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

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NAMS Annual Meeting Orlando 2016

Tissue Selective Estrogen Complex

(conjugated estrogen/bazedoxifene)

past

3rd Wulf Utian Translational Science Symposium

A Conversation About Hormone Therapy: Is There an Appropriate Dose, Route, and Duration of Use?

The concept

• For menopausal women with a uterus in need of MHT
• A non-progestogenic compound to oppose the proliferative effect
• f 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

The compound

Pairing conjugated estrogens (CE) with the selective estrogen receptor modulator bazedoxifene (BZA) to achieve clinical results based on their blended tissue selective activity profile

The evidence

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The evidence: CE/BZA SMART trials

Randomized, double-blind, placebo (PBO)- and active-controlled Phase 3 studies in non-hysterectomized postmenopausal (PM) women

*VMS ‐ Vasomotor Symptoms **VVA ‐ Vulvar/Vaginal Atrophy

#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

Population Treatment Arms N# Duration Region SMART‐1 Generally Healthy PM BZA 10,20,40/ CE 0.45 BZA 10,20,40/ CE 0.625 Raloxifene 60 PBO 1,274 2 years US: 54% Europe: 12% Latin America: 34% SMART‐2 Moderate‐ Severe VMS* BZA 20/ CE 0.45 BZA 20/ CE 0.625 PBO 318 3 months US: 100% SMART‐3 Moderate‐ Severe VVA** BZA 20/ CE 0.45 BZA 20/ CE 0.625 BZA 20, PBO 542 3 months US: 100% SMART‐5 Subset with Bothersome Moderate‐ Severe VMS* BZA 20/ CE 0.45 BZA 20/ CE 0.625 CE 0.45/ MPA 1.5 BZA 20, PBO 346 1 year US: 78% Europe: 16% Latin America: 5% Asia Pacific: 1%

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Group Cases/n Year 1 Incidence Year 1 1-sided 95% UL Cases/n Year 2 Incidence Year 2 1-sided 95% UL

40/0.45 0/309 0.00 0.96 0/268 0.00 1.11 20/0.45 0/336 0.00 0.89 1/293 0.34 1.61 10/0.45 5/321 1.56 3.25 9/278 3.24 5.58 40/0.625 0/311 0.00 0.96 0/267 0.00 1.12 20/0.625 1/314 0.32 1.50 2/271 0.74 2.30 10/0.625 15/345 4.39 6.67 24/295 8.14 11.25 RAL 0/298 0.00 0.96 0/261 0.00 1.14 Placebo 0/312 0.00 1.00 0/260 0.00 1.15

SMART 1 (Study 303) Endometrial Hyperplasia Rate

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SMART 1 (Study 303): Percentage of Subjects with Cumulative Amenorrhea over 1 Year

10 20 30 40 50 60 70 80 90 100 1 2 3 4 5 6 7 8 9 10 11 12 13 4-Week Intervals % Subjects

10/0.625 20/0.625 40/0.625 10/0.45 20/0.45 40/0.45 Placebo Raloxifene BZA10/CE0.625 different from placebo at the 3 time points

SMART 2: Daily Number of Moderate to Severe Hot Flushes (LOCF)

CE 0.45/BZA20: Statistically different from placebo from week 3 onward CE 0.625/BZA20: Statistically different from placebo from week 2 onward

2 4 6 8 10 12 1 2 3 4 5 6 7 8 9 10 11 12 Mean Daily Number

• f Hot Flushes

Weeks

Placebo (n=63) CE 0.45/BZA 20 (n=123) CE 0.625/BZA 20 (n=122)  51%  74%  80% Pinkerton et al. Menopause. 2009;16:1116‐1124

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Adjusted Mean Change from baseline in Vasomotor Functioning SMART-5

‐4 ‐3.5 ‐3 ‐2.5 ‐2 ‐1.5 ‐1 ‐0.5 BZA 20 mg/ CE 0.45 mg BZA 20 mg/ CE 0.625 mg BZA 20 mg CE 0.45/ MPA 1.5mg PBO

3 Months 12 Months

**P<0.001 vs PBO. *P<0.05 vs PBO. >CID = Difference between BZA/CE and PBO exceeds CID, indicating clinically relevant benefit with BZA/CE vs PBO.

* * * * * * * * * * * *

Lumbar Spine BMD Adjusted Mean % Change (< 5 yrs LMP)

P-value vs placebo ≤ 0.001 (all CE/BZA groups at 6, 12, 18 and 24 m) P-value versus baseline ≤ 0.001 (all CE/BZA groups at 6, 12, 18 and 24 m) *P-value versus RAL ≤ 0.05

BMD change relative to placebo: CE 0.625/BZA 20:  3.72% at 2 y CE 0.45/BZA 20:  3.61% at 2 y BMD change relative to placebo: CE 0.625/BZA 20:  3.72% at 2 y CE 0.45/BZA 20:  3.61% at 2 y

* * * * * * * *

6 months 12 months 18 months 24 months

• 3
• 2
• 1

1 2 Adjusted Mean % Change Months of Therapy

CE 0.625/BZA 20 (n=96) CE 0.45/BZA 20 (n=102) Placebo (n=99) Raloxifene (n=96)

Lindsay et al. Fertil Steri. 2009;92:1045–1052

SMART 5 Adjusted Change From Baseline in Breast Density at year 1

†Includes all women enrolled in the breast density substudy who took at least 1 dose of study drug, had a

baseline breast density evaluation, and had at least 1 post-baseline evaluation.

*P <0.001 vs placebo.

–0.38 (0.22) –0.44 (0.22) –0.24 (0.30) 1.60* (0.35) –0.32 (0.23)

CE 0.45 mg/BZA 20 mg (n = 186) CE 0.625 mg/BZA 20 mg (n=191) BZA 20 mg (n=98) CE 0.45 mg/MPA 1.5 mg (n=68) Placebo (n=182)

Pinkerton et al. Obstet Gynecol. 2013. 121:959‐68

SMART 3: Vaginal Maturation Index

1 2 3 4 5 6 7 8 9 10 Screening Week 4 Week 12

% Superficial Cells Placebo CE 0.45/BZA 20 CE 0.625/BZA 20 BZA 20

*† *† *† *†

SMART 3: Superficial cells SMART 3: Parabasal cells

10 20 30 40 50 60 70 80 Screening Week 4 Week 12 % Parabasal Cells Placebo CE 0.45/BZA 20 CE 0.625/BZA 20 BZA 20

*†*† *† *†

*P<0.05 vs. placebo; †P<0.05 vs. BZA alone. *P<0.05 vs. placebo; †P<0.05 vs. BZA alone. Kagan et al. Menopause. 2010;17:281‐289

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SMART Trials: Coagulation Parameters

Decrease in antithrombin III and fibrinogen No significant change in protein C activity Effect on fibrinolysis Small decreases from baseline in PAI-1 activity and PAI-1 antigen levels Small increases from baseline in plasminogen activity No effect on partial thromboplastin time, prothrombin time, or serum concentrations of D-dimer

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
• steoporosis, therapy should only be considered for women at

significant risk of osteoporosis and non-estrogen medication should be carefully considered.

The reality

CE/BZA is a much better drug than is profiled in the FDA registered indications When: as with MHT, should be initiated within the window of

• pportunity

How much: The only dose registered is CE 0.45/BZA 20mg CE 0.625/BZA was superior in terms of treatment of GSM 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.

CE/BZA may be the best option We need more breast data (breast cancer endpoint) We need more safety data (VTE and stroke)