1

SERM’sIES Winter Conference 24.11.05

Iris Vered,

Sheba Medical Center

Tel Hashomer

2 Brzozowski AM. Nature 1997; 389:753

Estradiol, Raloxifene & the ER: Estradiol, Raloxifene & the ER: Same Ligand Binding SiteSame Ligand Binding Site

2004

Estradiol, Kd= 86 pM Raloxifene, Kd= 54 pM

3

Action of SERM’s in Target Tissues

ER

4

SERM’s Developed for Osteporosis

• Raloxifene, Evista®, Eli Lilly. – FDA approved 01 Oct. 1999

• Idoxifene, BMS (failed phase III)• Lasofoxifene, Oporia®, Pfizer• Arzoxifene, Eli Lilly• Bazedoxifene, Wyeth

5

Multiple Outcomes of Raloxifene Evaluation (MORE) Trial Summary

• Randomized, double-blind, placebo-controlled osteoporosis treatment trial in postmenopausal women with osteoporosis (N=7705)

• 4 years of treatment• 3 treatment arms:

– Placebo (n=2576)– Raloxifene 60 mg/d (n=2557)– Raloxifene 120 mg/d (n=2572)

• 1ary endpoints: vertebral fracture, BMD, safety• 2ary endpoints: all osteoporotic fractures, cardiovascular

health, breast cancer, cognitive function

6

MORE Trial Results, 4 YearsPostmenopausal women with osteoporosistreated with raloxifene had:• A modest increase in lumbar spine & femoral

neck BMD• A decreased risk of new vertebral fractures • No reduction in risk for all non-vertebral

fractures• A decreased risk of new non-vertebral fractures

at 6 major sites*: clavicle, humerus, wrist, pelvis, hip, leg in women with prevalent vertebral fractures

• A lower incidence of breast cancer

7

Effect of Raloxifene on Invasive Breast Cancer Incidence, MORE

Arrow denotes annual mammogram (*optional)

Cauley J. Breast Cancer Res Treatment 65:125-34, 2001

2.0

1.5

1.0

0.5

0.00 1 2 3 4

Years since Randomization

% o

f Ran

dom

ize

d P

atie

nts

72%

Total Cases = 61

RR = 0.28 (95% CI = 0.17-0.4)

RLX (pooled)1.3 per 1000 Women-Yrs

Placebo 4.7 per 1000 Women-Yrs

*

NNT = 93

8

CORE: a Follow-up to the MORE Trial; Continuing Outcomes Relevant to Evista

MORE TrialCORE Trial

Aim Osteoporosis treatment Breast cancer prevention

Design Randomized, double-blind, placebo-controlled

Double-blind, placebo-controlled,

Subjects Postmenop. osteoporotic womenMORE participants who chose to continue

Treatment time

4 years4 years additional (8 total)

Treatment arms

1. Placebo (n=2576)

2. Raloxifene 60 mg/d (n=2557)

3. Raloxifene 120 mg/d (n=2572)

1. Placebo (n=1286)

2. Raloxifene 60 mg/d (n=2725)

Primary endpoint

Spine #’s, BMD, safetyInvasive breast cancer

Secondary endpoints

All osteoporotic #’s, cardiovascular health, breast cancer, cognitive function

Invasive (ER+) breast cancer, nonvertebral #’s, overall safety

9

Skeletal Effects of Raloxifene after 8 Years: Strength & Limitations

• Strength: Placebo controlled for 8 years• Limitations:

– Differences between the women who did & did not enroll in CORE

– Disparities between the placebo & raloxifene groups in CORE

– A greater use of bone-active drugs in the placebo group after year 3

– 20% elected not to take the study drug

Siris ES, JBMR 2005, 20(9):1514

10

Siris ES, JBMR 2005; 20(9):1514

Skeletal Effects of Raloxifene after 8 Years

11

Skeletal Effects of Raloxifene; Change in Lumbar Spine BMD after 7 Years, N=386

Siris ES, JBMR 2005, 20(9):1514

a: p<0.05 from placebob: p<0.05 from baselinec: p<0.05 from year 4

No studydrug

12

Skeletal Effects of Raloxifene; Change in Femoral Neck BMD after 7 Years: N=386

Siris ES, JBMR 2005, 20(9):1514

a: p<0.05 from placebob: p<0.05 from baselinec: p<0.05 from year 4

13

Skeletal Effects of Raloxifene after 8 Years: for “Non-vertebral 6” in MORE & CORE, N=7705*

