Il sistema RANK/RANKL/OPG come nuovo bersaglio terapeutico ... · The RANKL/RANK/OPG Pathway is an...

G.C. Isaia G.C. Isaia

Firenze 03 Dicembre 2010 Firenze 03 Dicembre 2010

AZIENDA OSPEDALIEROAZIENDA OSPEDALIERO--UNIVERSITARIA SAN GIOVANNI BATTISTA DI TORINOUNIVERSITARIA SAN GIOVANNI BATTISTA DI TORINODIPARTIMENTO DI DISCIPLINE MEDICODIPARTIMENTO DI DISCIPLINE MEDICO--CHIRURGICHECHIRURGICHES.C. GERIATRIA E MALATTIE METABOLICHE DELLS.C. GERIATRIA E MALATTIE METABOLICHE DELL’’OSSO OSSO Centro di Riferimento Regionale per le Malattie Metaboliche dellCentro di Riferimento Regionale per le Malattie Metaboliche dell’’ossoosso

Il sistema RANK/RANKL/OPG come nuovo bersaglio terapeutico nell’Osteoporosi

Il sistema RANK/RANKL/OPG come nuovo bersaglio terapeutico nell’Osteoporosi

Compromised bone strength predispose persons to increased risk of fractureBone strength reflects the integration of bone density and bone quality

Boyle WJ, et al. Nature 2003;423: 337-342;NIH Consensus Development Panel. JAMA. 2001;285: 785-795.

Normal

“Osteoporosis is one of the most common and debilitating chronic diseases, and a global healthcare problem.”

International Osteoporosis FoundationOsteoporosis

“Osteoporosis has financial, physical, and psychosocial consequences, all of which significantly affect the individual, the

family, and the community.”NIH Consensus Statement

Definition of osteoporosis

Osteoporosis Affects Over Osteoporosis Affects Over 200 Million People Worldwide200 Million People Worldwide11

30% of all postmenopausal women have osteoporosis1

The major complication of osteoporosis is hip fracture1

Lifetime risk for hip, vertebral, and wrist fractures, estimated at 40%, is similar to risk of coronary heart disease2

1. Reginster J-Y and Burlet N. Bone. 2006;38:S4-S9; 2. WHO Scientific Group. WHO Technical Report Series: 921. 2003:1; National Osteoporosis Foundation. Available at: www.iofbonehealth.org/facts-and-statistics. 3. Gullberg B, et al. Osteoporos Int 1997;7:407-413.

Increasing worldwide prevalence of hip fracture3

0100020003000

2000 2025 2050

Men Women

Proj

ecte

d nb

hip

frac

ture

s (w

orld

wid

e by

yea

r, x

1000

)

Osteoporotic fractures in ItalyOsteoporotic fractures in Italy

Rossini et al “Incidenza e costi delle fratture di femore in Italia”: Reumatismo, 2005Piscitelli et al “ Hip fractures in Italy: 2000-2005 extension study” Osteoporosis Int 2009

Nel 2002 • 80.800 fratture di femorenegli anziani over 65

il 79% di queste fratture si verifica nella popolazione femminile

467.500.000

Osteoporotic fractures in ItalyOsteoporotic fractures in Italy

Rossini et al “Incidenza e costi delle fratture di femore in Italia”: Reumatismo, 2005Piscitelli et al “ Hip fractures in Italy: 2000-2005 extension study” Osteoporosis Int 2009

Nel 2002 • 80.800 fratture di femorenegli anziani over 65

il 79% di queste fratture si verifica nella popolazione femminile

Nel 2005• incremento a 94.471 fratture di femore

467.500.000

Excessive Remodelling Contributes Excessive Remodelling Contributes to Osteoporosisto Osteoporosis

Increased fracture risk


Increased bone remodelling




Structural deterioration




Structural deterioration

Increased skeletal fragility


The RANKL/RANK/OPG Pathway is an Essential The RANKL/RANK/OPG Pathway is an Essential Mediator of Osteoclast Formation, Function and Mediator of Osteoclast Formation, Function and

SurvivalSurvival

Kostenuik PJ. Curr Opin Pharmacol 2005;5:618-625; Boyle WJ, et al. Nature 2003;423:337-342;Kostenuik PJ, et al. Curr Pharm Des 2001;7:613-635.


SurvivalSurvival


RANK Ligand (RANKL)– Signalling protein expressed by osteoblasts/bone lining cells– Binds to RANK and promotes osteoclast formation, function

and survival


SurvivalSurvival



and survival

RANK– Expressed by osteoclasts and their precursors– Activated by RANK Ligand binding


SurvivalSurvival



and survival

RANK– Expressed by osteoclasts and their precursors– Activated by RANK Ligand binding

Osteoprotegerin (OPG)– Protein secreted by osteoblasts/bone lining cells – Natural inhibitor of RANK Ligand– Blocks RANK Ligand signalling to balance bone remodelling

Boyle WJ, et al. Nature 2003;423:337-342. Kostenuik PJ, et al. Curr Pharm Des. 2001;7:613-635.

