HRT: Neue Kombinationen

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1 HRT: Neue Kombinationen 4. Februar 2015 Gyndolomiti Cumulative Hazards of Invasive Breast Cancer WHI Conj. Estrogen + MPA Cumulative Hazards of Invasive Breast Cancer WHI Estrogen only CE+MPA Time, y WHI JAMA 2002 Stefanick MI, et al. JAMA 2006 Anderson GL. et al. Lancet Oncol 2012 Cumulative Incidence of Breast and Endometrial Cancer with HRT SERMs and Breast Cancer Beral Study Collaborators, Lancet 2003 Cuzick J. et al. Lancet

2 SERMs and Cancer Side Effects Optimale HRT Besserung klimakterischer Symptome Steigerung von Libido und Stimmung Günstige Effekte auf QoL Keine Risikosteigerung bez. Mammakarzinom Keine Endometriumsproliferation Effekt auf vaginale Atrophie Prophylaxe der Osteoporose Cuzick J. et al. Lancet 2013 Konjugierte Tissue Selective Estrogene Estrogen Complex (TSEC) Bazedoxifen The 10 most abundant CE components Global Gene Expression Profiles of Estrogen and CE/SERM Combinations CE/SERM Combinations Exhibit Differential Gene Regulation Patterns Complex development of 3 rd -generation SERMs Komm BS et Lyttle CR. Ann NY Acad Sci

3 Mean Daily Number of Hot Flushes Tissue Specific Effects in Preclinical Studies Selective Estrogens Menopause And Response to Therapy (SMART) Trials Studies Treatment Duration Main Endpoints Treatment Arms No. of Subjects 3068A1-203-EU 12 weeks Pilot dose finding BZA 5, 10, 20 mg / CE 0.3 mg Endometrial safety BZA 5, 10, 20 mg / CE mg Estrogen deficiency symptoms CE 0.3, mg Bone markers CE mg / MPA1.5 mg BZA 5 mg SMART1 24 months Dose ranging BZA 10, 20, 40 mg / CE 0.45 mg 3115A1-303-US/EU/BR Endometrial hyperplasia at 12m BZA10, 20, 40 mg / CE mg Bone mineral density at 24m Raloxifene 60 mg Vasomotor symptoms Vaginal maturation SMART2 3 months Vasomotor symptoms BZA 20 mg / CE 0.45 mg 3115A1-305-US SMART3 3115A1-306-US 3 months Vulvar/vaginal atrophy BZA 20 mg / CE 0.45 mg BZA 20 mg 652 SMART5 3115A WW 12 months Endometrial hyperplasia Bone mineral density Breast density BZA 20 mg / CE 0.45 mg CE 0.45 mg / MPA 1.5 mg BZA 20 mg 1843 Komm BS et Mirkin S. J Cell Physiol 2013 SMART4 3115A1-304-WW 12 months Ext 1 year Endometrial hyperplasia Bone mineral density Supportive Safety Study BZA 20 mg / CE 0.45 mg CE 0.45 mg / MPA 1.5 mg 1061 Mittlere bis schwere VMS Mittlere bis schwere vulvovaginale Atrophie Prophylaxe Osteoporose Endometrium Protektion SMART-1 SMART-2 SMART-3 Klinische Phase III Studien SMART-4 SMART-5 Daily Number of Moderate to Severe Hot Flushes Weeks Weeks BZA 20/CE 0.45: Statistically different from placebo from week 3 onward BZA 20/CE 0.625: Statistically different from placebo from week 2 onward 51% 74% 80% Sleeping Problems (Scale from MOS) SMART 1: Lumbar Spine BMD (< 5 yrs LMP) Time slept (min) Time to fall asleep Sleep adequacy Sleep disturbance min NS min Somnolence NS NS Sleep Problem Index I Sleep Problem Index II 6-point Likert scale; recall 4 weeks, SMART 2 (Study 305):Adjusted Mean Change From Baseline at Week 12 P-value vs placebo (all BZA/CE groups at 6, 12, 18 and 24 m) P-value versus baseline (all BZA/CE groups at 6, 12, 18 and 24 m) P-value versus RAL < months 12 months 18 months 24 months 3