Siris ES, JBMR 2005, 20(9):1514

•SQ: semiquantitative visual assesment of spine radiogpaphs

* No effect among 386 US-sites compliant participants who did not use other bone-active agents

14

EVA (Evista® Vs. Alendronate comparison trial)

• Head-to-head, double-blind, randomized trial for fracture risk reduction efficacy

• Original protocol: – 3000 postmenopausal women– age 50-80y– FN BMD T-score: -4.0 to -2.5– no prevalent spine fractures– no prior use of bone-active agents– duration: 5 y

• Early discontinuation due to slow enrollment, insufficient power to detect non-inferiority

Recker R, ASBMR 2005; s97

15

EVA (Evista® / Alendronate comparison trial)

Recker R, ASBMR 2005; s97

BMD increase at 2 y (%)

ALNRLXP

Lumbar spine5.42.5<0.05

Femoral neck3.92.3<0.05

Total hip3.91.8<0.05

16

Comparison of Alendronate & Raloxifene to Prevent Bone Loss after Discontinuation of HRT*

* within 6 months of discontinuing HRT** 32.8% of women on RLX Vs 1.8% of women on ALN lost > 3% of

lumbar spine BMD

% change from baseline at 12 months

Treatment Lumbar spine BMD**

Total hip BMD

NTX-u

Alendronate +2.3 (1.5, 3.1)+1.1 (0.5, 1.6)-48.2 (-55.2, -40.0)

Raloxifene -1.4 (-2.1, -0.6)-0.5 (-1.0, 0.1)-3.1 (-46.6, 12.5)

McClung MR, ASBMR 2005; s397

17

Breast Cancer Objectives: CORE Trial

Primary endpoint• Determine the effect of raloxifene on incidence of

invasive breast cancer over a long-term period in postmenopausal women with osteoporosis 1

Secondary analyses• Incidence of invasive ER (+) breast cancer over 8 years 1

• Incidence of invasive breast cancer in postmenopausal women stratified by their 5-year predicted risk of developing breast cancer using the Gail model during the 4 years of the CORE trial 2

1. Martino S. J Nat Cancer Inst 2004, 96(23):17512. Cauley J, et al. Abst #1018, ASCO June 2004.

18 Martino S , J Natl Cancer Inst. 2004 Dec 1;96(23):1751

19

MORE-CORE Interval

Placebo RLX

Median time between the end of participation in MORE & enrollment in CORE

10.6 months range: 2.6 – 62 months

Interval < 2 years94%95%

Had taken HRT or a SERM during the interval

17.7%18.4%

20

MORE + CORE, 8 yrs

HR 0.34 (95% CI = 0.22-0.50)

P<.001

n=7705* first 4 years ; n=4011 final 4 years

22

RaloxifenePlacebo

The Effect of Raloxifene on Invasive Breast Cancer Incidence

RRR 66%

n=5213

1

2

3

4

5

6

Inci

denc

e (

per

1000

Wom

en-Y

ears

)

0

28 24

CORE , 4 yrs

HR 0.41 (95% CI = 0.24-0.71)

P<.001

RRR 59%

24

21

Cumulative Incidence of Invasive Breast Cancer

Cu

mm

ula

tiv

e in

cid

en

ce (

/10

00

Wo

me

n)

4.2 cases per1000 woman-years

1.4 cases per1000 woman-years

HR=0.3495% CI=0.22-0.50

P<0.001

PlaceboRLX

Martino S , J Natl Cancer Inst. 2004 Dec 1;96(23):1751

22

Incidence of Breast Cancer for the Primary

CORE Breast Cancer Analysis Dataset

Breast cancer type

Rate per 1000 women-yearsHRP

Placebo RLX

Invasive 5.22.10.41<0.001

• ER pos.3.91.30.34<0.001

• ER neg.0.550.611.130.86

• ER unknown0.740.170.240.071

Noninvasive 0.370.611.780.47

All 5.52.70.50.005

The Effect of Raloxifene on Invasive Breast Cancer by Gail Risk Assessment: CORE

0

2

4

6

8

Inci

den

ce (

per

10

00 W

ome

n-Y

ea

rs)

Low Risk (<1.67%)