RANK Ligand

RANK

Osteoblasts

The RANKL/RANK/OPG Pathway Is The RANKL/RANK/OPG Pathway Is Involved in Regulating Bone RemodellingInvolved in Regulating Bone Remodelling

RANK Ligand

OsteoclastPrecursors

RANK

DifferentiatedOsteoclast

RANK

Activated Osteoclast

d st

Osteoblasts

RANK Ligand is a Key Mediator of Bone Resorption

orsNK

OPG: osteoprotegerinBoyle WJ, et al. Nature 2003;423:337-342. Kostenuik PJ, et al. Curr Pharm Des 2001;7:613-635.

RANK Ligand

RANK

OPG

Osteoblasts

OPG is the Natural Endogenous OPG is the Natural Endogenous Inhibitor of RANK LigandInhibitor of RANK Ligand

RANK LigandOPG

OPG Binds to RANK LigandOestrogen


RANK


RANK

Activated OsteoclastOsteoclast

Osteoblasts

Bone Resorption and Formation are Balanced in Premenopausal Women

OPG: osteoprotegerinBoyle WJ, et al. Nature 2003;423:337-342. Kostenuik PJ, et al. Curr Pharm Des 2001;7:613-635.

RANK Ligand

RANK

OPG

Osteoblasts

OPG is the Natural Endogenous OPG is the Natural Endogenous Inhibitor of RANK LigandInhibitor of RANK Ligand

Oestrogen Limits the

Expression of RANK Ligand

RANK LigandOPG

OPG Binds to RANK LigandOestrogen


RANK


RANK

Activated OsteoclastOsteoclast

Osteoblasts

Bone Resorption and Formation are Balanced in Premenopausal Women

Role of OPG in the Regulation of Role of OPG in the Regulation of Bone Mineral Density in miceBone Mineral Density in mice

Bolon B, et al. Arthritis Rheum. 2002; 46: 3121-3135. Reprinted with permission of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc.

X

Increased BMDDecreased BMDNo BMD Change

Normal OPG absent OPG excess

RANK Ligand

RANK

OPG

Osteoblasts

Reduction in Oestrogen Increases RANK Reduction in Oestrogen Increases RANK Ligand Expression, Causing Increased Bone Ligand Expression, Causing Increased Bone

ResorptionResorption

OPG: osteoprotegerinBoyle WJ, et al. Nature 2003;423:337-342. Eghbali-Fatourechi G, et al. J Clin Invest 2003;111:1221-1230.

Decreased Oestrogen

Decreased Oestrogen Increases

RANK Ligand Expression

Excess RANK Ligand

Expression Overwhelms

OPG

RANK LigandOPG


RANK

DifferentiatedOsteoclasts RANK

Activated OsteoclastsOverwhelms

OPG

al. J Clin Invest 2003;111:1221-1230.

sOsteoblastsExpression

Overwhelms OPG

al. J Clin Invest 2003;111:1221-1230.

Imbalanced Resorption and Formation

Increased RANK Ligand in Postmenopausal Women Leads to

Excessive Bone Resorption

RANK Ligand is an Essential Mediator for Osteoclast Formation, Function and

Survival

Unopposed RANK Ligand Activity Unopposed RANK Ligand Activity Causes Long Bone Fragility FracturesCauses Long Bone Fragility Fractures

Radiograph of 1-month-old OPG knockout mouse with spontaneous fragility fractures

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

X

Increased RANK Ligand/OPG Increased RANK Ligand/OPG Ratio Promotes Bone LossRatio Promotes Bone Loss

Alterations of the RANK Ligand/OPG ratio are critical in the pathogenesis of bone diseases that result from increased bone resorption

RANK LigandOPG

PreventsOsteoclast Activation

Promotes Osteoclast Activation

Osteoclast Activity

Hofbauer L et al. JAMA 2004; 292: 490-495; Lacey D et al. Cell 1998; 93: 165-176; Boyle W et al. Nature 2003; 423: 337-342

Pharmacologic PropertiesPharmacologic Properties

IgG2 immunoglobulin isotypeHigh affinity for human RANK LigandHigh specificity for RANK Ligand– No detectable binding to

TNFα, TNFβ, TRAIL, or CD40L

No neutralizing antibodies detected in clinical trials to dateEffects on bone resorption appear reversible

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

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

Denosumab is the First Fully Human Denosumab is the First Fully Human Monoclonal Antibody Targeting RANK Ligand Monoclonal Antibody Targeting RANK Ligand

in Clinical Developmentin Clinical Development

Fully human monoclonal antibody

Pharmacokinetic Properties Pharmacokinetic Properties of Denosumabof Denosumab

Administered via an SC injectionSignificant reduction in bone turnover markers within 12 to 72 hours and sustained for up to 6 monthsMean half-life approximates 30 days with 1 mg/kg or 60 mg SC dosingAn every-6-month dosing schedule is being evaluated for denosumab

Bekker PJ, et al. J Bone Miner Res. 2004;19:1059.Jang G, et al. J Bone Miner Res. 2006;21(suppl 1):S190. Abstract SA403 and poster.McClung MR, et al. N Engl J Med. 2006;23:821-831.Peterson MC, et al. J Bone Miner Res. 2005;20(suppl 1):S293. Abstract SU446 and poster.

