1. 1 SERM’s IES Winter Conference 24.11.05 Iris Vered, Sheba Medical Center Tel Hashomer

2. 2 Brzozowski AM. Nature 1997; 389:753 Estradiol, Raloxifene & the ER: Same Ligand Binding Site 2004 Estradiol, K d = 86 pM Raloxifene, K d = 54 pM

3. 3 Action of SERM’s in Target Tissues ERER

4. 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. 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. 6 MORE Trial Results, 4 Years Postmenopausal women with osteoporosis treated 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. 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 0.0 0123401234 Years since Randomization % of Randomized Patients 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. 8 CORE: a Follow-up to the MORE Trial; Continuing Outcomes Relevant to Evista CORE TrialMORE Trial Breast cancer preventionOsteoporosis treatmentAim Double-blind, placebo-controlled, Randomized, double-blind, placebo-controlled Design MORE participants who chose to continue Postmenop. osteoporotic womenSubjects 4 years additional (8 total)4 years Treatment time 1.Placebo (n=1286) 2.Raloxifene 60 mg/d (n=2725) 1.Placebo (n=2576) 2.Raloxifene 60 mg/d (n=2557) 3.Raloxifene 120 mg/d (n=2572) Treatment arms Invasive breast cancerSpine #’s, BMD, safety Primary endpoint Invasive (ER+) breast cancer, nonvertebral #’s, overall safety All osteoporotic #’s, cardiovascular health, breast cancer, cognitive function Secondary endpoints

9. 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. 10 Siris ES, JBMR 2005; 20(9):1514 Skeletal Effects of Raloxifene after 8 Years

11. 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 placebo b: p<0.05 from baseline c: p<0.05 from year 4 No study drug

12. 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 placebo b: p<0.05 from baseline c: p<0.05 from year 4

13. 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. 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. 15 EVA (Evista® / Alendronate comparison trial) Recker R, ASBMR 2005; s97 BMD increase at 2 y (%) PRLXALN <0.052.55.4Lumbar spine <0.052.33.9Femoral neck <0.051.83.9Total hip

16. 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 NTX-u Total hip BMD Lumbar spine BMD** Treatment -48.2 (-55.2, -40.0)+1.1 (0.5, 1.6)+2.3 (1.5, 3.1)Alendronate -3.1 (-46.6, 12.5)-0.5 (-1.0, 0.1)-1.4 (-2.1, -0.6)Raloxifene McClung MR, ASBMR 2005; s397

17. 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):1751 2.Cauley J, et al. Abst #1018, ASCO June 2004.

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

19. 19 MORE-CORE Interval RLXPlacebo 10.6 months range: 2.6 – 62 months Median time between the end of participation in MORE & enrollment in CORE 95%94%Interval < 2 years 18.4%17.7% Had taken HRT or a SERM during the interval

20. 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 Raloxifene Placebo The Effect of Raloxifene on Invasive Breast Cancer Incidence RRR 66% n=5213 1 2 3 4 5 6 Incidence (per 1000 Women-Years) 0 28 24 CORE, 4 yrs HR 0.41 (95% CI = 0.24-0.71) P<.001 RRR 59% 24

21. 21 Cumulative Incidence of Invasive Breast Cancer Cummulative incidence (/1000 Women) 4.2 cases per 1000 woman-years 1.4 cases per 1000 woman-years HR=0.34 95% CI=0.22-0.50 P<0.001 Placebo RLX Martino S, J Natl Cancer Inst. 2004 Dec 1;96(23):1751

22. 22 Incidence of Breast Cancer for the Primary CORE Breast Cancer Analysis Dataset PHR Rate per 1000 women-years Breast cancer type RLXPlacebo <0.0010.412.15.2Invasive <0.0010.341.33.9 ER pos. 0.861.130.610.55 ER neg. 0.0710.240.170.74 ER unknown 0.471.780.610.37Noninvasive 0.0050.52.75.5All

23. The Effect of Raloxifene on Invasive Breast Cancer by Gail Risk Assessment: CORE 0 2 4 6 8 Incidence (per 1000 Women-Years) 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=1475 High 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 6 8 67%67%

24. 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. 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. 26 Arterial and VTE Event Rate in MORE Duvernoy CS, Menopause 2005; 12 (4) 444

27. 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. 28 Effect of Raloxifene on Prevention of Dementia and Cognitive Impairment Yaffe K. Am J Psychiatry. 2005;162(4):683 PRRTreatment groupCognitive outcome 0.321.18RLX 60 mg Mild cognitive impairment 0.040.67RLX 120mg 0.600.82RLX 60 mg Alzheimer’s dis. 0.120.52RLX 120mg 0.760.90RLX 60 mg Any dementia 0.780.91RLX 120mg 0.451.12RLX 60 mg Dementia or mild cognitive impairment 0.0540.73RLX 120mg

29. 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. 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. 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 95% CIUnadjusted odds ratio 0.26 - 0.730.43Raloxifene 1.43 – 3.862.35Tamoxifen Adjusted odds ratio 0.29 – 0.850.50Raloxifene 0.77 – 2.991.50Tamoxifen

32. 32 Results from the Women’s Health Initiative JAMA, JULY 17, 2002, 288:321 Events / 10,000 p-y Δ Rate PlaceboERT 151170+15%Global index 3037+29%CHD 2129+41%Stroke 1634+100%VTE 3038+26%Breast ca. 1610-37%Colorectal ca. 1510-34%Hip fracture

33. 33 Risk-Benefit Safety Profile of Raloxifene 4 Years: MORE Data, WHI global Index Barrett-Connor E. JBMR 2004,19:1270 95% CI Hazard ratio Annualized % RLXPlacebo 0.62-0.920.751.391.83Global index 0.56-1.400.880.280.32Coronary heart dis. 0.43-1.070.680.250.37Stroke 0.91-17.33.970.090.02Pulm. Embolism 0.13-0.430.240.10.4Invasive breast ca. 0.22-2.180.690.040.06Endometrial ca. 0.45-1.610.850.150.17Colorectal ca. 0.60-1.470.940.310.33Hip fracture 0.56-1.280.850.350.41Total mortality

34. 34 MORE: Multiple Outcomes of Raloxifene Evaluation CORE: Continuing Outcomes Relevant to EVISTA RUTH: Raloxifene Use for The Heart STAR: Study of Tamoxifen & Raloxifene Large-Scale Raloxifene Clinical Trials 0 5000 10000 15000 20000 7,705 4,011 10,101 19,000 Number of Enrolled Women Osteoporosis Prevention MORECORERUTHSTAR 1,764

35. 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. 36 Raloxifene Use for The Heart Trial 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. 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. 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. 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. 40 Cost-effectiveness of Raloxifene – the Model Kanis J. Osteoporos. Int. 2005;16:15 RR 0.52Spine fracture, no prior spine fracture 0.65Spine fracture, with prior spine fracture 0.38All breast cancer 0.6 Cardiovascular events (in a high-risk subgroup) 3.1Venous thromboembolism

41. 41 Cost-effectiveness of Raloxifene - UK Kanis J. Osteoporos. Int. 2005;16:15 Cost per year gained (£) With prior spine fractureNo prior spine fracture Life-yearQALYLife-yearQALYAge 18,000 50 24,000 23,00060 19,00018,00019,00018,00070 21,00020,00021,000 80

42. 42 True Cost of Medications in Israel is the Best Kept Secret Feasibility of Cost-effectiveness Analysis in Israel?

43. 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?