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

2. S elective E strogen R eceptor Modulator 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.
Not an estrogen and not a hormone
Binds to estrogen receptors
Has estrogen-like effects in some tissues
Blocks estrogen effects in some tissues

3. Evista Update EVA : Evista versus Alendronate MORE CORE
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
Adapted from Recker R et al, ASBMR 2005, JBMR 2005, 20,Suppl 1,S97

5. Baseline Characteristics
Raloxifene
(N=707)
Alendronate
(N=716)
P-value
Age (years)
65.5
65.7
0.56
Caucasian (%)
86.7
86.9
0.83
BMI (kg/m2)
24.8
24.6
0.42
LS BMD (g/cm2)
0.82
0.79
T-score
-2.32
-2.34
0.65
FN BMD (g/cm2)
0.61
0.98
-2.39
0.77
Total Hip BMD (g/cm2)
0.71
T-Score
-1.99
-2.01
0.64
Adapted from Recker R et al, ASBMR 2005, JBMR 2005, 20,Suppl 1,S97

6. EVA Trial: Incidence of VFx and Non-V Fx
Women with ≥1 new Fx, n(%)
Type of Fx ALN, 10mg/d RLX 60mg/d P value
N= N=699
Age, yrs ± ±
Vert or Non Vert 22 (3.1) 20 (2.9)
Vertebrala (3.1) 5 (1.9)
Moderate/Severe 4 (1.6)
Clinical Vertebral 3 (0.4)
NonVertebral (2.0) (2.2)
Nonvertebral-Sixb 11 (1.5) (1.4)
b Includes the clavicule, humerus, wrist, pelvis, hip and leg.
Recker R et al, ASBMR 2005, Abstract in JBMR 2005, 20,Suppl 1,S97

7. MORE Multiple Outcomes of Raloxifene Evaluation
Source:
Review:
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 ( IU)
Primary endpoints: radiographic vertebral fracture, BMD, safety
Secondary endpoints: all osteoporotic fractures, cardiovascular health, breast cancer, cognitive function
Reviewer Memo:
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:
Ettinger B et al. JAMA 282:637-45, 1999
Cummings SR et al. JAMA 281: , 1999
Slide Modified:
Memo:

8. Annual incidence per 1000 women
Incidence Rates for Vertebral, Wrist and Hip Fractures in Women After Age 50
Source: 40 30 20 10
Review:
Vertebrae
Reviewer Memo:
Annual incidence per 1000 women
Hip
Wrist
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:
Age (Years)
Wasnich RD: Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. 4th edition, 1999,
Slide Modified:
Memo:

9. Risk of New Clinical Vertebral Fractures at 1 Year
Women with and without
Prevalent Vertebral Fractures
Women with
Prevalent Vertebral Fractures
2.2
2.2
2.0
2.0
RR 0.34 (95% CI, )
1.8
1.8
1.6
1.6
1.4
1.4
66%
New Clinical Vertebral Fracture
% of Women with
1.2
1.2
1.0
1.0
RR 0.32 (95% CI, )
0.8
0.8
0.6
68%
0.6
0.4
0.4
0.2
0.2
0.0
0.0
Placebo
RLX 60
Placebo
RLX 60
Marici et al, Arch. Int med, 2002

10. Effect of Raloxifene on New Clinical Vertebral Fractures at 6 Months
0.44%
(n=10)
Qu Y, et al. CMRO, 2005, 21 (12):

11. Cumulative Incidence of New Clinical
Vertebral Fractures in the First Year of MORE*
*P=0.007 in the first 6 months for
each raloxifene group compared with placebo
Qu Y, et al. CMRO, 2005, 21 (12):

12. Effect of Raloxifene on New Clinical Vertebral Fractures at 3 Months
0.22%
(n=5)
Qu Y, et al. CMRO, 2005, 21 (12):

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 MORE Trial - 3 Years
Source:
Review:
RR 0.07* (95% CI = 0.01, 0.56)
1.6
1.2
Reviewer Memo:
Incident Vertebral Fractures
% of Women with 2
93%
0.8
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
0.4
Placebo
N=1457
Raloxifene 60 mg/day
N=1401
*p = 0.001
Lufkin E et al. North American Menopause Society 12th Annual Meeting Program and Abstract Book, P21, p70, October 4-6, 2001
Slide Modified:
Memo:

