over an 8-year period.

29. Breast Cancer Assessment

30. The women who comprised the CORE breast cancer primary analysis dataset (N=5213) and the CORE enrollees (N=4011) were subsets of the MORE cohort and, as expected, were similar to each other and to the MORE participants with respect to the MORE baseline characteristics shown. In addition, there was no difference (p>0.05) in any of the baseline characteristics shown between the raloxifene and placebo groups in any of the 3 populations.The women who comprised the CORE breast cancer primary analysis dataset (N=5213) and the CORE enrollees (N=4011) were subsets of the MORE cohort and, as expected, were similar to each other and to the MORE participants with respect to the MORE baseline characteristics shown. In addition, there was no difference (p>0.05) in any of the baseline characteristics shown between the raloxifene and placebo groups in any of the 3 populations.

31. 4-year CORE Results N=5213 This slide shows the primary endpoint of the CORE trial as a Kaplan-Meier curve, with cumulative breast cancer incidence plotted against time, beginning January�1,�1999 and continuing to the end of CORE ( approximately 4 years) 52 cases of invasive breast cancer (28 in the placebo group and 24 in the Raloxifene group) were reported and confirmed by adjudication. During the 4 years of the CORE trial, the incidence of invasive breast cancer was reduced in the Raloxifene treated group by 59%, compared to the group of women randomized to placebo. This difference is significant with a P value of <.001. The absolute risk for the placebo groups is 5.2 cases per 1000 women-years and 2.1 for the raloxifene group. Thus, the absolute risk reduction for the raloxifene group was 3.1 cases per 1000 women-years. 4-year CORE Results N=5213 This slide shows the primary endpoint of the CORE trial as a Kaplan-Meier curve, with cumulative breast cancer incidence plotted against time, beginning January�1,�1999 and continuing to the end of CORE ( approximately 4 years) 52 cases of invasive breast cancer (28 in the placebo group and 24 in the Raloxifene group) were reported and confirmed by adjudication. During the 4 years of the CORE trial, the incidence of invasive breast cancer was reduced in the Raloxifene treated group by 59%, compared to the group of women randomized to placebo. This difference is significant with a P value of <.001. The absolute risk for the placebo groups is 5.2 cases per 1000 women-years and 2.1 for the raloxifene group. Thus, the absolute risk reduction for the raloxifene group was 3.1 cases per 1000 women-years.

32.

33. Incidence of Invasive ER+ and ER- Breast Cancer8 Years of MORE Plus CORE Trials This slide shows the annual incidence rate per 1000 woman-years of follow-up for adjudicated invasive breast cancers over the 8 years of the MORE plus CORE trials for the 7705 MORE participants. Over the 8 years of the MORE plus CORE trials, 98 breast cancers were adjudicated as invasive with 88 of these having estrogen receptor status confirmed (75% of confirmed breast cancers were estrogen receptor positive). The numbers of ER-positive breast cancers in the placebo and raloxifene groups were 44 and 22, respectively. Women with estrogen receptor positive breast cancer treated with raloxifene had a significant 76% reduction in breast cancer occurrence during the 8 yrs of the MORE plus CORE trials. The occurrence of ER negative breast cancer remained low and was not significantly changed with raloxifene treatment. The numbers of ER-negative breast cancers in the placebo and raloxifene groups were 7 and 15, respectively. This slide shows the annual incidence rate per 1000 woman-years of follow-up for adjudicated invasive breast cancers over the 8 years of the MORE plus CORE trials for the 7705 MORE participants. Over the 8 years of the MORE plus CORE trials, 98 breast cancers were adjudicated as invasive with 88 of these having estrogen receptor status confirmed (75% of confirmed breast cancers were estrogen receptor positive). The numbers of ER-positive breast cancers in the placebo and raloxifene groups were 44 and 22, respectively. Women with estrogen receptor positive breast cancer treated with raloxifene had a significant 76% reduction in breast cancer occurrence during the 8 yrs of the MORE plus CORE trials. The occurrence of ER negative breast cancer remained low and was not significantly changed with raloxifene treatment. The numbers of ER-negative breast cancers in the placebo and raloxifene groups were 7 and 15, respectively.

