BAZEDOXIFENO. NUEVO SERM EN EL MANEJO DE LA OSTEOPOROSIS

Transcription

1 BAZEDOXIFENO. NUEVO SERM EN EL MANEJO DE LA OSTEOPOROSIS Dr. Santiago Palacios Palacios Institute of Woman s Health Chairman of CAMS (Council of Affiliated Menopause Societies) President of SIBOMM (Ibero American Society of Osteology and Mineral Metabolism) Antonio Acuña, Madrid Phone: ipalacios@institutopalacios.com

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3 Diapositivas / Slides

4 Contenido HISTORIA DE LOS SERMs CLASIFICACIÓN DE LOS SERMs LOS SERMs A SUPERAR NUEVOS SERMs SERMs COMBINADOS CONCEPTO SECUENCIAL

5 Tamoxifen Functions as an Estrogen in Some Environments % Change in Spinal BMD From Baseline 3 Placebo 2 Tamoxifen Baseline Months Love RR, et al. N Engl J Med. 1992;326:

6 Evolution of SERM Development 1, st generation Tamoxifen 2nd generation Raloxifene 3rd generation Lasofoxifene Bazedoxifene N O HO O S O OH N O N N N O Tamoxifen Raloxifene HO HO OH Lasofoxifene Bazedoxifene 1. Komm BS, et al. Ann N Y Acad Sci. 2001;949: Hall JM, McDonnell DP. Menopausal Med. 2008;16:S1,S3-S6.

7 Contenido HISTORIA DE LOS SERMs CLASIFICACIÓN DE LOS SERMs LOS SERMs A SUPERAR NUEVOS SERMs SERMs COMBINADOS CONCEPTO SECUENCIAL

8 SELECTIVIDAD OSEA DE LOS SERMS, SEGUN ESTUDIOS IN VITRO Loss of BMD Antagonist Agonist Maintenance of BMD Bazedoxifene 2 4 Raloxifene 1,2,4,5 Lasofoxifene 5 Tamoxifen 1 Reference estrogens Sato M, et al. FASEB J. 1996;10: Komm BS, et al. Endocrinology. 2005;146: Kharode Y, et al. Endocrinology. 2008;149: Komm BS, et al. Ann N Y Acad Sci. 2001;949: Armamento-Villareal R, et al. J Bone Miner Res. 2005;20:

9 Bazedoxifene Does Not Exhibit Uterotrophic Activity in Rodents Mean Uterine Wet Weight ± SE (mg) a Vehicle b c f e a E2 CE BZA RAL LAS Treatment Groups labeled with the same letter are statistically similar (P>0.05). Adapted with permission from Peano BJ, et al. Effects of various selective estrogen receptor modulators with or without conjugated estrogens on mouse mammary gland. Endocrinology. April 2009;150(4): Copyright 2009, The Endocrine Society. 9

10 SELECTIVIDAD ENDOMETRIAL DE LOS SERMS Does not increase uterine wet weight Antagonist Agonist Increases uterine wet weight Bazedoxifene 1 4 Raloxifene 1 6 Lasofoxifene 1,3,4 Tamoxifen 6,7 Reference estrogens Komm BS, et al. Ann N Y Acad Sci. 2001;949: Komm BS, et al. Endocrinology. 2005;146: Crabtree JS, et al. Mol Cell Endocrinol. 2008;287: Peano BJ, et al. Endocrinology. 2009;150: Qu Q, et al. Endocrinology.2000;141: Stygar D, et al. Reprod Biol Endocrinol. 2003;1: Carthew P, et al. Toxicol Sci. 1999;48:

11 Bazedoxifene: Effects on Ductal Invasion in the Mouse Mammary Gland Mean Ductal Invasion ± SE (mm) b b c c a a Vehicle E2 CE BZA RAL LAS Treatment Groups labeled with the same letter are statistically similar (P>0.05). Adapted with permission from Peano BJ, et al. Effects of various selective estrogen receptor modulators with or without conjugated estrogens on mouse mammary gland. Endocrinology. April 2009;150(4): Copyright 2009, The Endocrine Society. 11

12 PROLIFERACIÓN DE CELULAS DE CANCER MAMARIO DE LOS SERMS Inhibits breast cancer cell proliferation Antagonist Agonist Stimulates breast cancer cell proliferation Bazedoxifene 1 3 Raloxifene 3,4 Tamoxifen 4 Lasofoxifene 3 Reference estrogens Komm BS, et al. Ann N Y Acad Sci. 2001;949: Komm BS, et al. Endocrinology. 2005;146: Chang KCN, et al. J Steroid Biochem Mol Biol. 2010;118: Nuttall ME, et al. Am J Physiol 12 Cell Physiol. 2000;279:C1550-C1557.

