bazedoxifeno. nuevo serm en el manejo de la osteoporosis · 2016. 9. 13. · bazedoxifeno. nuevo...

BAZEDOXIFENO. NUEVO SERM EN EL MANEJO DE LA

OSTEOPOROSIS

Dr. Santiago PalaciosPalacios 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, 9 - 28009 MadridPhone: +34 91 578 05 17

E-mail: [email protected]

mailto:[email protected]

Diapositivas / Slides

www.institutopalacios.com

• HISTORIA DE LOS SERMs• CLASIFICACIÓN DE LOS SERMs• LOS SERMs A SUPERAR• NUEVOS SERMs• SERMs COMBINADOS• CONCEPTO SECUENCIAL

Contenido

Months

% Cha

nge in Spina

l BMD

From

Bas

eline

Baseline 3 6 12 18 24

‐3

‐2

‐1

0

1

2

3 Placebo

Tamoxifen

Tamoxifen Functions as an Estrogenin Some Environments

Love RR, et al. N Engl J Med. 1992;326:852-856. 5

Evolution of SERM Development1,2

1. Komm BS, et al. Ann N Y Acad Sci. 2001;949:317-326. 2. Hall JM, McDonnell DP. Menopausal Med. 2008;16:S1,S3-S6.

N O

HO S

O ON

OH

N

O

HO

HO

O

N

OH

N

BazedoxifeneLasofoxifene

RaloxifeneTamoxifen

1st generation

Tamoxifen 2nd generation

Raloxifene 3rd generation

Lasofoxifene Bazedoxifene

1971 20091997


Contenido

SELECTIVIDAD OSEA DE LOS SERMS, SEGUN ESTUDIOS IN

VITRO

1. Sato M, et al. FASEB J. 1996;10:905-912. 2. Komm BS, et al. Endocrinology. 2005;146:3999-4008. 3. Kharode Y, et al. Endocrinology. 2008;149:6084-6091. 4. Komm BS, et al. Ann N Y Acad Sci. 2001;949:317-326. 5. Armamento-Villareal R, et al. J Bone Miner Res. 2005;20:2178-2188.

Antagonist AgonistLossof BMD

Maintenanceof BMD

Reference estrogens1‐3

Raloxifene1,2,4,5

Tamoxifen1Lasofoxifene5

Bazedoxifene2‐4

Bazedoxifene Does Not Exhibit Uterotrophic Activity in Rodents

Mea

n Uterine W

et W

eigh

t ±SE (m

g)

Treatment

0Vehicle

10

20

30

40

50

60

70

80

E2 CE BZA RAL LAS

a

b

c

ae

f

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):1897-1903. Copyright 2009, The Endocrine Society. 9

Groups labeled with the same letter are statistically similar (P>0.05).

SELECTIVIDAD ENDOMETRIAL DE LOS SERMS

1. Komm BS, et al. Ann N Y Acad Sci. 2001;949:317-326. 2. Komm BS, et al. Endocrinology. 2005;146:3999-4008. 3. Crabtree JS, et al. Mol Cell Endocrinol. 2008;287:40-46. 4. Peano BJ, et al. Endocrinology. 2009;150:1897-1903. 5. Qu Q, et al. Endocrinology.2000;141:809-820. 6. Stygar D, et al. Reprod Biol Endocrinol. 2003;1:40. 7. Carthew P, et al. Toxicol Sci. 1999;48:197-205.

Tamoxifen6,7Raloxifene1‐6

Antagonist AgonistDoes notincrease

uterine wet weight

Increases uterine wet weight

Reference estrogens5‐7

Lasofoxifene1,3,4Bazedoxifene1‐4

‐4.0

‐3.0

‐2.0

‐1.0

0

1.0

2.0

3.0

4.0

5.0

a

b b

a

cc

Bazedoxifene: Effects on Ductal Invasionin the Mouse Mammary Gland

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):1897-1903. Copyright 2009, The Endocrine Society.

Treatment

Mea

n Duc

talInv

asion ±SE (m

m)

Vehicle E2 CE BZA RAL LAS

11

PROLIFERACIÓN DE CELULAS DE CANCER MAMARIO DE LOS

SERMS

121. Komm BS, et al. Ann N Y Acad Sci. 2001;949:317-326. 2. Komm BS, et al. Endocrinology. 2005;146:3999-4008. 3. Chang KCN, et al. J Steroid Biochem Mol Biol. 2010;118:117-124. 4. Nuttall ME, et al. Am J Physiol Cell Physiol. 2000;279:C1550-C1557.

