Click here to load reader

Serge Rozenberg CHU St Pierre VUB-ULB Belgium serge ... · PDF fileSerge Rozenberg CHU St Pierre VUB-ULB Belgium ... Research funding IRIS- King Baudouin Fondation, Vesale research

  • View
    219

  • Download
    0

Embed Size (px)

Text of Serge Rozenberg CHU St Pierre VUB-ULB Belgium serge ... · PDF fileSerge Rozenberg CHU St...

  • In the center of the city, in the center of life, with passion for care

    Serge Rozenberg CHU St Pierre VUB-ULB Belgium

    [email protected]

    Clinical overview of conjugated

    estrogens/bazedoxifene (CE/BZA)

    BMS 14.11.2015

  • Conflict of interest & Disclosure

    Conflicts of interest: nil

    Disclosure SR

    Research funding IRIS- King Baudouin Fondation, Vesale research Foundation, Amgen, MSD

    Speakers bureau &/or Advisory Boards

    Abbot, Pfizer, Will, Gedeon Richter, MSD, Amgen

  • 1. Kagan R. J Womens Health (Larchmt). 2012;

    the OPTIMAL Menopausal Therapy

    should demonstrate1

    Favorable safety and tolerability profile

    Relief of menopausal symptoms

    Prevention of osteoporosis, CVD, Cognitive function

    No stimulation of the endometrium, breast and ovary

  • 1. Kagan R. J Womens Health (Larchmt). 2012;

    the OPTIMAL Menopausal Therapy

    should demonstrate1

    Favorable safety and tolerability profile

    Relief of menopausal symptoms

    Prevention of osteoporosis, CVD, Cognitive function

    No stimulation of the endometrium, breast and ovary

  • Variations in Associated Breast Cancer Risk Between CE alone and

    CE/MPA

    Cumulative hazards,

    adjusted for age and

    race/ethnicity, for

    invasive breast cancer

    by randomization

    assignment in the WHI

    CE-alone and CE/MPA

    trials

    Anderson GL, et al. Lancet

    Oncol. 2012;

    0 0

    1 2 3 4 5 6 7 8 9 10 11 12 13

    0.01

    0.02

    0.03

    0.04

    0.05

    Cu

    mu

    lati

    ve

    ha

    za

    rd

    Time since randomization (years)

    CE/MPA

    Placebo (in CE/MPA arm)

    HR 1.25 (95% CI 1.071.46)

    CE alone

    Placebo (in CE-alone arm)

    HR 0.77 (95% CI 0.620.95)

    CE/MPA

    CE alone

    Placebo (CE-alone)

    Placebo (CE/MPA)

  • Estrogen only therapy

  • Endometrial cancer

    Hysterectomy specimen showing cancer invading myometrium

    following unopposed estrogen therapy for 15 years

    Courtesy Dr David Sturdee

  • Bazedoxifene (BZA) specifically selected in

    combination with conjugated estrogens

    1. Crabtree J, et al. Mol Cell Endocrinol. 2008;

    2. Kharode Y, et al. Endocrinolology. 2008;

    3. Duavive SmPC

    Estrogen Receptor activity is dimmed

    Estrogen Receptor activity is turned on

    CEs are agonists BZA is an antagonist

    In the uterus

    The BZA component reduces the risk of endometrial hyperplasia that can occur with the conjugated estrogens component alone1-3.

    This means that progestins are not needed

  • From the Womens Health Initiative to the combination

    of estrogen and selective estrogen receptor

    modulators to avoid progestin addition

    Marie-Ccile Valera, Pierre Gourdy, Florence Trmollires, Jean-Franois Arnal

    Maturitas Volume 82, Issue 3, November 2015, Pages 274277

    http://www.sciencedirect.com.ezproxy.ulb.ac.be/science/article/pii/S0378512215300190http://www.sciencedirect.com.ezproxy.ulb.ac.be/science/article/pii/S0378512215300190http://www.sciencedirect.com.ezproxy.ulb.ac.be/science/article/pii/S0378512215300190http://www.sciencedirect.com.ezproxy.ulb.ac.be/science/article/pii/S0378512215300190http://www.sciencedirect.com.ezproxy.ulb.ac.be/science/article/pii/S0378512215300190http://www.sciencedirect.com.ezproxy.ulb.ac.be/science/article/pii/S0378512215300190http://www.sciencedirect.com.ezproxy.ulb.ac.be/science/article/pii/S0378512215300190http://www.sciencedirect.com.ezproxy.ulb.ac.be/science/article/pii/S0378512215300190http://www.sciencedirect.com.ezproxy.ulb.ac.be/science/article/pii/S0378512215300190http://www.sciencedirect.com.ezproxy.ulb.ac.be/science/article/pii/S0378512215300190http://www.sciencedirect.com.ezproxy.ulb.ac.be/science/article/pii/S0378512215300190http://www.sciencedirect.com.ezproxy.ulb.ac.be/science/journal/03785122http://www.sciencedirect.com.ezproxy.ulb.ac.be/science/journal/03785122http://www.sciencedirect.com.ezproxy.ulb.ac.be/science/journal/03785122/82/3

  • Other combinations of an estrogen (E2) + a SERM studied have not produced favorable results

    Objective: To compare effects of 52 weeks treatment with either raloxifene 60 mg/day alone (RLX) or in combination with 17B-estradiol 1 mg/day (RLX + E2) on vasomotor symptoms (n = 83) and endometrial safety (n = 123) in postmenopausal women who transitioned from estrogen-progestin therapy. Endometrial effect: Women in the RLX + E2 group had significantly increased endometrial thickness at 52 weeks from baseline and RLX alone had no increase. Two women (3,28%)* in the RLX + E2 group had endometrial hyperplasia (one with atypia) on the exit biopsy. No one in RLX alone did.