13 SERMs Are a New Class of ER Modulators Whose Relative Agonist/Antagonist Activities Differ Between Tissues Bone Uterus Brain Breast (vaso) Estradiol Tamoxifen Raloxifene Lasofoxifene Bazedoxifene Cummings SR et al, N Engl J Med. 2010; 362:

14 Contenido HISTORIA DE LOS SERMs CLASIFICACIÓN DE LOS SERMs LOS SERMs A SUPERAR NUEVOS SERMs SERMs COMBINADOS CONCEPTO SECUENCIAL

15 SERM 1ª GENERACIÓN TAMOXIFENO SERM 2ª GENERACIÓN RALOXIFENO Prevención y tto. del cáncer de mama Tto. y prevención de la osteoporosis postmenopáusica Efectos + sobre lípidos Riesgo tromboembolismo venoso Sofocos No han demostrado efecto + sobre fracturas no vertebrales Tamoxifeno cc de endometrio EN BUSCA DE UN NUEVO SERM

16 Contenido HISTORIA DE LOS SERMs CLASIFICACIÓN DE LOS SERMs LOS SERMs A SUPERAR NUEVOS SERMs SERMs COMBINADOS CONCEPTO SECUENCIAL

17 New SERMs Ospemifene Vaginal atrophy 2011 Arzoxifene Lasofoxifene Bazedoxifene Bazedoxifene + premarin Breast and osteoporosis submission withdrawn Osteo fract prev (EMEA) 2010 Osteo fract prev (EMEA) 2010 Climacteric symptoms 2011

18 Ospemifene: Drug Summary Box

19 Lasofoxifene Climacteric symptoms Undefined Bone BMD 1 Breast Risk Endometrium Undefined CV LDL 1 Chemical structure available at: 1. McClung MR, et al. Menopause. 2006;13:377.

20 Lasofoxifene Osteoporosis Clinical Program Phase 1 N=814 PK/PD Bioequivalence Metabolism Special Populations Drug Interactions Phase 2 N=321 E/P 1 yr CORAL N=410 raloxifene 2 yr N=394 placebo 1 yr Phase 3 OPAL N=1894 prevention prevention 2 yr PEARL N=8556 treatment 3 yr

21 N Engl J Med 2010;362:690 Lasofoxifene: Mayor Outcomes at 5 years

22 COMPOSICIÓN Y QUÍMICA INDOL CON DOS ANILLOS FENILOS AFINIDAD A REα > REβ

23 Bazedoxifene Clinical Development Clinical profile of bazedoxifene was studied in 2 large, multicenter, double-blind, randomized, placebo- and active-controlled studies Treatment Study: Study 301 Prevention Study: Study 300 1,874 postmenopausal women Phase 1 18 studies Single dose up to 120 mg Multiple doses up to 80 mg Phase A1 200 BR (6 months) 3068A1 204 US/CA (3 months) 3068A1 205 CN (3 months) Phase 3: >10,000 patients Prevention Study: 24 months Treatment Study: 36 months; extended to 5 years; then extended to 7 years 23

24 Osteoporosis Prevention Study: Design Pivotal, 2 year, phase 3, multicenter, double blind, randomized, placebo and active controlled study Bazedoxifene 20 mg Raloxifene 60 mg Placebo Women 45 years of age and 1 year postmenopausal LS or FN BMD T-score between 1 and 2.5 or risk factors Primary end point: percentage change from baseline in LS BMD (L1 to L4) at 24 months Main secondary end point: percentage change from baseline in BMD of the total hip and FN LS = lumbar spine; FN = femoral neck. DOF Protocol 3068A1-300/ Miller PD, et al. J Bone Miner Res. 2008;23:

25 Prevention Study: Lumbar Spine BMD Months P<0.001 vs. placebo (PBO) for all bazedoxifene (BZA) groups and raloxifene (RLX) at each time point. P=NS vs. RLX for all BZA groups at each time point. ITT LOCF, using ANCOVA with BMD as covariate. DOF Protocol 3068A1-300/ Miller PD, et al. J Bone Miner Res. 2008;23:

26 Prevention Study: Total Hip and Femoral Neck BMD P<0.001 vs. PBO for all BZA groups and RLX at each time point. P=NS vs. RLX for all BZA groups at each time point. ITT LOCF, using ANCOVA with BMD as covariate. DOF Protocol 3068A1-300/ Miller PD, et al. J Bone Miner Res. 2008;23:

27 Osteoporosis Treatment Study: Design 206 sites in Asia-Pacific countries, Canada, Europe, Latin America, South Africa, and the United placebo Statesand active controlled study (n=7490) Pivotal, 3 year, phase 3, multicenter, double blind, randomized, Bazedoxifene 20 mg Raloxifene 60 mg Placebo Calcium 1,000 1,200 mg and Vitamin D IU daily Silverman SL, et al. J Bone Miner Res. 2008;23:

28 Bazedoxifene Reduced New Vertebral Fractures Bazedoxifene also maintained BMD at the lumbar spine after 3 years of treatment (P<0.001) Reduction in New Vertebral Fractures: 3 Year Data 1,2 Incidence of Fracture (%) RRR in new vertebral fractures 2.3 All Subjects Bazedoxifene 20 mg 4.1 Placebo RRR in new vertebral fractures 42% * 45% * Subjects With Previous Fracture HR=0.58; 95% CI, * HR=0.55; 95% CI, * *P<0.05 vs. placebo. RRR = relative risk reduction; HR = hazard ratio; CI = confidence interval. Silverman SL, et al. J Bone Miner Res. 2008;23:

29 Bazedoxifene Reduced Nonvertebral Fractures in Women With High Fracture Risk Reduction in Nonvertebral Fracture: 3 Year Data 1,2 Bazedoxifene 20 mg Placebo Raloxifene 60 mg RRR in nonvertebral fractures RRR in nonvertebral fractures Kaplan-Meier Fracture Rate (%) % * 44% Bazedoxifene 20 mg Placebo Bazedoxifene 20 mg Raloxifene 60 mg HR=0.50; 95% CI, * HR=0.56; 95% CI, High-risk women (n=1,772) had a femoral neck T-score 3.0 and/or 1 moderate or severe vertebral fractures or multiple mild vertebral fractures. *P=0.02 vs. placebo; P=0.05 vs. raloxifene. RRR = relative risk reduction. 1. Silverman SL, et al. J Bone Miner Res. 2008;23: Data on file. Wyeth Pharmaceuticals Inc. 29

30 Osteoporosis Treatment Study: 5-Year Extension 5 year extension for efficacy and safety (n=4,216) BZA 20 mg BZA 40/20 mg After 4 years Placebo Extended for 2 additional years 7 year extension Mean age 65 years Subjects receiving BZA 40 mg were transitioned to BZA 20 mg after 4 years Findings at 5 years are reported for BZA 20 mg, BZA 40/20 mg, and placebo only Raloxifene 60 mg treatment arm was discontinued in the 4th year Primary end point remained the incidence of new vertebral fractures Secondary end point remained the incidence of nonvertebral fractures Data on file. Pfizer Inc. 30

31 Bazedoxifene: Effects on New Vertebral Fractures Reduction in New Vertebral Fractures: 5 Year Data Bazedoxifene 20 mg Placebo Incidence of Fracture (%) RRR in new vertebral fractures 4.5 All Subjects 6.8 RRR in new vertebral fractures 35% * 33% 5.7 Subjects With Previous Fracture 8 Bazedoxifene also maintained BMD at the lumbar spine after 5 years of treatment (P=0.01) *P=0.014 vs. placebo. Data on file. Pfizer Inc. 31

32 Bazedoxifene: Reduction in Nonvertebral Fractures in High-Risk Women: 5-Year Data 1,2 Bazedoxifene 20 mg (n=443) Placebo (n=448) Kaplan-Meier Fracture Rate (%) RRR in nonvertebral fractures 42%* % * 5.2 RRR in nonvertebral fractures RRR in nonvertebral fractures 37% Years 4 Years 5 Years HR=0.53; 95% CI, * HR=0.58; 95% CI, * HR=0.63; 95% CI, High-risk women (n=1,324) had a femoral neck T-score 3.0 and/or 1 moderate or severe vertebral fractures or multiple mild vertebral fractures. *P<0.05 vs. placebo. 1. Silverman SL, et al. J Bone Miner Res. 2008;23: Brown JP. J Rheumatol (11):

33 SAFETY AND TOLERABILITY OF BAZEDOXIFENE IN TWO PHASE III CLINICAL TRIALS Palacios S. Curr Med Res Opin Apr 30

34 Bazedoxifene: Effects on Endometrial Thickness Change in Endometrial Thickness After 2 Years 1* Mean Change in Endometrial Thickness (mm) BZA 20 mg RAL 60 mg Placebo Endometrial carcinoma at year 3 n=0 n=2 n=3 *Transvaginal ultrasound data from a safety analysis of the phase 3 fracture prevention trial for bazedoxifene reported by Silverman et al in 753 subjects at year 2. 1,2 1. Christiansen C, et al. BMC Musculoskelet Disord. 2010;11: Silverman SL, et al. J Bone Miner Res. 2008;23:

35 Bazedoxifene: Effects on Mammographic Breast Density Change in Mammographic Breast Density Mean Change in Mammographic Breast Density (%) 0.3 E BZA 20 mg RAL 60 mg Placebo (n=92) (n=119) (n=125) Of the mammograms from 1,243 women who were 62 years of age, had completed 24 months of the study, were >85% compliant, and had undergone mammography at baseline and at month 24, 442 mammograms were technically acceptable and had adequate penetration for analysis. Harvey JA, et al. Menopause. 2009;16:

36 Contenido HISTORIA DE LOS SERMs CLASIFICACIÓN DE LOS SERMs LOS SERMs A SUPERAR NUEVOS SERMs SERMs COMBINADOS CONCEPTO SECUENCIAL

37 Gene Expression Profiles of SERMs and SERM/CE Combinations in Rat Uterus (Heirarchical Clustering) Vehicle CE BZA LAS RAL BZA/CE LAS/CE RAL/CE E2

38 Bazedoxifeno/CE: (fase 2) Reduce los síntomas vasomotores de la menopausia

39 Bazedoxifeno/CE: (fase 2) Reduce estímulo endometrial de los estrógenos

40 Contenido HISTORIA DE LOS SERMs CLASIFICACIÓN DE LOS SERMs LOS SERMs A SUPERAR NUEVOS SERMs SERMs COMBINADOS CONCEPTO SECUENCIAL