Antagonist AgonistInhibitsbreast

cancer cell proliferation

Tamoxifen4

Stimulatesbreast

cancer cell proliferation

Raloxifene3,4Reference estrogens1‐4

Lasofoxifene3

Bazedoxifene1‐3

SERMs Are a New Class of ER Modulators Whose Relative Agonist/Antagonist Activities

Differ Between Tissues

Estradiol

Tamoxifen

Raloxifene

Lasofoxifene1

Bazedoxifene

+ +

+

-

-

-

+ +

-

-

-

-

+ +

+

+

+

+

+ +

-

-

-

-

Bone Uterus Brain Breast(vaso)

131. Cummings SR et al, N Engl J Med. 2010; 362:686-696.


Contenido

SERM 1ª GENERACIÓNTAMOXIFENO

Prevención y tto. delcáncer de mama

SERM 2ª GENERACIÓNRALOXIFENO

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


Contenido

New SERMs

Ospemifene Vaginal atrophy 2011

Arzoxifene Breast and osteoporosis submission withdrawn

Lasofoxifene Osteo fract prev (EMEA) 2010

Bazedoxifene Osteo fract prev (EMEA) 2010

Bazedoxifene + premarin Climacteric symptoms 2011

Ospemifene: Drug Summary Box

Lasofoxifene

Chemical structure available at: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?sid=789595.1. McClung MR, et al. Menopause. 2006;13:377.

Climactericsymptoms

Undefined

Bone ↑↑ BMD1

Breast ↓↓ Risk

Endometrium Undefined

CV ↓↓ LDL1

1997 1998 1999 2000 2001 2002 2003 2004 2005 2006

Phase 1

Phase 2

Phase 3

Lasofoxifene Osteoporosis Clinical Program

3 yr

PK/PD Bioequivalence Metabolism Special Populations Drug Interactions

raloxifene

placebo

prevention

prevention

treatment

OPAL

PEARL

N=814

N=321

N=410

N=394

N=1894

N=8556

2 yr

1 yr

1 yr

2 yr

E/P

2010

CORAL

N Engl J Med 2010;362:690

Lasofoxifene: Mayor Outcomes at 5 years

COMPOSICIÓN Y QUÍMICA

• INDOL CON DOS ANILLOS FENILOS• AFINIDAD A REα > REβ

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

23

Phase 1• 18 studies

• Single dose up to 120 mg•Multiple doses up to 80 mg

Phase 2• 3068A1‐200‐BR (6 months)

• 3068A1‐204‐US/CA (3 months)• 3068A1‐205‐CN (3 months)

Prevention Study: 24 months

Treatment Study: 36 months; extended to 5 years; then extended to 7 years

Phase 3: >10,000 patients

1,874 postmenopausal women

Osteoporosis Prevention Study: Design

– 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

24

Pivotal, 2‐year, phase 3, multicenter, double‐blind, randomized, placebo‐ and active‐controlled study

LS = lumbar spine; FN = femoral neck.DOF Protocol 3068A1-300/ Miller PD, et al. J Bone Miner Res. 2008;23:525-535.

Bazedoxifene 20 mg Raloxifene 60 mg Placebo

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;23:525-535. 25

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;23:525-535. 26

Osteoporosis Treatment Study: Design

• 206 sites in Asia-Pacific countries, Canada, Europe, Latin America, South Africa, and the United States

Silverman SL, et al. J Bone Miner Res. 2008;23:1923-1934. 27

Calcium 1,000‐1,200 mg and Vitamin D 400‐800 IU daily

Bazedoxifene 20 mg Raloxifene 60 mg Placebo

Pivotal, 3‐year, phase 3, multicenter, double‐blind, randomized,placebo‐ and active‐controlled study (n=7490)

Bazedoxifene Reduced New Vertebral Fractures

• Bazedoxifene also maintained BMD at the lumbar spine after 3 years of treatment (P<0.001)

28

*P<0.05 vs. placebo. RRR = relative risk reduction; HR = hazard ratio; CI = confidence interval.