15. Semiquantitative Evaluation of Vertebral Fracture Severity
Source:
Semiquantitative Evaluation of Vertebral Fracture Severity
Review:
Middle
Anterior
Posterior
Fracture Grade
0- Normal
1- Mild
(20-25%*)
2- Moderate
(26-40%*)
3- Severe
(>40%*)
Reviewer Memo:
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.
*Percent reduction in anterior, mid and/or posterior vertebral height
Adapted from: Genant HK et al. J Bone Miner Res 8: , 1993
Slide Modified:
Memo:

16. Moderate/Severe Vertebral Fracture
Risk of At Least 1 New
Moderate/Severe Vertebral Fracture
MORE Trial – 3 Year 5 10 15 20
RR 0.39
(95% CI 0.17, 0.69)
RR 0.63
(95% CI 0.49, 0.83)
Moderate/Severe Vertebral Fracture
% of Women with At Least 1 New
Placebo
RLX 60 mg/d
37%
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.
61%
Without Preexisting
Vertebral Fractures
With Prevalent
Siris E et al. Osteoporosis Int 13:907, 2002

17. % of Women with at Least 1 New Nonvertebral Fracture
Reduction of 47% of at Least 1 New Nonvertebral* Fracture in Women With Baseline SQ Grade 3 MORE Trial - 3 Years
RH=0.53 (95% CI 0.29, 0.99)
P=0.04 20 15
47%
% of Women with at Least 1 New Nonvertebral Fracture 10 5
Placebo
Raloxifene 60 mg/d
* Clavicle, humerus, wrist, pelvis, hip, leg
Delmas PD et al. Bone 2003;33;4:

18. Raloxifene prevents Non Vertebral Fracture in Women with 2 Prevalent Vertebral Fractures (n= 1369, mean age 69y MORE Trial - 3 Years – pooled raloxifene
Nonvertebral Fracture *
RR=0.69 (95% CI 0.48, 0.99)
P<0.05 40 30
% of Women With at Least 1 New non-Vertebral Fracture 20
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.
31% 10
Placebo
Raloxifene
* Clavicle, humerus, wrist, pelvis, hip, leg
Farrerons et al., CTI, 2003;72(4):391(P230)

19. * Randomized Studies of Antiresorptives in
Source:
Randomized Studies of Antiresorptives in
Postmenopausal Osteoporotic Women *
Risk of Vertebral Fractures
Review:
LS BMD**
Relative Risk (95% CI)
Raloxifene
Preexisting vertebral
2.2
60 mg/d
fracture (VFx) 1
No preexisting VFx 1
2.9
Reviewer Memo:
Alendronate
Preexisting VFx 2
6.2
5/10 mg/d
No preexisting VFx 3
6.8
Risedronate
Preexisting VFx 4
4.3
5 mg/d
Preexisting VFx 5
5.9
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.
Calcitonin
Preexisting VFx 6
0.7
200 IU/d
*Not head - to -
head comparison, **vs placebo
0.5
1.0 1
Data on file, Eli Lilly & Co. 2
Black DM et al.
Lancet
348:1535 -
1541, 1996 3
Cummings SR et al.
JAMA
280:2077
2082, 1998 4
Harris ST et al.
282:1344
1352, 1999 5
Reginster JY et al.
Osteoporosis Int
11:83
91, 2000 6
Chesnut CH et al.
Am J Med
109:267
276, 2000
Slide Modified:
Memo:

20. Differences in Trial Design: Baseline fractures
Ca and Vitamin D Supplementation / Ethical rules
Baseline fractures and age quite different between trials
Differences in calcium and vitamin D supplementation, a regimen that has been shown to reduce the risk of hip fractures, may have also contributed to the different results in hip.
The estimated number of patients who received calcium and vitamin D supplementation in the FIT and WHI HRT trial was %.
All patients in the MORE trial were supplemented in the trial.
MORE had stringent ethical rules : patients having a fracture or losing too much BMD could discontinue: ¾ more patients discontinued in placebo, strong bias against raloxifene
Also ¾ more patients took additional bone active drug in 4th year

21. Number Needed to Treat (NNT) to Prevent 1 Vertebral Fracture
Study Duration (Years)
NNT
Without Preexisting Vertebral Fracture
Raloxifene 60 mg/d†
Alendronate 5/10 mg/d‡
With Preexisting Vertebral Fracture
Raloxifene 60 mg/d‡
Alendronate 5/10 mg/d‡
Risedronate 5 mg/d‡
*Not head-to-head comparisons
†Delmas PD, et al. J Clin Endocrinol Metab. 2002; 87:
‡Marcus R, et al. Endocrine Rev. 2002;23:16-37.

22. Japan-China trials: Any New Clinical Fractures
Asian Women with Osteoporosis - One Year 10 9
RR: 0.11 ( ) 8 7
RR: 0.17 ( ) 6 5
6.0%
(n=12) 4 3 2
1.0%
(n=2)
0.7%
(n=2) 1
Raloxifene
60 mg/day
Raloxifene
Pooled
Placebo
Nakamura et a, IBMS-ECTS Geneva, June 2005, and Bone 36, Suppl 2

23. Raloxifene Bone Efficacy - Summary
Source:
Raloxifene Bone Efficacy - Summary
Review:
Significant reduction in risk of vertebral fractures
66%  in risk of clinical vertebral fractures during the first year
55%  in risk of women without preexisting vertebral fractures at 3 years of therapy.
Efficacy sustained in the 4th year (40-50% reduction).
93%  in risk of multiple vertebral fractures at 3 yr in those without preexisting vertebral fractures
47%  in risk of non vertebral fractures in women with severe vertebral fractures or 31% in women with 2 pre-existing fractures
Improves properties of bone quality
34% reduction of non vertebral fractures in MORE+CORE 8 y in women with pre-existing SQ3 fracture
Easy to use and good tolerability
Reviewer Memo:
Raloxifene Clinical Profile
Slide Modified:
Memo:

24. Completed and Ongoing Large-Scale Raloxifene Clinical Trials
Source:
Review:
19,365
20000
15000
10,101
Reviewer Memo:
Number of Enrolled Women
10000
7,705
4,011
5000
1,400 –1y
1,764
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 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
Osteoporosis
Prevention
MORE
CORE
RUTH
STAR
EVA
MORE, Multiple Outcomes of Raloxifene Evaluation; CORE, Continuing Outcomes Relevant to EVISTA; RUTH, Raloxifene Use for The Heart; STAR, Study of Tamoxifen and Raloxifene; EVA, EVISTA-Alendronate Comparison
2004
Slide Modified:
Memo:

25. Breast Cancer
Cardiovascular Effects

26. Effect of Raloxifene on All Breast Cancer MORE Trial - 4 Years
Source:
0.0
2.0
1.0
1.5
0.5
% of Randomized Patients 1 2 3 4
RR = 0.38 (95% CI = )
NNT = 94
62%
Review:
Reviewer Memo:
Placebo
RLX (pooled)
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 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. *
Total Cases = 77
Years since Randomization
Arrow denotes annual mammogram (*optional)
Sourced from Cauley J et al. Breast Cancer Res Treatment 65:125-34, 2001
2004
Slide Modified:
Memo:

27. MORE plus CORE Study Design
Source:
MORE plus CORE Study Design
Review:
Gap
MORE Conclusion
CORE Screening
MORE (N=7705)
CORE (n=4011)
Three Treatment
Two Treatment
Groups
Groups
Placebo
Placebo
Reviewer Memo:
Raloxifene HCl 60 mg/day
Raloxifene HCl 60 mg/day
Raloxifene HCl 120 mg/day
As the 4 years of the MORE trial were concluding, it was decided to enroll as many of these women as possible into the CORE trial– for an additional 4 years, thus providing 8-year data. Of the original 7,705 MORE participants, 4,011 chose to continue in the CORE trial.
Women continuing in CORE were not re-randomized but the randomization assignment from MORE was carried forward into CORE.
The MORE trial, compared 3 treatment groups - placebo, raloxifene 60 mg/d, and raloxifene 120 mg/day for 4 years. The CORE trial compared 2 treatment groups – raloxifene 60mg/d and placebo. Women assigned to raloxifene 60mg/d or 120 mg/d in MORE were assigned to 60 mg/d in CORE. Women assigned to placebo in MORE were assigned to placebo in CORE.
Raloxifene 60mg/d was chosen as the dose for CORE because it is the dose approved for prevention and treatment of osteoporosis and because the reduction in incidence of breast cancer observed in the MORE trial was similar for both doses.
Similar to the MORE trial, twice as many women were assigned to the raloxifene group as to the placebo groups
Median time between the end of MORE and enrollment in CORE was 10.6 months. For approximately 95% of those assigned to raloxifene and 94% of those assigned to placebo the interval between the end of MORE and enrollment in CORE was less than 2 years.
Year 1 2 3 4 5 6 7 8
8 Years Total Follow-up
Martino S, et al. J. Natl. Cancer Inst. 2004;96(23):
Slide Modified:
Memo:

28. Martino S, et al. J. Natl. Cancer Inst. 2004;96(23):1751-1761
Source:
CORE Study Objectives
Review:
Determine the effect of raloxifene on incidence of invasive breast cancer over an additional 4 years of therapy (8 years total for MORE + CORE)
Determine the effect of raloxifene on incidence of invasive, ER(+) breast cancer over the same time period
Assess the tolerability of raloxifene over 8 years
Reviewer Memo:
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, 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.
Martino S, et al. J. Natl. Cancer Inst. 2004;96(23):
Slide Modified:
Memo:

29. Breast Cancer Assessment
Source:
Breast Cancer Assessment
Review:
Clinical breast exams:
MORE: every 6 months
CORE: every 12 months
Mammograms:
MORE: baseline and after 2, 3, and 4 years of treatment
CORE: baseline and after years 2 and 4 of treatment
Breast cancer cases adjudicated by an independent committee of physicians blinded to treatment assignment and not affiliated with study sponsor
Reviewer Memo:
Breast cancer events were assessed by clinical breast exams every 6 months during MORE, and then yearly during CORE.
Mammograms were required in MORE at baseline and years 2, 3, 4, and in CORE at baseline and years 2 and 4, corresponding to 6 and 8 years after randomization in MORE, respectively.
For both MORE and CORE Breast cancer cases were adjudicated by an independent panel of physicians blinded to treatment assignment.
Martino S, et al. J. Natl. Cancer Inst. 2004;96(23):
Slide Modified:
Memo:

30. CORE Demographics at MORE Baseline
Source:
CORE Demographics at MORE Baseline
MORE
Participants
(N = 7705)
CORE Primary
Analysis Dataset
(N = 5213)
CORE
Enrollees
(N = 4011)
Review:
Characteristic
Mean age, yr
Age  60 years (%)
Mean BMI, kg/m
Caucasian, (%)
Current smoker, (% yes)
Mean time postmenopause, yr
Family history of
breast cancer, (%)
Hysterectomy, (% yes)
Previous hormone therapy, (%)
65.8
80.1
25.2
Reviewer Memo:
96.2
16.0
17.9
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.
11.9
20.4
25.6
Martino S, et al. J. Natl. Cancer Inst. 2004;96(23):
Slide Modified:
Memo:

31. Incidence of Invasive Breast Cancer
Source:
Incidence of Invasive Breast Cancer
4 Years of CORE
Review:
4.0
Placebo
5.2 per 1000 Women-Yrs
HR 0.41 (95% CI = )
3.0
Reviewer Memo:
N=5213
p <0.001
59%
Cumulative Incidence (%)
2.0
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.
1.0
Raloxifene
2.1 per 1000 Women-Yrs
0.0
Jan 1, 1999
Year
Martino S, et al. J. Natl. Cancer Inst. 2004;96(23):
Slide Modified:
Memo:

32. Incidence of Invasive Breast Cancer
Source:
Incidence of Invasive Breast Cancer
8 Years of MORE plus CORE (N=7705)
Review:
4.0
Placebo
4.2 per 1000 Women-Yrs
HR 0.34 (95% CI = )
3.0
Reviewer Memo:
p <0.001
Cumulative Incidence (%)
66%
2.0
8-year MORE plus CORE Results N=7705
This slide shows the Kaplan-Meier curve for the cumulative breast cancer incidence plotted against time over the 8 years of the MORE plus CORE trials beginning at randomization in MORE to the end of CORE
Over the 8-year period, raloxifene reduced the incidence of invasive breast cancer by 66% (p value < .001) compared with placebo.
A total of 98 cases of invasive breast cancer (58 in the placebo group and 40 in the Raloxifene group) were reported and confirmed by adjudication.
Absolute risk in the placebo group was 4.2 cases per 1000 woman-years and 1.4 cases for the raloxifene group. Thus, in the raloxifene group there was an absolute risk reduction of 2.8 cases per 1000 women-years.
1.0
Raloxifene
1.4 per 1000 Women-Yrs
0.0 1 2 3 4 5 6 7 8
Years in Study
Martino S, et al. J. Natl. Cancer Inst. 2004;96(23):
Slide Modified:
Memo:

33. Incidence of Invasive ER+ and ER- Breast Cancer 8 Years of MORE Plus CORE Trials
HR 0.24
(95% CI = 0.15 to 0.40)
P <.001 4
3.5
Placebo (N=2576)
Raloxifene (N=5129) 3
2.5
Incidence/1000 woman-years 2
1.5
HR 1.06
(95% CI = 0.43 to 2.59)
P = .90
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. 1
0.5
n=44
n=22
n=7
n=15
ER+ breast cancer
ER- breast cancer
Martino S, et al. J. Natl. Cancer Inst. 2004;96(23):

34. Summary of Adverse Outcomes over the 8 Years of MORE-CORE (N=4011)
Percentage of participants who experienced event (n)
P-value
Placebo
(N=1286)
Raloxifene
(N=2725)
Mortality
2.3 (29)
1.7 (47)
0.27
All cancers†
8.6 (110)
5.7 (156)
0.001
All cancers† excluding breast cancer
6.3 (81)
4.6 (126)
0.027
Hospitalization
40.9 (526)
38.8 (1057)
0.21
Treatment-emergent AEs
99.0 (1273)
98.6 (2688)
0.45
Treatment-emergent serious AEs
45.5 (585)
42.3 (1154)
0.07
Study discontinuation CORE due to AE
2.4 (31)
1.9 (53)
0.35
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.
†Excluding non-melanoma skin cancers
Martino S et al. Curr Med Res Opin 2005

35. Summary of Gynecologic AE Data over the 8 Years of MORE-CORE (N=4011)
Percentage of participants
who experienced event (n)
P-value
Placebo
(N=1286)
Raloxifene
(N=2725)
Uterine cancer†‡
0.39 (4)
0.32 (7)
0.75
Endometrial hyperplasia‡
0.29 (3)
0.37 (8)
>0.99
Ovarian cancer
0.16 (2)
0.11 (3)
0.66
Postmenopausal bleeding‡§
5.4 (55)
5.5 (120)
0.87
Vulvovaginal signs and symptoms
5.8 (75)
5.0 (135)
0.26
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.
Martino S et al. Curr Med Res Opin 2005

36. Adverse Events Reported During MORE Plus CORE – 8 Years
Source:
Adverse Events Reported
During MORE Plus CORE – 8 Years
Review:
Number (%)
Placebo Raloxifene p-value
(n=1286) (n=2725)
Reviewer Memo:
Flushing (hot flushes) 89 (6.9) 342 (12.6) <0.001
Leg cramps 152 (11.8) 407 (14.9) 0.008
Peripheral edema 120 (9.3) 288 (10.6) 0.240
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.
Martino S, et al. J. Natl. Cancer Inst. 2004;96(23):
Slide Modified:
Memo:

37. Raloxifene and Non-Vertebral Fx at 8 yrs:
Poisson analyses
CORE
CORE/MORE
[0.86,1.17]
[0.83, 1.07]
[0.63, 0.96]
1.0
[0.43,1.02]
Incidence RR (95%CI) at 6 sites
0.94
[0.44, 0.92]
Incidence RR (95%CI) at 6 sites
0.78
0.66
0.64 N
Adapted from Siris ES et al; J Bone Miner Res 2005; 20:

38. Cardiovascular Effects

39. Pathophysiology of Atherothrombosis
Foam
Cells
Fatty
Streak
Intermediate
Lesion
Atheroma
Fibrous
Plaque
Complicated
Lesion
Plaque Rupture
Clinical 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. 
Endothelial injury
Lipid accumulation
Inflammation

40. Effect of Raloxifene 60 mg/d on Cardiovascular Risk Factors
-7%
-12% 0%
-4%
-10%
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:
2. Johnston C et al. Arch Intern Med 2000;160:
3. Harper KD et al., J American Geriatrics Soc 2000;48:S51
Total
Chol
LDL-C
HDL-C TG
Fibrinogen
*P<0.05 vs. placebo
Adapted from Walsh BW et al., JAMA 1998;279:

41. Cumulative Incidence of Cardiovascular Events
MORE Trial – 4 Years
Source:
All Enrolled Women
N = 7705
High-Risk Women
n = 1035
Review:
Total number of events = 272
Total number of events = 97 14 12 10 8 6 2
Placebo
RLX 60 mg/d 14
Placebo
RLX 60 mg/d
40% 12
Reviewer Memo: 10 8 6 4 4
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:
Barrett-Connor E et al., JAMA 2002; 287:847-57
RR=0.86
(95% CI= ) 2
RR=0.60
(95% CI= ) 12 12 24 24 36 36 48
Months Since Randomization
Adapted from Barrett-Connor E et al. JAMA 287:847-57, 2002
Slide Modified:
Memo:

42. RUTH Study Raloxifene Use for The Heart
10,101 patients, DBRCT, placebo vs raloxifene (60 mg/d)
Entry: postmenopausal women at high risk for, or suffering 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.
DBRCT= double-blind, randomized, controlled trial
CHD=coronary heart disease
MI=myocardial infarction
Wenger NK, et al. Am J Cardiol.2002;90:

43. NSABP-P2 (STAR) Study Study 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)
Vogel V, et al. Clin Breast Cancer. 2002;3:

44. WHI Estrogen-Progestin Trial Global 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
Endometrial cancer
Colorectal cancer
Hip fracture
Death due to other causes
Writing Group for the Women’s Health Initiative. JAMA. 2002;288:

45. Global Safety Index Assessing Risk and Benefit
1.3
NNH = 88
Increased Harm
Relative Risk
1.2
HR 1.15
95% CI
MORE2
Raloxifene 60 mg/d
1.1 1 1
WHI1
CEE/MPA
0.9
Relative Risk
0.8
HR 0.75
95% CI
Not head-to-head trials.
0.7
NNT = 69
1. Adapted from: Writing Group for the Women’s Health Initiative. JAMA. 2002;288:
Increased Benefit
2. Barrett-Connor E. et al., J Bone Minral Res, 2004:Aug; 19, .
0.6

46. Effect of Raloxifene on WHI Global Risk-Benefit Index
HR, 0.75
95% CI,
HR, 0.75
95% CI,
Annualized %
Event Rate
Placebo
Raloxifene
60 mg/d
Raloxifene
120 mg/d
Barrett-Connor E. et al., J Bone Minral Res, 2004:Aug; 19,

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.