HR 0.67 (CI = 0.23-1.92)

n=604 n=1243

HR 0.33 (CI = 0.16-0.67)

n=674 n=1475High Risk (1.67%)

Raloxifene (n=2718)*

Placebo (n=1278)

Cauley J, et al. Abst #1018, ASCO 2004

*Effect of raloxifene on breast cancer incidence did not differ between high-risk and low-risk populations (interaction P=.28)

18 13 68

67%

24

Adverse Events, MORE + CORE, 8 Years

Solicited AE’sPlacebo (%) RLX (%) P

Vaginal Bleeding*1.361.250.87

Endometrial hyperplasia0.290.37>0.99

Endometrial cancer0.390.320.75

Thromboembolic dis.1.011.720.094

• DVT0.781.140.32

• PE0.20.60.048

Retinal vein thrombosis0.160.22>0.99

*Hysterectomized patients were excluded from analysis

25

Adverse Events, MORE + CORE, 8 years

Placebo (%) (n=1286)

RLX (%) (n=2725)

P

Death2.31.70.27

Hot flushes6.912.2<0.001

Leg cramps11.814.90.008

Peripheral edema9.3310.570.24

Ovarian cancer0.20.10.658

Stroke2.52.90.536

Myocardial infarction2.62.71.000

Breast symptoms4.94.20.323

26

Arterial and VTE Event Rate in MORE

Duvernoy CS, Menopause 2005; 12 (4) 444

27

Effect of Raloxifene on Prevention of Dementia and Cognitive Impairment: MORE

• After 3 years, those who had clinical symptoms of dementia or scored in the lowest 10th percentile on cognitive screening were evaluated by a blinded dementia specialist and had brain scans and laboratory tests to evaluate dementia etiology– 5,153 / 5,386 (95.7%) cognitively normal– 181 (3.4%) mild cognitive impairment– 52 (1.0%) dementia, 36 Alzheimer's disease

Yaffe K. Am J Psychiatry. 2005;162(4):683

28

Effect of Raloxifene on Prevention of Dementia and Cognitive Impairment

Yaffe K. Am J Psychiatry. 2005;162(4):683

Cognitive outcome Treatment group RRP

Mild cognitive impairment RLX 60 mg1.180.32

RLX 120mg0.670.04

Alzheimer’s dis.RLX 60 mg0.820.60

RLX 120mg0.520.12

Any dementia RLX 60 mg0.900.76

RLX 120mg0.910.78

Dementia or mild cognitive impairment

RLX 60 mg1.120.45

RLX 120mg0.730.054

29

Urinary Incontinence in Postmenopausal

Women Treated with Raloxifene or Estrogen

• Based on adverse event data, in an osteoporosis prevention trial

• 619 hysterectomized women, age 40-60 y• Randomized to placebo, raloxifene 60 or 150

mg/d, or CEE 0.625 mg/d• Followed for up to 3 years

• Urinary incontinence was self-reported and rated by participants

Goldstein SR. Menopause. 2005;12(2):160

30

Incidence & Severity of Urinary Incontinence in Postmenopausal Women

Treated with Raloxifene or Estrogen

Goldstein SR. Menopause. 2005;12(2):160

* Significantly different from placebo and both doses of raloxifene (P < 0.020)

31

Effect of Raloxifene Vs Tamoxifen on the Risk for Development of Endometrial Cancer

• Case control study– 547 cases of endometrial cancer– 1412 controls

DeMichele A, ASCO 2005

Unadjusted odds ratio95% CI

Raloxifene 0.430.26 - 0.73

Tamoxifen 2.351.43 – 3.86

Adjusted odds ratio

Raloxifene 0.500.29 – 0.85

Tamoxifen 1.500.77 – 2.99

32

Results from the Women’s Health Initiative

JAMA, JULY 17, 2002 , 288:321

Δ RateEvents / 10,000 p-y

ERTPlacebo

Global index+15%170151

CHD +29%3730

Stroke+41%2921

VTE+100%3416

Breast ca.+26% 3830

Colorectal ca.-37%1016

Hip fracture-34%1015

33

Risk-Benefit Safety Profile of Raloxifene 4 Years: MORE Data, WHI global Index

Barrett-Connor E. JBMR 2004,19:1270

Annualized %Hazard

ratio95% CI

Placebo RLX

Global index1.831.390.750.62-0.92

Coronary heart dis.0.320.280.880.56-1.40

Stroke 0.370.250.680.43-1.07

Pulm. Embolism0.020.093.970.91-17.3

Invasive breast ca.0.40.10.240.13-0.43

Endometrial ca.0.060.040.690.22-2.18

Colorectal ca.0.170.150.850.45-1.61

Hip fracture0.330.310.940.60-1.47

Total mortality0.410.350.850.56-1.28

34

MORE: Multiple Outcomes of Raloxifene EvaluationCORE: Continuing Outcomes Relevant to EVISTA RUTH: Raloxifene Use for The HeartSTAR: Study of Tamoxifen & Raloxifene

