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Nuevos fármacos:

DenosumabAdolfo Díez PérezHospital del Mar -Institut Municipal

d’Investigacions Mèdiques

U BUniversitat Autònoma

de Barcelona

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Regulación del remodelamiento

Harada S and Rodan GA. Nature. 2003;423:349-55.

BMP LRP5/Wnt

Intermittent PTHβ-blockers

AndrogensMechanical

load

SOST β-adrenergic

LeptinImmobilisation

Ageing

Bone mass

Oestrogen deficiency Immobilisation

Oestrogen

SERMsBisphosphonates

Calcitonin

CalciumVitamin D

Low Ca (PTH)

Bone formation

Bone resorption

Novel EST Sequence Identified in a Rat Foetal Intestinal cDNA Library

Tissue Distribution of OPG• Human:

– lung, heart, placenta, kidney, osteoblasts

• Mouse:– Embryo: placenta, skin, major arteries,

gastrointestinal tract, bone, cartilage – Adult: lung, liver, kidney, brain, testis,

articular cartilage

Ribs

Mandible

Maxilla

Palate Skin

Major arteriesVertebraeAbdominalaorta

GI tract

La ausencia de actividad OPG causafracturas por fragilidad

Radiografía de un ratón de 1 mes de edad OPG knockout con fracturas espontáneas por fragilidad

RatRatóónnOPG OPG Knockout Knockout

Bucay N, et al. Genes Dev. 1998;12:1260-1268.

Efecto de los niveles de OPG en la regulación de la densidad ósea

Radiografías de fémur de ratón

Ratón knockout OPG: no producciónnatural de OPG

Ratón transgénicoOPG: producciónaumentada de OPG

Bolon B, et al. Arthritis Rheum. 2002;46:3121-3135.

Efecto de RANK y Ligando RANK en la regulación de la densidad mineral

Normal Ausencia deLigando RANK1

Ausencia deRANK2

Aumento de BMD

1 Kong YY et al. Nature 1999; 397: 315–323; 2 Li J et al. Proc Natl Acad Sci USA 2000; 97: 1566–1571

RANKL como mediador esencial de la formación, función y supervivencia del

osteoclastoPre-FusionOsteoclast

CFU-M

OsteoblastsActivated Osteoclast

MultinucleatedOsteoclast

HormonesGrowth factorsCytokines

RANKLRANKOPG

Bone Formation

Bone ResorptionAdapted from Boyle WJ, et al. Nature. 2003;423:337-342.

In the presence of M-CSFCFU-M=colony forming unit macrophageM-CSF=macrophage colony stimulating factor

Provided as an educational resource. Do not copy or distribute.© 2007 Amgen. All rights reserved.

Inhibición de OPG y estimulación de RANKL por glucocorticoides

hOB lineage cells

Hofbauer LC et al. Endocrinology 1999; 140: 4382–4389

Los estrógenos estimulan la expresión génica y producción protéica de OPG por hOB

Dose TimeDose

Time

OPG protein secretion by 17β-E2 in FOB/ER-9 cells

OPG nRNA levels by 17β-E2 in FOB/ER-9 cells

Hofbauer LC et al. Endocrinology 1999; 140: 4367-70

Boyle WJ et al. Nature 2003; 423: 337-42

Diferenciación de células precursoras hematopoyéticas a osteoclasto

RANKL como mediador esencial de la formación, función y supervivencia del

osteoclastoPre-FusionOsteoclast

CFU-M

OsteoblastsActivated Osteoclast

MultinucleatedOsteoclast


RANKLRANKOPG

Bone Formation

Bone ResorptionAdapted from Boyle WJ, et al. Nature. 2003;423:337-342.



Efecto de la OPG recombinante sobreOsteoclastos y Mineralización

Rapid but reversible reductions in OC.N. and increases in Bone Mineralization in Intact Rats

*Significantly different from vehicle, P < 0.05 OcS%BS = osteoclast surface

***

Osteoclast Surface in Proximal Tibia

rhOPG(5mg/kg)

Vehicle

***

0 3015 20 25105Time (Days After Treatment)

OcS

%B

S

6

8

4

0

12

2

10

von Kossa Staining of Proximal Tibia

Capparelli C, et al. J Bone Miner Res. 2003;18:852–858

Denosumab se une al Ligando RANK e Inhibe la Formación, Función y Supervivencia del Osteoclasto

RANKLRANKOPGDenosumab

Bone Formation


Bone ResorptionInhibited

Osteoclast Formation, Function, and Survival Inhibited

CFU-M Pre-FusionOsteoclast



Osteoblasts

Propiedades Farmacológicas de Denosumab

• Isotipo de inmunolobulinaIgG2

• Alta afinidad por el LigandoRANK humano

• Alta especificidad por el Ligando RANK

– No unión detectable a TNFα, TNFβ, TRAIL, or CD40L

• No se han detectadosanticuerpos neutralizantes

Denosumab

TNF = tumor necrosis factor; TRAIL = TNFα-related apoptosis-inducing Ligand.