4 Mean change in endometrial thickness with varying doses of BAZ/CE Incidence of Endometrium-related AEs AE, n (%) (n = 1,224) (n = 1,234) (n = 1,069) Endometrial disorder 2 (0.2) 2 (0.2) 0 Endometrial hyperplasia 2 (0.2) 4 (0.3) 2 (0.2) Endometrial hypertrophy 3 (0.2) 8 (0.6) 2 (0.2) Uterine polyp 11 (0.9) 10 (0.8) 4 (0.4) Includes cumulative data (up to 2 years) from SMART-1, SMART-2, SMART-3, and SMART-5. Komm BS et Pickar JH. 6th IMS Workshop Proceedings 2006 Incidence of Select Ovarian-related AEs Cumulative Incidence of Endometrial and Ovarian Cancer AE n (%) Ovarian cyst 11 (0.7) 10 (0.6) 10 (0.8) Ovarian disorder 1 (0.1) 1 (0.1) 1 (0.1) Ovarian mass 1 (0.1) 0 0 Pelvic mass (0.1) Endometrial Cancer, n women-years (95% CI) 0.4 (0.0, 2.4) 0.0 (0.0, 1.5) 0.0 (0.0, 1.7) Relative risk (95% CI) 0.9 (0.2, 4.8) 0.7 (0.1, 3.7) Ovarian Cancer, n women-years (95% CI) 0.0 (0.0, 1.5) 0.0 (0.0, 1.5) 0.0 (0.0, 1.7) Relative risk (95% CI) 0.7 (0.1, 3.8) 0.7 (0.1, 3.7) Includes cumulative data (up to 2 years) from SMART-1, SMART-2, SMART-3, SMART-4 and SMART-5. Includes adnexal mass, ovarian fibroma, palpable adnexa, increased fullness adnexa, and ovarian volume increased. Includes cumulative data (up to 2 years) from SMART-1, SMART-2, SMART-3, SMART-4, and SMART-5. Incidence of Select Breast-related AEs Cumulative Incidence of Breast Cancer AE, n (%) Breast cyst 7 (0.4) 2 (0.1) 4 (0.3) Breast mass 2 (0.1) 3 (0.2) 4 (0.3) Fibrocystic breast disease 2 (0.1) 1 (0.1) 1 (0.1) BZA 20 mg/ CE 0.45 mg BZA 20 mg/ CE mg Events women-years (95% CI) 1.0 (0.0, 3.2) 0.0 (0.0, 1.5) 1.4 (0.0, 4.2) Relative risk (95% CI) 1.1 (0.3, 3.8) 0.4 (0.1, 2.0) Includes cumulative data (up to 2 years) for SMART-1, SMART-2, SMART-3, SMART-4, and SMART-5. Includes cumulative data (up to 2 years) from SMART-1, SMART-2, SMART-3, SMART-4, and SMART-5. 4

5 Incidence of breast pain/tenderness, % Mean (SE) adjusted change from baseline, % SMART 5 Cumulative Amenorrhea (1 year) Venous Thromboembolic Events Cases (n) Rate Per 1000 Women Years (95% CI) Excess AE Rate from PBO (95% CI) Hazard Ratio vs PBO (95% CI) p-value BZA 20/CE (0.39,5.46) 1.12 (-1.47,3.7) 2.46 (0.26,23.67) 0.44 BZA20/CE (0.00,1.87) (-2.23,0.72) BZA 20/CE (0.19,2.73) 0.18 (-1.64,2) 1.24 (0.13,11.88) 0.85 ALL BZA/CE (0.38,2.24) 0.27 (-1.42,1.96) 1.26 (0.15,10.54) (0.02,4.20) BZA, bazedoxifene; CE, conjugated estrogens; MPA, medroxyprogesterone acetate. a P vs all other treatment groups. VTE = DVT + PE Data represent all adjudicated events: TE, AE + Post-Therapy AE Breast Pain/Tenderness Breast Density (Year 1 and 2) (SMART-5 breast density substudy; SMART-1 ancillary study) n=186 n=191 n=97 n=68 n=129 n=105 n=125 n=126 Incidence of breast pain/tenderness with BZA/CE was similar to BZA and placebo and significantly lower than with CE/MPA at all time points evaluated Other breast-related AEs were uncommon ( 1%) and similar among groups NS vs placebo NS vs placebo P vs placebo, BZA/CE, and raloxifene; P<0.05 vs raloxifene. Changes in breast density with BZA/CE and BZA were similar compared with placebo, supporting a neutral effect of treatment on changes in breast density TSEC Besserung klimakterischer Symptome Kein Brustspannen, keine Dichtezunahme Mammakarzinom? Keine Endometriumproliferation Besserung der vaginalen Atrophie Prophylaxe der Osteoporose 5