Large-Scale Raloxifene Clinical Trials

0

5000

10000

15000

20000

7,705

4,011

10,101

19,000N

um

be

r of

Enr

olle

d W

om

en

OsteoporosisPrevention

MORE CORE RUTH STAR

1,764

35

STAR• Objectives:

– Compare Raloxifene Vs Tamoxifen for reduction of the incidence rate of invasive breast cancer in postmenopausal women

– Compare the effects on the incidence of• Intraductal / lobular carcinoma in-situ • Endometrial cancer • Ischemic heart disease,• Fractures (hip, spine, or Colles’)

– Safety of these regimens– Quality of life

• N = 19,000• Length : 5 years• Primary results are expected in 2006

36

Raloxifene Use for The HeartTrial Design

• Double-blind, placebo-controlled, long-term coronary & breast cancer outcomes trial in postmenopausal women at risk of acute coronary events

• Combination of secondary and primary prevention (women with documented CAD and / or risk factors)

• Started in 1998 (enrollment complete 8/2000)

• N=10,101

• Length: up to 7.5 y

Mosca LM et al., Am J Cardiol 2001;88:392-395

37

NICE Recommendation on Raloxifene; 10/2005 Draft

• Not recommended as a treatment option for primary prevention of fractures– The breast cancer benefit should not be a

driver of any positive recommendation– The cost effectiveness of fracture prevention

is unfavorable relative to bisphosphonates & strontium

38

NICE Recommendation on Raloxifene; 10/2005 Draft

• For secondary prevention of osteoporotic fractures:– Raloxifene was not as effective or cost-effective as

bisphosphonates or strontium for treating osteoporosis

– The effect on prevention of breast cancer has not been assessed by the regulatory authorities

– The long-term risks beyond 8 years are uncertain

• Raloxifene should be recommended as a treatment option when bisphosphonates or strontium are contraindicated / impractical / ineffective

39

Cost-effectiveness of Raloxifene

• Examining the health economic implications of raloxifene treatment for 5 years, followed by no treatment for 5 years

• In a UK setting

• Based on the results of MORE

• Compared to no treatment

• The threshold of cost effectiveness used by NICE* for starting treatment between age 50-80y 30,000 £

*National Institute of Clinical Excellence

Kanis J. Osteoporos. Int. 2005;16:15

40

Cost-effectiveness of Raloxifene – the Model

Kanis J. Osteoporos. Int. 2005;16:15

RR

Spine fracture, no prior spine fracture0.52

Spine fracture, with prior spine fracture0.65

All breast cancer 0.38

Cardiovascular events (in a high-risk subgroup)

0.6

Venous thromboembolism3.1

41

Cost-effectiveness of Raloxifene - UK

Kanis J. Osteoporos. Int. 2005;16:15

Cost per year gained (£)

No prior spine fractureWith prior spine fracture

Age QALYLife-yearQALYLife-year

5018,00018,00018,00018,000

6023,00024,00024,00024,000

7018,00019,00018,00019,000

8021,00021,00020,00021,000

42

True Cost of Medications in Israel is the Best Kept Secret

Feasibility of Cost-effectiveness Analysis in Israel ?

43

Summary & Unanswered Questions

• Raloxifene is an alternative for bisphosphonates for treatment / prevention of osteoporosis when hip fracture risk is estimated to be low

• Raloxifene is less effective than bisphosphonates in preventing bone loss in postmenopausal women

• Raloxifene reduces the risk of invasive ER+ breast cancer– What is the best drug for prevention of breast cancer?– Who should be treated? – The optimal duration of preventive therapy?– Is there a survival benefit?– Should postmenopausal women at increased risk of breast cancer

receive raloxifene ?• If they are taking other anti-osteoporotic agents?• If they do not have osteoporosis?

– Can SERM’s be combined with HRT?