34. Summary of Adverse Outcomes over the 8 Years of MORE-CORE (N=4011) Over the 4 years of CORE, and the combined 8 years of MORE plus CORE, there was no increase in mortality associated with raloxifene therapy. This is in agreement with the results of the MORE trial. Raloxifene was associated with a reduced incidence of all cancers, even when breast cancer was excluded from the analysis. This reduction in cancer incidence (when breast cancer excluded) was not due to an effect of raloxifene on any specific cancer. The clinical significance of this finding, if any, remains to be determined.Over the 4 years of CORE, and the combined 8 years of MORE plus CORE, there was no increase in mortality associated with raloxifene therapy. This is in agreement with the results of the MORE trial. Raloxifene was associated with a reduced incidence of all cancers, even when breast cancer was excluded from the analysis. This reduction in cancer incidence (when breast cancer excluded) was not due to an effect of raloxifene on any specific cancer. The clinical significance of this finding, if any, remains to be determined.

35. Summary of Gynecologic AE Data over the 8 Years of MORE-CORE (N=4011) These 8-year MORE-CORE findings are similar to those reported from MORE and other studies of shorter duration. No increased incidence of ovarian cancer, uterine cancer, endometrial hyperplasia, or postmenopausal bleeding associated with raloxifene treatment. These uterine data support a neutral effect of raloxifene on the uterus. Uterine polyps were more common in the raloxifene treatment group over the 8-year period. They were more frequently reported during the MORE trial period versus the CORE period (79 versus 9 events), presumably as a result of the uterine surveillance plan in place during MORE but not CORE. None of the uterine polyps diagnosed in the raloxifene treatment group were associated with an increase in reported bleeding or diagnosis of endometrial cancer over the 8 years, and most likely would not have been identified in a normal clinical setting, as demonstrated in CORE. The increased incidence of uterine polyps in the raloxifene group versus placebo during MORE may in part be related to an increased sensitivity of ultrasound in the active treatment group due to the presence of endometrial fluid. Raloxifene has previously been associated with an increase in endometrial cavity fluid, and it is feasible that this could have aided detection of these benign endometrial changes. Moreover, it is presumed that the greater incidence of endometrial biopsy in the raloxifene treatment group during the MORE period is at least in part the result of this increase in detection of benign endometrial changes during ultrasound in the raloxifene treatment group.These 8-year MORE-CORE findings are similar to those reported from MORE and other studies of shorter duration. No increased incidence of ovarian cancer, uterine cancer, endometrial hyperplasia, or postmenopausal bleeding associated with raloxifene treatment. These uterine data support a neutral effect of raloxifene on the uterus. Uterine polyps were more common in the raloxifene treatment group over the 8-year period. They were more frequently reported during the MORE trial period versus the CORE period (79 versus 9 events), presumably as a result of the uterine surveillance plan in place during MORE but not CORE. None of the uterine polyps diagnosed in the raloxifene treatment group were associated with an increase in reported bleeding or diagnosis of endometrial cancer over the 8 years, and most likely would not have been identified in a normal clinical setting, as demonstrated in CORE. The increased incidence of uterine polyps in the raloxifene group versus placebo during MORE may in part be related to an increased sensitivity of ultrasound in the active treatment group due to the presence of endometrial fluid. Raloxifene has previously been associated with an increase in endometrial cavity fluid, and it is feasible that this could have aided detection of these benign endometrial changes. Moreover, it is presumed that the greater incidence of endometrial biopsy in the raloxifene treatment group during the MORE period is at least in part the result of this increase in detection of benign endometrial changes during ultrasound in the raloxifene treatment group.