Silverman SL, et al. J Bone Miner Res. 2008;23:1923-1934.

2.3 2.6

4.14.8

0

1

2

3

4

5

All Subjects Subjects With Previous Fracture

Inci

denc

e of

Fra

ctur

e (%

)

Bazedoxifene 20 mg Placebo

RRR in newvertebralfractures


HR=0.58; 95% CI, 0.38-0.89* HR=0.55; 95% CI, 0.32-0.94*

Reduction in New Vertebral Fractures: 3‐Year Data1,2

42%* 45%*

Bazedoxifene Reduced Nonvertebral Fractures in Women With High Fracture Risk

Raloxifene 60 mg

4.9 4.9

9.1 8.4

0

2

4

6

8

10

Raloxifene60 mg

Bazedoxifene20 mg

Placebo Bazedoxifene20 mg

RRR in nonvertebral

fractures

RRR innonvertebral

fractures


Kap

lan-

Mei

er

Frac

ture

Rat

e (%

)

Reduction in Nonvertebral Fracture: 3‐Year Data1,2

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;23:1923-1934. 2. Data on file. Wyeth Pharmaceuticals Inc.

HR=0.50; 95% CI, 0.28-0.90* HR=0.56; 95% CI, 0.31-0.1.01†

29

50%* 44%†

Osteoporosis Treatment Study: 5-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.

BZA 20 mg BZA 40/20 mgAfter 4 years

Placebo

5‐year extension for efficacy and safety (n=4,216)

30

Extended for 2 additional years – 7‐year extension

4.55.7

6.88

0

2

4

6

8

10

All Subjects Subjects With Previous FractureInci

denc

e of

Fra

ctur

e (%

)

*P=0.014 vs. placebo.

Data on file. Pfizer Inc.

Bazedoxifene: Effects on New Vertebral Fractures

• Bazedoxifene also maintained BMD at the lumbar spine after 5 years of treatment (P=0.01)




Reduction in New Vertebral Fractures: 5‐Year Data

31

35%*33%

Bazedoxifene: Reduction in NonvertebralFractures in High-Risk Women: 5-Year Data1,2

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;23:1923-1934. 2. Brown JP. J Rheumatol. 2009 36(11):2566.

5.2

7.6

9.19.1

11.612.7

0

2

4

6

8

10

12

3 Years

RRR in nonvertebral

fractures

RRR innonvertebral

fractures

Bazedoxifene 20 mg (n=443) Placebo (n=448)

Kap

lan-

Mei

er

Frac

ture

Rat

e (%

)

RRR innonvertebral

fractures

4 Years 5 Years

HR=0.53; 95% CI, 0.30-0.95* HR=0.58; 95% CI, 0.35-0.98* HR=0.63; 95% CI, 0.38-1.03

32

47%*

42%*37%

SAFETY AND TOLERABILITY OF BAZEDOXIFENE IN TWO PHASE III

CLINICAL TRIALS

Palacios S. Curr Med Res Opin. 2010 Apr 30

Bazedoxifene: Effects on Endometrial Thickness

*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;11:130. 2. Silverman SL, et al. J Bone Miner Res. 2008;23:1923-1934.

-0.3-0.2-0.1

00.10.20.3

BZA 20 mg RAL 60 mg Placebo

Endometrial carcinoma at year 3 n=0 n=3

Mea

n C

hang

e in

Endo

met

rial T

hick

ness

(m

m)

n=2

Change in Endometrial Thickness After 2 Years1*

34

Bazedoxifene: Effects on Mammographic Breast Density

-1.5

-1.2

-0.9

-0.6

-0.3

E-16

0.3

BZA 20 mg RAL 60 mg Placebo

Mea

n C

hang

e in

M

amm

ogra

phic

Bre

ast

Den

sity

(%)

(n=92) (n=119) (n=125)

Change in Mammographic Breast Density

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;16:1193-1196. 35


Contenido

RAL BZA/CECEVehicle BZA E2RAL/CELAS LAS/CE

Gene Expression Profiles of SERMs and SERM/CE Combinations in Rat Uterus (Heirarchical Clustering)

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

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


Contenido

bazedoxifeno. nuevo serm en el manejo de la osteoporosis · 2016. 9. 13. · bazedoxifeno. nuevo...

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