48. Tolerability With Raloxifene Vs Alendronate
In the Clinical Practice at 12 Months
P<0.001 30
Raloxifene
(n=476)
25.8
Alendronate
(n=426) 25
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.
Turbí C et al. Clin Ther. 2004;26:245–256. 20
16.4
P<0.001
% Patients
P<0.001 15 11
9.9 10
4.8 5
3.4
Total Discontinuation Discontinuation
Discontinuation due to Aes due to GI disorders
Turbí C et al. Clin Ther 26: , 2004.
2004

49. treatment satisfaction quality of life
Comparison of Raloxifene and Bisphosphonates on
Adherence, Health Outcomes and Treatment Satisfaction
in Post-Menopausal Asian Women
CHOOSE Asia Observational Study
Objectives:
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.
Poster presented at IBMS-ECTS Geneva , June 2005, Bone 36, Suppl 2, 2005

50. Bisphosphonates (alendronate, risedronate, etidronate)
Methods - 1
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:
Raloxifene or
Bisphosphonates (alendronate, risedronate, etidronate)
VISIT 1
Baseline
VISIT 2
6 months
VISIT 3
12 months

51. Patient Baseline Characteristics
Raloxifene
N = 707
Bisphosphonates
N = 277
Age (years), Mean ± SD (range)
66.9 ± 8.5 (55-97)
67.7 ± 9.2 (55-91)
Race/ethnicity, n (%):
Chinese
Malay
Filipino
Indian sub-continent
Asian – other
364 (51.5)
6 (0.8)
186 (26.3)
144 (20.4)
7 (1.0)
120 (43.3)
3 (1.1)
79 (28.5)
69 (24.9)
6 (2.2)
Menopause, n (%)
Natural
Surgical
613 (86.7)
94 (13.3)
237 (85.6)
40 (14.4)
No. years since menopause,
Mean ± SD
17.6 ± 9.9
19.2 ± 10.3 *
Baseline fractures, n (%)
307 (43.4)
116 (41.9)
* p<0.05: ANOVA

52. Adherence Patient Discontinuations
Enrolled: N = 984
Raloxifene treatment n = 707
Bisphosphonates treatment n = 277
Alendronate n = 206
Risedronate n = 71
33.1%
6.8%
5.7%
2.8%
1.4%
Lost to follow up
Chose to leave
Stopped treatment
Switched treatment
Reason missing
37.5%
2.9% *
10.1% *
9.7% **
2.2%
Completed study %
* p<0.05; ** p<0.01
Fisher’s Exact Test
Completed study % **
Poster presented at IBMS-ECTS Geneva , June 2005, Bone 36, Suppl 2, 2005

53. Adherence Treatment Duration (days)
Raloxifene
Bisphosphonates
p<0.05*
100
200
300
400
500
Mean Period of Exposure to Medication (days)
* Wilcoxon rank sum test
Poster presented at IBMS-ECTS Geneva , June 2005, Bone 36, Suppl 2, 2005

54. Treatment Satisfaction at 12 months
100
p<0.01*
100
p<0.01* 80 80 60 60
Percent of patients
Percent of patients 40 40 20 20
no effect
satisfied
feel better
feel worse
dissatisfied
no opinion
Raloxifene
Bisphosphonates
* Fisher’s Exact Test
Poster presented at IBMS-ECTS Geneva , June 2005, Bone 36, Suppl 2, 2005

55. Quality of Life – Mean Change in Health State (VAS) Score
p<0.01* 2 4 6 8 10
Mean Change† from
Baseline to Endpoint
Raloxifene
Bisphosphonates
†Health State score was out of 100
* ANCOVA
Poster presented at IBMS-ECTS Geneva , June 2005, Bone 36, Suppl 2, 2005

56. Incidence of New Fractures6
p=0.058* 5
Raloxifene
Bisphosphonates 4
p<0.01*
Percentage of of new, self-reported fractures
* Fisher’s Exact Test 3 2
Fractures were self-reported 1
total
wrist
spine
humerus
other
Fracture site
There were no new fractures of the clavicle and pelvis for raloxifene or bisphosphonates