36. This slide shows the incidences of hot flushes, leg cramps, and peripheral edema, adverse events known to be associated with raloxifene therapy over the 8 years of the MORE plus CORE trials. For the 8 years of MORE plus CORE, hot flushes and leg cramps, but not peripheral edema, were reported significantly more often in the raloxifene group than in the placebo group. Raloxifene dose is 60mg/d in CORE and 60mg/d or 120 mg/d in MORE. P values based on 2-sided Fisher�s exact test. This slide shows the incidences of hot flushes, leg cramps, and peripheral edema, adverse events known to be associated with raloxifene therapy over the 8 years of the MORE plus CORE trials. For the 8 years of MORE plus CORE, hot flushes and leg cramps, but not peripheral edema, were reported significantly more often in the raloxifene group than in the placebo group. Raloxifene dose is 60mg/d in CORE and 60mg/d or 120 mg/d in MORE. P values based on 2-sided Fisher�s exact test.

38. Cardiovascular Effects Cardiovascular Effects

39. Pathophysiology of Atherosclerosis Atherosclerosis is the main pathology underlying cardiovascular diseases, in the coronaries leading eventually leading to myocardial ischemia or infarction when it occurs in the coronary arteries, and to transient ischemic attacks or stroke when it occurs in the carotid or cerebral arteries. Atherosclerosis is a chronic, progressive process. �One of the earliest manifestations of atherosclerosis is thought to be dysfunction of the vascular endothelium, caused by one or more �insults� to the endothelium: LDL (especially the oxidized form) and other atherogenic lipoproteins, homocysteine, components in cigarette smoke, aging, hyperglycemia, and hypertension are examples. Although endothelial dysfunction occurs early in the atherosclerotic process, it continues throughout the progression of the disease. In addition to impaired vasodilator function, damage to the endothelium also results in up-regulation of expression of various cellular adhesion molecules on the vascular wall, including selectins, ICAM-1 and VCAM-1. These molecules mediate the binding of circulating monocytes to the vascular wall, which then migrate through the vascular wall and take up residence in the vascular wall, where they begin to oxidize and accumulate LDL. Continued accumulation of lipid-laden macrophages, known as foam cells, forms the first visible manifestation of the atherosclerotic lesion known as a �fatty streak.� �From the fatty streak lesion, the atherosclerotic process continues to progress with continued accumulation of macrophages, and later leukocytes. Pro-inflammatory cytokines (including IL-6, TNF-alpha, and interferons) released by macrophages within the lesion exert local effects that continue to support progression of the lesion. Systemically, these inflammatory cytokines may also stimulate C-reactive protein synthesis from the liver � an effect that has been hypothesized to account for the higher levels of circulating CRP observed in patients with CHD compared to those without. Recognition of this process of lipid and macrophage accumulation leading to inflammatory reaction at the vessel wall, which in turn feeds back to support further lipid accumulation, is the basis for the notion that atherosclerosis is an inflammatory disease. �The morphology of the lesion also evolves, from a simple fatty streak lesion to a more complex fibrous plaque, characterized by a core of lipid surrounded by a fibrous cap. These advanced atherosclerotic lesions have been categorized into 2 broad groups: lesions with a thick fibrous cap with a small lipid core and low macrophage content, and lesions with a thin fibrous cap with a large lipid core and high macrophage content. The former is generally considered a �stable� plaque less prone to rupture, and thus cause an acute event; whereas the latter is considered an unstable, or vulnerable, plaque more prone to rupture and thus cause an acute event. The factors determining the vulnerability of a plaque to rupture is currently an important area of research � one of these factors is thought to be the activity of matrix metalloproteinases (MMP�s) within the lesion. MMP activity degrades the collagen matrix of the fibrous cap, causing it to thin, weaken, and become for prone to rupture. Rupture of vulnerable plaques is now thought to be the major underlying cause of acute cardiovascular events.� Pathophysiology of Atherosclerosis Atherosclerosis is the main pathology underlying cardiovascular diseases, in the coronaries leading eventually leading to myocardial ischemia or infarction when it occurs in the coronary arteries, and to transient ischemic attacks or stroke when it occurs in the carotid or cerebral arteries. Atherosclerosis is a chronic, progressive process. �One of the earliest manifestations of atherosclerosis is thought to be dysfunction of the vascular endothelium, caused by one or more �insults� to the endothelium: LDL (especially the oxidized form) and other atherogenic lipoproteins, homocysteine, components in cigarette smoke, aging, hyperglycemia, and hypertension are examples. Although endothelial dysfunction occurs early in the atherosclerotic process, it continues throughout the progression of the disease. In addition to impaired vasodilator function, damage to the endothelium also results in up-regulation of expression of various cellular adhesion molecules on the vascular wall, including selectins, ICAM-1 and VCAM-1. These molecules mediate the binding of circulating monocytes to the vascular wall, which then migrate through the vascular wall and take up residence in the vascular wall, where they begin to oxidize and accumulate LDL. Continued accumulation of lipid-laden macrophages, known as foam cells, forms the first visible manifestation of the atherosclerotic lesion known as a �fatty streak.� �From the fatty streak lesion, the atherosclerotic process continues to progress with continued accumulation of macrophages, and later leukocytes. Pro-inflammatory cytokines (including IL-6, TNF-alpha, and interferons) released by macrophages within the lesion exert local effects that continue to support progression of the lesion. Systemically, these inflammatory cytokines may also stimulate C-reactive protein synthesis from the liver � an effect that has been hypothesized to account for the higher levels of circulating CRP observed in patients with CHD compared to those without. Recognition of this process of lipid and macrophage accumulation leading to inflammatory reaction at the vessel wall, which in turn feeds back to support further lipid accumulation, is the basis for the notion that atherosclerosis is an inflammatory disease. �The morphology of the lesion also evolves, from a simple fatty streak lesion to a more complex fibrous plaque, characterized by a core of lipid surrounded by a fibrous cap. These advanced atherosclerotic lesions have been categorized into 2 broad groups: lesions with a thick fibrous cap with a small lipid core and low macrophage content, and lesions with a thin fibrous cap with a large lipid core and high macrophage content. The former is generally considered a �stable� plaque less prone to rupture, and thus cause an acute event; whereas the latter is considered an unstable, or vulnerable, plaque more prone to rupture and thus cause an acute event. The factors determining the vulnerability of a plaque to rupture is currently an important area of research � one of these factors is thought to be the activity of matrix metalloproteinases (MMP�s) within the lesion. MMP activity degrades the collagen matrix of the fibrous cap, causing it to thin, weaken, and become for prone to rupture. Rupture of vulnerable plaques is now thought to be the major underlying cause of acute cardiovascular events.�

40. Effect of Raloxifene 60 mg/d on Cardiovascular Risk Factors Effects of Raloxifene on Cardiovascular Risk Factors These data summarize the effects of raloxifene 60 mg/day relative to placebo on more traditional risk factors for cardiovascular disease in 95 healthy postmenopausal women treated for 6 months. Raloxifene significantly lowered total and LDL cholesterol, and fibrinogen, but did not increase either HDL cholesterol or triglycerides.1 � Similar effects on serum lipids and fibrinogen were maintained through 3 years in osteoporosis prevention and treatment trials.2,3 � 1. Walsh et al., JAMA 1998;279:1445-51 2. Johnston C et al. Arch Intern Med 2000;160:3444-3450. 3. Harper KD et al., J American Geriatrics Soc 2000;48:S51 � Effects of Raloxifene on Cardiovascular Risk Factors These data summarize the effects of raloxifene 60 mg/day relative to placebo on more traditional risk factors for cardiovascular disease in 95 healthy postmenopausal women treated for 6 months. Raloxifene significantly lowered total and LDL cholesterol, and fibrinogen, but did not increase either HDL cholesterol or triglycerides.1 � Similar effects on serum lipids and fibrinogen were maintained through 3 years in osteoporosis prevention and treatment trials.2,3 � 1. Walsh et al., JAMA 1998;279:1445-51 2. Johnston C et al. Arch Intern Med 2000;160:3444-3450. 3. Harper KD et al., J American Geriatrics Soc 2000;48:S51 �

41. Cumulative Incidence of Cardiovascular Events: MORE Trial � 4 Years CV Events were analyzed both in the total MORE population, and in a subset of women determined retrospectively to be at increased risk for cardiovascular events. Each women was assigned a CV risk score based on history of a prior CV event or the presence of multiple cardiovascular risk factors. The criteria used was based on that previously established to enroll women with or at increased risk of CHD events into the Raloxifene Use for The Heart (RUTH) trial, and has been published previously.1,2 Women with a CV risk score of 4 or more were included in the high CV risk subset (N=676 in the placebo and RLX 60 mg/d groups; approximately 13% of the women in these treatment groups) This slide shows the cumulative incidence of all cardiovascular events (coronary + cerebrovascular events) through 4 years among all women enrolled (left panel) and among women in the high-risk subset (right panel).3 Events occurring in the placebo group are depicted in white and in the raloxifene 60 mg/d group in yellow. Relative risk and 95% confidence intervals were calculated from the incidence of cardiovascular events at 4 years in the raloxifene 60 mg/d group versus the placebo group. In the overall population of women, there is no significant difference in the incidence of events at any time up to 4 years. In contrast, in the high-risk subset, the incidence of events in the raloxifene group begins to be lower than placebo after approximately 1 year, and the event curves continue to diverge during the following 3 years. These findings suggest that the statistically significant risk reduction observed in the raloxifene group at 4 years was cumulative over time as expected with a preventive therapy. However, these results require confirmation in a randomized clinical trial designed to determine the effect of raloxifene on cardiovascular events. Mosca L et al., Am J Cardiol 2001;88:392-5 Wenger N et al., Am J Cardiol 2002;90:1204-10 Barrett-Connor E et al., JAMA 2002; 287:847-57 Cumulative Incidence of Cardiovascular Events: MORE Trial � 4 Years CV Events were analyzed both in the total MORE population, and in a subset of women determined retrospectively to be at increased risk for cardiovascular events. Each women was assigned a CV risk score based on history of a prior CV event or the presence of multiple cardiovascular risk factors. The criteria used was based on that previously established to enroll women with or at increased risk of CHD events into the Raloxifene Use for The Heart (RUTH) trial, and has been published previously.1,2 Women with a CV risk score of 4 or more were included in the high CV risk subset (N=676 in the placebo and RLX 60 mg/d groups; approximately 13% of the women in these treatment groups) This slide shows the cumulative incidence of all cardiovascular events (coronary + cerebrovascular events) through 4 years among all women enrolled (left panel) and among women in the high-risk subset (right panel).3 Events occurring in the placebo group are depicted in white and in the raloxifene 60 mg/d group in yellow. Relative risk and 95% confidence intervals were calculated from the incidence of cardiovascular events at 4 years in the raloxifene 60 mg/d group versus the placebo group. In the overall population of women, there is no significant difference in the incidence of events at any time up to 4 years. In contrast, in the high-risk subset, the incidence of events in the raloxifene group begins to be lower than placebo after approximately 1 year, and the event curves continue to diverge during the following 3 years. These findings suggest that the statistically significant risk reduction observed in the raloxifene group at 4 years was cumulative over time as expected with a preventive therapy. However, these results require confirmation in a randomized clinical trial designed to determine the effect of raloxifene on cardiovascular events. Mosca L et al., Am J Cardiol 2001;88:392-5 Wenger N et al., Am J Cardiol 2002;90:1204-10 Barrett-Connor E et al., JAMA 2002; 287:847-57

