9/28/2016 The compound Tissue Selective Estrogen Complex - PDF document

9/28/2016 The compound Tissue Selective Estrogen Complex (conjugated estrogen/bazedoxifene) Pairing conjugated estrogens (CE) with the selective estrogen receptor modulator bazedoxifene (BZA) to achieve clinical results based on their blended tissue selective activity profile 3 rd Wulf Utian Translational Science Symposium A Conversation About Hormone Therapy: Is There an Appropriate Dose, Route, and Duration of Use? NAMS Annual Meeting Orlando 2016 past The concept The evidence • For menopausal women with a uterus in need of MHT • A non-progestogenic compound to oppose the proliferative effect of CE on the endometrium • That does not oppose the beneficial effect of CE on vasomotor symptoms • That is breast friendly • That prevents bone-loss • That promotes vaginal health • That does not have a cumulative effect on the risk of DVT 1

9/28/2016 The evidence: CE/BZA SMART trials SMART 1 (Study 303): Percentage of Subjects with Cumulative Amenorrhea over 1 Year Randomized, double-blind, placebo (PBO)- and active-controlled Phase 3 studies in non-hysterectomized postmenopausal (PM) women Population Treatment Arms N # Duration Region 100 90 BZA 10,20,40/ CE 0.45 US: 54% SMART ‐ 1 Generally 1,274 2 years 80 BZA 10,20,40/ CE 0.625 Europe: 12% Healthy PM 70 Raloxifene 60 Latin America: 34% PBO % Subjects 60 50 Moderate ‐ BZA 20/ CE 0.45 318 3 months US: 100% SMART ‐ 2 Severe VMS* BZA 20/ CE 0.625 40 PBO 30 BZA 20/ CE 0.45 SMART ‐ 3 Moderate ‐ 542 3 months US: 100% 20 BZA 20/ CE 0.625 Severe VVA** 10 BZA 20, PBO 0 BZA 20/ CE 0.45 US: 78% SMART ‐ 5 Subset with 346 1 year 1 2 3 4 5 6 7 8 9 10 11 12 13 BZA 20/ CE 0.625 Europe: 16% Bothersome CE 0.45/ MPA 1.5 Latin America: 5% 4-Week Intervals Moderate ‐ BZA 20, PBO Asia Pacific: 1% Severe VMS* 10/0.625 20/0.625 40/0.625 10/0.45 7 20/0.45 40/0.45 Placebo Raloxifene *VMS ‐ Vasomotor Symptoms **VVA ‐ Vulvar/Vaginal Atrophy BZA10/CE0.625 different from placebo at the 3 time points # N = all randomized subjects took at least 1 dose BZA 20 mg/CE 0.45 mg, BZA 20 mg/CE 0.625 mg or Placebo SMART 1 (Study 303) SMART 2: Daily Number of Moderate to Severe Hot Endometrial Hyperplasia Rate Flushes (LOCF) 12 Placebo (n=63) CE 0.45/BZA 20 (n=123) 10 Mean Daily Number CE 0.625/BZA 20 (n=122) Cases/n Incidence 1-sided Cases/n Incidence 1-sided of Hot Flushes 8 Group Year 1 Year 1 95% UL Year 2 Year 2 95% UL 40/0.45 0/309 0.00 0.96 0/268 0.00 1.11 6  51% 20/0.45 0/336 0.00 0.89 1/293 0.34 1.61 4 5/321 1.56 3.25 9/278 3.24 5.58 10/0.45  74% 40/0.625 0/311 0.00 0.96 0/267 0.00 1.12 2  80% 20/0.625 1/314 0.32 1.50 2/271 0.74 2.30 0 10/0.625 15/345 4.39 6.67 24/295 8.14 11.25 0 1 2 3 4 5 6 7 8 9 10 11 12 RAL 0/298 0.00 0.96 0/261 0.00 1.14 Weeks Placebo 0/312 0.00 1.00 0/260 0.00 1.15 CE 0.45/BZA20: Statistically different from placebo from week 3 onward CE 0.625/BZA20: Statistically different from placebo from week 2 onward 6 Pinkerton et al. Menopause. 2009;1 6:1116 ‐ 1124 2