    1. Stovall D, et al. Menopause: The Journal of The North American Menopause Society. 2007;

    *For the safety analyses, data from women randomized before and after the protocol amendment were pooled, which included 62 women in the raloxifene group and 61 women in the raloxifene + estrogen group

  • EFFICACY:

    VASOMOTOR

    SYMPTOMS

    SMART-2

  • DUAVIVE Efficacy for the Treatment of Moderate to

    Severe VMS Associated With Menopause

    14

    1. Pinkerton JV, et al. Menopause. 2009;

    Postmenopausal women

    with a uterus

    Age 42-64 year

    (avg 53 yr)

    (N=318*)

    DUAVIVE (CE 0.45/BZA 20)

    (n=127)

    Placebo

    (n=63)

    12-week randomized, double-blind, placebo-controlled study1

    Inclusion criteria

    Postmenopausal women with an intact uterus

    Minimum of 7 moderate to severe hot flushes per day or at least 50 per week at screening

    Change from baseline to

    Weeks 4 and 12 in:

    Average daily number of

    moderate to severe hot

    flushes

    Average daily severity

    score of hot flushes

    Primary End Points

    *Safety population (took at least one dose)

  • Significant Reduction vs Placebo in

    Average Daily Number of Hot Flushes

    DUAVEE [package insert]. New York, NY: Pfizer Inc; 2013.

    ANCOVA=analysis of covariance.

    Reduction in average daily number of

    moderate to severe hot flushes primary end point

    Ad

    jus

    ted

    mean

    ch

    an

    ge

    fro

    m b

    aselin

    e

    Week 4 Week 12

    3.1

    2.7

    Treatment

    difference 5.9*

    2.8

    7.6*

    4.9

    Treatment

    difference

    22

    *P

  • Reduction in the Observed Average Daily Number

    of Moderate to Severe Hot Flushes

    Data on file. CSR-67461. Protocol 3115A1-305. Table 15.11. Pfizer Inc; New York, NY.

    % change from baseline to week 12*

    74% for DUAVIVE

    51% for placebo

    Observed Average Daily Number of Hot Flushes*

    Ob

    serv

    ed a

    vera

    ge d

    aily

    nu

    mb

    er o

    f m

    od

    erat

    e to

    sev

    ere

    ho

    t fl

    ush

    es

    0 1 2 3 4 5 6 7 8 9 10 12 0 1

    11

    2

    4 3

    6 5

    7 8 9

    10

    2.8

    5.4

    DUAVIVE (n=122) Placebo (n=62)

    Weeks

    Primary analysis showed statistically significant separation at weeks 4 and 12

    Average daily number of hot flushes from baseline to week 12*

    10.3 to 2.8 for DUAVIVE

    10.5 to 5.4 for placebo

    *Based on mathematical means;

    not statistically analyzed.

    10.5 10.3

    Pinkerton JV, et al. Menopause. 2009;

  • Significant Reduction vs Placebo in

    Average Daily Severity Score of Hot Flushes

    17

    Week 4 Week 12

    0.5

    0.6 Treatment

    difference

    Treatment

    difference

    DUAVEE [package insert]. New York, NY: Pfizer Inc; 2013.

    Reduction in average daily severity score of hot flushes primary end point

    Ad

    jus

    ted

    me

    an

    ch

    an

    ge

    fro

    m b

    aselin

    e

    *P

  • Reduction in the Observed Average

    Daily Severity Score of Hot Flushes

    Observed Average Daily Severity Score of Hot Flushes*

    1.9

    DUAVIVE (n=122) Placebo (n=62)

    Weeks

    Ob

    serv

    ed a

    vera

    ge d

    aily

    sev

    erit

    y sc

    ore

    of

    ho

    t fl

    ush

    es

    0

    0.5

    1.0

    1.5

    2.5

    2.0

    0 1 2 3 4 5 6 7 8 9 10 12 11 0 1 2 3 4 5 6 7 8 9 10 12 11

    1.4

    Data on file. CSR-67461. Protocol 3115A1-305. Table 15.11. Pfizer Inc; New York, NY.

    Primary analysis at weeks 4 and 12; prespecified secondary end points at all other weeks

    % change from baseline to week 12*

    39% for DUAVIVE

    14% for placebo

    Average daily severity score of hot flashes from baseline to week 12*

    2.3 to 1.4 for DUAVIVE

    2.3 to 1.9 for Placebo

    *Based on mathematical means;

    not statistically analyzed.

    2.3

    2.3

    Pinkerton JV, et al. Menopause. 2009;

  • Effects on bone mineral density (BMD)

    SMART 51,2

    20

    12-month, double-blind, randomized, placebo- and active-controlled study

    Primary end point: endometrial hyperplasia at 1 year

    Secondary: BMD changes at 1 year

    1. DUAVEE [package insert]. New York, NY: Pfizer Inc; 2013; 2. Pinkerton J Clin Endocrin Metab 2014

    *This study included a different dose of CE/BZA and comparators. The schematic shown he