42. RUTH StudyRaloxifene Use for The Heart 10,101 patients, DBRCT, placebo vs raloxifene (60 mg/d) Entry: postmenopausal women at high risk for, orsuffering from, heart disease Primary endpoints Coronary: CHD death, non-fatal MI, or hospitalized acute coronary syndrome other than MI Invasive breast cancer Length of trial: up to 7.5 years with anticipated completion in 2006 The RUTH Trial is currently underway. All women have been enrolled and will be entering at least the fourth year of the study by January 2004. The RUTH Trial is currently underway. All women have been enrolled and will be entering at least the fourth year of the study by January 2004.

43. NSABP-P2 (STAR) StudyStudy of Tamoxifen And Raloxifene 19,747 patients, double-blind, randomized Tamoxifen (20 mg/d) vs raloxifene (60 mg/d) Entry: postmenopausal, high risk for invasive breast cancer (lobular carcinoma in situ or 5-year risk of >1.67% by the Gail model) Primary endpoint Invasive breast cancer Secondary endpoints: Uterine safety, nonvertebral fracture, cardiovascular, overall toxicity and side effects Started 1999 with final analyses when 327 cases have occurred but women will continue to be followed; results anticipated in 2006 Enrollment in STAR is 15, 496 as of 3/03/03 (STAR website as of 8/06/03)Enrollment in STAR is 15, 496 as of 3/03/03 (STAR website as of 8/06/03)

44. WHI Estrogen-Progestin TrialGlobal Index Assessment of Risk-Benefit Defined to summarize important aspects of health benefits vs risks Defined for each woman as the earliest occurrence of: Coronary heart disease (CHD) Pulmonary embolism Invasive breast cancer Stroke

45. Global Safety Index Assessing Risk and Benefit

46. Effect of Raloxifene on WHI Global Risk-Benefit Index

47. Raloxifene Administration and Tolerability Single daily dose (60 mg tablets) Liver metabolism (glucuronidation) May be given without regard to meals or time of day No adjustment needed for most commonly used concomitant medications Can be used with Calcium and Vit D (recommended in patients with fractures) No GI side effects Raloxifene Administration and Tolerability Raloxifene is taken as a single tablet daily without regard to meals or time of day. No adjustments are required for commonly used concomitant medications and, consistent with its profile as an estrogen receptor antagonists in the uterus, no concomitant progesterone is required with raloxifene. Raloxifene is not associated with GI side effects, breast pain, or vaginal bleeding. The greater incidence of hot flashes and leg cramps with raloxifene was discussed in a previous slide; however, these effects were generally not associated with patients discontinuing raloxifene therapy. Raloxifene Administration and Tolerability Raloxifene is taken as a single tablet daily without regard to meals or time of day. No adjustments are required for commonly used concomitant medications and, consistent with its profile as an estrogen receptor antagonists in the uterus, no concomitant progesterone is required with raloxifene. Raloxifene is not associated with GI side effects, breast pain, or vaginal bleeding. The greater incidence of hot flashes and leg cramps with raloxifene was discussed in a previous slide; however, these effects were generally not associated with patients discontinuing raloxifene therapy.