9/28/2016 Adjusted Mean Change from baseline in SMART 5 Adjusted Change From Baseline in Vasomotor Functioning SMART-5 Breast Density at year 1 3 Months 12 Months 0 1.60* (0.35) BZA 20 mg/ CE 0.45 mg/BZA 20 mg (n = 186) ‐ 0.5 CE 0.45 mg CE 0.625 mg/BZA 20 mg (n=191) BZA 20 mg (n=98 ) ‐ 1 BZA 20 mg/ CE 0.45 mg/MPA 1.5 mg (n=68) CE 0.625 mg Placebo (n=182) ‐ 1.5 BZA 20 mg ‐ 2 ‐ 2.5 CE 0.45/ MPA * –0.24 (0.30) * 1.5mg ‐ 3 * * * –0.32 (0.23) –0.38 (0.22) –0.44 (0.22) * * * * PBO ‐ 3.5 * * * ‐ 4 † Includes all women enrolled in the breast density substudy who took at least 1 dose of study drug, had a **P <0.001 vs PBO. baseline breast density evaluation, and had at least 1 post-baseline evaluation. *P <0.05 vs PBO. * P <0.001 vs placebo. >CID = Difference between BZA/CE and PBO exceeds CID, indicating clinically relevant benefit with BZA/CE vs PBO . Pinkerton et al. Obstet Gynecol. 2013. 121:959 ‐ 68 Lumbar Spine BMD Adjusted Mean % Change SMART 3: Vaginal Maturation Index (< 5 yrs LMP) SMART 3: Superficial cells SMART 3: Parabasal cells 2 10 * * Adjusted Mean % Change Placebo 80 Placebo 9 CE 0.45/BZA 20 1 * * * CE 0.45/BZA 20 CE 0.625/BZA 20 * % Superficial Cells 70 CE 0.625/BZA 20 * 8 BZA 20 BZA 20 0 * 7 60 * † * † -1 % Parabasal Cells 6 50 * † 5 * † -2 40 4 6 months 12 months 18 months 24 months -3 30 Months of Therapy 3 * † * † * † 20 * † 2 CE 0.625/BZA 20 (n=96) CE 0.45/BZA 20 (n=102) Placebo (n=99) Raloxifene (n=96) 1 10 BMD change relative to placebo: BMD change relative to placebo: P -value vs placebo ≤ 0.001 (all CE/BZA groups at 6, 12, 18 and 24 m) 0 0 P -value versus baseline ≤ 0.001 (all CE/BZA groups at 6, 12, 18 and 24 m) CE 0.625/BZA 20:  3.72% at 2 y CE 0.625/BZA 20:  3.72% at 2 y Screening Week 4 Week 12 Screening Week 4 Week 12 * P -value versus RAL ≤ 0.05 CE 0.45/BZA 20:  3.61% at 2 y CE 0.45/BZA 20:  3.61% at 2 y * P <0.05 vs. placebo; † P <0.05 vs. BZA alone. * P <0.05 vs. placebo; † P <0.05 vs. BZA alone. Lindsay et al. Fertil Steri. 2009;92:1045–1052 Kagan et al. Menopause. 2010;17: 281 ‐ 289 3

9/28/2016 The reality SMART Trials: Coagulation Parameters CE/BZA is a much better drug than is profiled in the FDA registered indications Decrease in antithrombin III and fibrinogen When: as with MHT, should be initiated within the window of opportunity No significant change in protein C activity How much: The only dose registered is CE 0.45/BZA 20mg Effect on fibrinolysis CE 0.625/BZA was superior in terms of treatment of GSM Small decreases from baseline in PAI-1 activity and PAI-1 antigen levels Small increases from baseline in plasminogen activity How long: Although duration of use is restricted to shortest possible time, we know that in terms of VMS this period may be long. Our real concern with long term MHT is breast safety. No effect on partial thromboplastin time, prothrombin time, or serum CE/BZA may be the best option concentrations of D-dimer We need more breast data (breast cancer endpoint) We need more safety data (VTE and stroke) 13 The registration Duavee is indicated in women with a uterus for: • Treatment of Moderate to Severe Vasomotor Symptoms Associated with Menopause • Prevention of Postmenopausal Osteoporosis Important Limitations of Use (as per PI) • Use Duavee for the shortest duration consistent with treatment goals and risks for the individual woman. Postmenopausal women should be re-evaluated periodically as clinically appropriate to determine if treatment is still necessary. • When prescribing solely for the prevention of postmenopausal osteoporosis, therapy should only be considered for women at significant risk of osteoporosis and non-estrogen medication should be carefully considered. 4