Bekker PJ, et al. J Bone Miner Res. 2004;19:1059-1066. Elliott R, et al. Osteoporos Int.2007;18:S54. Abstract P149. McClung MR, et al. New Engl J Med. 2006;354:821-31.

Cambios en Hueso Cortical (Masa, Area y vBMD) en Monos OVX

Data: Mean ± SE*P< 0.05 vs. OVX-Veh^P< 0.05 vs. Sham-Veh

SHAM ControlOVX ControlOVX + 25 mg/kg DMABOVX + 50 mg/kg DMAB

Tibial Cortical AreaRadial Cortical Area

pQCT TibialDiaphysis

Ominsky et al. JBMR 2007 (Suppl 1) abstract 1082 Months of TreatmentMonths of Treatment

Tibial Cortical vBMDRadial Cortical vBMD

0 3 6 9 12 15

-3

-2

-1

0

1 *^*

Months of Treatment

% C

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asel

ine

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-8

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**^

* *

Months of Treatment

**

0 3 6 9 12 15-6-5-4-3-2-1012

**

**^^

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*******

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^

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Study Month

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101

102

103

104

Den

osum

abSe

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Con

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ratio

n (n

g/m

L)(M

ean ±

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)

Denosumab 0.01 mg/kg (n = 6)Denosumab 0.03 mg/kg (n = 6)Denosumab 0.1 mg/kg (n = 6)Denosumab 0.3 mg/kg (n = 6)Denosumab 1.0 mg/kg (n = 6)Denosumab 3.0 mg/kg (n = 6)

1 3 5 90 2 4 6

EC50

7 8

Denosumab Fase 1 en MujeresSanas Postmenopáusicas

Serum Levels of Denosumab

Dosis s.c. de 60 mg cada 6 meses

Bekker PJ, et al. J Bone Miner Res. 2004;19:1059-1066.

aP < 0.001 vs placebo

McClung MR, et al. N Engl J Med. 2006;354:821-831.

Time (Months)

a

Total Hip Distal 1/3 Radius

Denosumab 60 mg (N = 46)

Placebo (N = 46)Denosumab 14 mg (N = 53)

Open-label alendronate (N = 46)Denosumab 210 mg (N = 46)Denosumab 100 mg (N = 41)

Mea

n Pe

rcen

t Cha

nge

from

Bas

elin

e

Lumbar Spine

-2

-1

0

1

2

3

4

5

6

0 2 4 6 8 10 12-3 -3

-2

-1

0

1

2

3

0 2 4 6 8 10 12

4

5

6

a

-2

-1

0

1

2

3

4

0 2 4 6 8 10 12-3

5

6

a

Fase II Mujeres Postmenopáusicascon Baja DMO

Lumbar Spine Hip, and Distal 1/3 Radius BMD at 12 months

Efecto de 4 Años de Tratamientocon Denosumab en DMO Lumbar

Placebo 6 mg Q3M 14 mg Q3M 14 mg Q6M 100 mg Q6M60 mg Q6M

-4

-2

0

2

4

6

8

10

12

14

0 6 12 18 24 36 48

Per

cent

Cha

nge

(LS

Mea

n ±

SE

)

Months

Miller PD et al Bone 2008;doi:10.1016/j.bone.2008.04.007

Efecto de 4 Años de Tratamiento con Denosumab Sobre CTX y BSAP

Placebo 6 mg Q3M 14 mg Q3M 14 mg Q6M 100 mg Q6M60 mg Q6M

Bone-specific Alkaline Phosphatase

Med

ian

ng/m

L(Q

1, Q

3)

Med

ian µg

/L (Q

1, Q

3)

Serum C-telopeptide

0

0.2

0.4

0.6

0.8

1.0

0 6 12 18 24 30 36 42 480

4

8

12

16

20

0 6 12 18 24 30 36 42 48Months Months

Miller PD et al Bone 2008;doi:10.1016/j.bone.2008.04.007

CTX Sérico a los 5 Años con Denosumab

0.00.10.20.30.40.50.60.70.80.91.0

Seru

m C

TX (n

g/m

l)

BL 1 month 6 months 12 months 24 months 36 months 48 months 60 months

Each box-and-whisker plot shows the middle 80% of the observations (deleting the top and bottom 10% of the data). Horizontal lines represent the premenopausal range from the BONTURNO study Reference Range Study: 0.11 to 0.51 ng/mL for CTX )

Adami et al Calcif Tissue Int. 2008 May;82(5):341-7

Estudio fase III: FREEDOM





Cummings SR et al. N Engl J Med 2009; 361: 756-65

Efecto de Denosumab sobre el Riesgo de Fractura Vertebral




Risk Ratio0,32

(0,26-0,41)P<0,001

Efecto de Denosumab sobre el Riesgo de Fractura No-vertebral



Hazard Ratio0,80

(0,67-0,95)P=0,01


Efecto de Denosumab sobre el Riesgo de Fractura de Fémur



Hazard Ratio0,60

(0,37-0,97)P=0,04


Efecto sobre los Marcadores Bioquímicos de Remodelamiento


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CTx y BSAP tras Interrupción de Denosumab o Alendronato

*P < 0.001 at month 36 and = 0.05 at month 48 vs placebo†P = 0.008 at month 36 vs placebo

Miller P, et al. Bone 2008;43:222-9.