48. Compliance and Satisfaction with Raloxifene Versus Alendronate for the Treatment of Postmenopausal Osteoporosis in Clinical Practice: An Open-Label, Prospective, Nonrandomized, Observational Study. This open-label, prospective, multicenter, nonrandomized, observational, comparative study was conducted at 154 centers across Spain. The primary aim of this study was to assess the compliance of postmenopausal women at risk for osteoporotic fractures who were treated with raloxifene hydrochloride (RLX 60-mg tablet once daily) versus alendronate sodium (ALN 10-mg tablet once daily) during a 12-month observational period in a routine clinical setting. Assignment to either RLX or ALN treatment was determined by the physician and was based on each patient�s clinical profile. A total of 902 women (RLX group, n = 476; ALN group, n = 426) were included in the study (mean age, 64.4 [6.9] years). Information on adverse effects (AEs) was based on data from the Compliance Questionnaire that Include 2 questions: �Is the patient going to continue on the ini-tially assigned osteoporosis treatment?� and �If not, please specify the reason and time of discontinuation.� The proportion of patients who withdrew from the study prematurely was statistically higher in the ALN group (25.8%) than in the RLX group (16.4%) (P <0.001). Among 188 patients discontinuing prematurely (both treatment groups), 139 (74%) discontinued during the first 3 months of observation. AEs were significantly less frequently the reason for RLX discontinuation compared with the ALN group (4.8% vs 11.0%; P < 0.001). The most common AEs that caused withdrawal were gastrointestinal disorders (GI) (RLX group, 3.4%;ALN group, 9.9%; P < 0.001). Dyspepsia, upper abdominal pain, and abdominal discomfort were the AEs reported most frequently by the study population, and all of these AEs were reported significantly more frequently in the ALN group than in the RLX group (P < 0.05). No venous thromboembolic events were recorded in the RLX group throughout the study. Turb� C et al. Clin Ther. 2004;26:245�256. Compliance and Satisfaction with Raloxifene Versus Alendronate for the Treatment of Postmenopausal Osteoporosis in Clinical Practice: An Open-Label, Prospective, Nonrandomized, Observational Study. This open-label, prospective, multicenter, nonrandomized, observational, comparative study was conducted at 154 centers across Spain. The primary aim of this study was to assess the compliance of postmenopausal women at risk for osteoporotic fractures who were treated with raloxifene hydrochloride (RLX 60-mg tablet once daily) versus alendronate sodium (ALN 10-mg tablet once daily) during a 12-month observational period in a routine clinical setting. Assignment to either RLX or ALN treatment was determined by the physician and was based on each patient�s clinical profile. A total of 902 women (RLX group, n = 476; ALN group, n = 426) were included in the study (mean age, 64.4 [6.9] years). Information on adverse effects (AEs) was based on data from the Compliance Questionnaire that Include 2 questions: �Is the patient going to continue on the ini-tially assigned osteoporosis treatment?� and �If not, please specify the reason and time of discontinuation.� The proportion of patients who withdrew from the study prematurely was statistically higher in the ALN group (25.8%) than in the RLX group (16.4%) (P <0.001). Among 188 patients discontinuing prematurely (both treatment groups), 139 (74%) discontinued during the first 3 months of observation. AEs were significantly less frequently the reason for RLX discontinuation compared with the ALN group (4.8% vs 11.0%; P < 0.001). The most common AEs that caused withdrawal were gastrointestinal disorders (GI) (RLX group, 3.4%;ALN group, 9.9%; P < 0.001). Dyspepsia, upper abdominal pain, and abdominal discomfort were the AEs reported most frequently by the study population, and all of these AEs were reported significantly more frequently in the ALN group than in the RLX group (P < 0.05). No venous thromboembolic events were recorded in the RLX group throughout the study. Turb� C et al. Clin Ther. 2004;26:245�256.

49. Primary: To demonstrate that raloxifene is associated with better adherence compared with daily dosing bisphosphonates in Asian postmenopausal women at increased risk of osteoporotic fractures. Secondary: To demonstrate that raloxifene therapy is associated with improved: treatment satisfaction quality of life compared with bisphosphonates.

50. Study Design One-year, open-label, observational study conducted in: Hong Kong Malaysia Pakistan Philippines Singapore Taiwan. Postmenopausal women aged 55 years or older and at increased risk of osteoporosis. Study treatments administered by a physician during the normal course of care:

51. Patient Baseline Characteristics

54. Treatment Satisfaction at 12 months

56. Incidence of New Fractures Fractures were self-reportedFractures were self-reported