Discontinued Treatment

–100

–50

0

50

100

†

Discontinued Treatment

–100

–50

0

50

100*

Perc

ent C

hang

e(M

edia

n [Q

1, Q

3])

Time (months) Time (months)

Denosumab 210 mg Q6MOpen-label alendronate

0 12 24 36 48 0 12 24 36 48

Serum CTx BSAP

Reversibilidad del Efecto de Denosumab sobre el Remodelamiento

DiscontinuationStudy

FREEDOM study

STAND study

CTXDenosumab

treatment studiesDiscontinuation

biopsy study

Baseline Month 12 Noof study treatment

0.00.10.20.30.40.50.60.70.80.9

Seru

m C

TX le

vels

, med

ian

(IQR

)-

ng/m

L

Denosumab discontinued for 24 months

Brown J. et al. ASBMR 2010

Acontecimientos Adversos de Denosumab vs. Placebo



* NA denotes not applicable.P values are based on the log-rank test, except for between-group comparisons of deaths and cardiovascular events,

which were based on the Cox proportionalhazards model with adjustment for the baseline cardiovascular risk score.



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* NA denotes not applicable.P values are based on the log-rank test, except for between-group comparisons of deaths and cardiovascular events,

which were based on the Cox proportionalhazards model with adjustment for the baseline cardiovascular risk score.


Acontecimientos Adversos Graves de Denosumab vs. Placebo


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* NA denotes not applicable.P values log-rank test, except for between-group comparisons of deaths and cardiovascular events, which were based

on the Cox proportionalhazards model with adjustment for the baseline cardiovascular risk score. ‡P≤0.05 for the between-group comparison (MedDRA). ¶ Excludes falls that occurred on the same day as a fracture.§ P≤0.01 for the between-group comparison.


Acontecimientos Adversos Poco frecuentes (< 1-2%)

Descubrimiento y desarrollo de la VíaRANK/RANKL/OPG y Denosumab

RANKL = RANK ligandOPG = osteoprotegerinOPGL = OPG Ligand (OPG-binding molecule)

1. Anderson DM, et al. Nature. 1997;390:175-179.2. Simonet WS, et al. Cell. 1997;89:309-319.3. Lacey DL, et al. Cell. 1998;93:165-176.4. Yasuda H, et al. Proc Natl Acad Sci U S A.

1998;95:3597-3602.5. Kong Y, et al. Nature. 1999;397:315-323.6. Kong Y, et al. Nature. 1999;402:304-309.7. Burgess TL, et al. J Cell Biol. 1999;145:527-538.

8. Bekker PJ, et al. J Bone Miner Res. 2004;19:1059-1066.9. Available at: www.clinicaltrials.gov. Accessed June 16, 2008.10. McClung MR, et al. N Engl J Med. 2006;354:821-831.11. Miller PD, et al. Bone. 2008;43:222-229.12. Bone HG, et al. J Clin Endocrinol Metab. 2008;93(6):2149-2157.13. Brown JP, et al. J Bone Miner Res. 2009;24:153-161.14. Kendler DL, et al. [Published online ahead of print July 13,

2009]. J Bone Miner Res. doi:10.1359/JBMR.090716.15. Cummings SR, et al. N Engl J Med. 2009 Aug 20;361(8):756-65.

2009

OPG is disclosed in patent filings as an important regulator of bone density

1995 1997 1999 2000 2001OPG protein enters human testing

OPG-Fc and Fc-OPG enter human testing

First dose of denosumabadministered in human on June 30th

Additional approaches to inhibiting RANKL are explored in humans

Identification and cloning of RANK/ RANKL and OPG publishedin Natureand Cell 1,2

Publicationsof scientific findings in journals including Nature and Journal ofCell Biology 5-7

1998

A molecule that binds to OPG was identified and referred to as OPGL; found to be identical to RANKL; OPG recognized as a decoy receptor3,4

2004 2006First single-dose study of denosumabin post-menopausal women published in JBMR8

Phase 2 trial in post-menopausal women with low BMD published in NEJM10

Phase 3 trials with denosumabin post-menopausal women initiated9

2008Key denosumabclinical data published:

Ph 2 PMO 4-year data in Bone11

Ph 3 DEFENDtrial inJCEM12

DECIDE Ph 3 trial in JBMR13

Key denosumabclinical data published:

Ph 3 STAND in JBMR14

Ph 3 FREEDOM in NEJM15

Conclusiones• El tratamiento con Ac monoclonalesanti-RANKL (Denosumab) en inyecciónsubcutánea cada 6 meses, es un supresor de la resorción:

• Potente• Altamente selectivo• Reversible

Conclusiones

• Denosumab es eficaz en reducirlas fracturas:

• Vertebrales• No vertebrales• De fémur

• La posología es muy adecuada• El tratamiento es seguro

nuevos fármacos: denosumab - fesemi.org · nuevos fármacos: denosumab adolfo díez pérez...

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