Denosumab Binds RANK Ligand and Inhibits Denosumab Binds RANK Ligand and Inhibits Osteoclast Formation, Function, and SurvivalOsteoclast Formation, Function, and Survival

RANKL

RANK

OPG

Denosumab

Bone Formation

CFU-M Pre-fusionOsteoclast

Osteoblasts

HormonesGrowth FactorsCytokines

OsteoclastFunction and Survival

Inhibited

OsteoclastFormation Inhibited

CFU-GM = colony forming unit granulocyte-macrophage; M-CSF = macrophage colony stimulating factor. Boyle WJ, et al. Nature 2003;423:337-342.

Bone Resorption

Phase 1Phase 1SingleSingle--Dose Study of Denosumab in Healthy Dose Study of Denosumab in Healthy

Postmenopausal Women: Changes in Bone Resorption Postmenopausal Women: Changes in Bone Resorption Measured by NTxMeasured by NTx

NTx = N-telopeptide; uNTx = urinary NTx.

Placebo (n = 12)Denosumab 0.3 mg/kg (n = 6)Denosumab 1.0 mg/kg (n = 6)Denosumab 3.0 mg/kg (n = 7)

0

–50

50

–100 1 3 5 90 2 4 6 7 8

Perc

ent C

hang

e uN

Tx/C

reat

inin

e(M

ean

+ SE

)

Study Month

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

Phase 2 Phase 2 Serum Denosumab Concentrations and PercentSerum Denosumab Concentrations and Percent

Change From Baseline for Serum CTxChange From Baseline for Serum CTx

Jang G, et al. J Bone Miner Res. 2006;21(suppl 1):S190.Peterson MC, et al. J Bone Miner Res. 2005;20(suppl 1):S293.

Postmenopausal women with low BMD (N = 41–47; phase 2 study)

Months

0 1 2 3 4 5 6

Seru

m D

enos

umab

Con

cent

ratio

n ( n

g/m

L)

0

2,000

4,000

6,000

8,000

10,000

12,000 Percent Change in Serum

CTx

From B

aseline

–100

–80

–60

–40

–20

0

Denosumab Serum CTx

Rapid absorption of denosumab and suppression of serum CTx (by 3 days)

Phase 3 The FREEDOM Trial

Cummings SR, et al. N Engl J Med. 2009;361:756-765

Placebon = 3,935

Denosumab 60 mg SC Q6Mn = 3,933

SCREENING

Day 1Visit

Study Month

END

OF

TREATMENT

362461Study Visit(month)

Study population7,808 Postmenopausal womenT-score < –2.5 at the lumbar spine or total hip and not < –4.0 at either siteExclusion any severe or > 2 moderate vertebral fractures

Primary endpointNew vertebral fracture* over 36 months

Secondary endpointsTime to first nonvertebral fractureTime to first hip fracture

Calcium and Vitamin D

International, placebo-controlled study

RANDOMIZATION

12

* Defined as an increase of at least one grade in a vertebral body that was normal at baselineSC = subcutaneous; Q6M = once every 6 months Cummings SR, et al. N Engl J Med. 2009;361:756-765


Study Design

Intent-to-treat, last observation carried forward analysis*P < 0.001 for denosumab vs placebo† denosumab group relative increase in BMD vs placebo at month 36

Denosumab 60 mg Q6MPlacebo

Lumbar Spine

Study Months

−2

0

2

4

6

8

10

12

0 6 12 24 36

**

**

*

Perc

ent C

hang

e in

BM

D

Total Hip

Study Months

36−2

0

2

4

6

8

10

12

0 6 12 24

***

**

Perc

ent C

hang

e in

BM

D

9.2%

6.0%

†

†



% Change in BMD over 36 Months

*P < 0.001 for denosumab vs placebo† denosumab group relative decrease vs placebo at month 36CTx-1 = type 1 C-telopeptide; P1NP = intact N-terminal propeptide of type I procollagen

Serum CTx-1 P1NPDenosumab 60 mg Q6MPlacebo

** *

* *

80

6040200

-20

-40-60-80

-100

Study Month

Med

ian

Perc

ent C

hang

e

0 6 12 24 36

Med

ian

Perc

ent C

hang

e

80

6040200

-20

-40-60-80

-100

Study Month0 6 12 24 36

**

**

*72%†

76%†



% Change in BTM over 36 Months (160 Pts)

PlaceboDenosumab

40%P = 0.04

20%P = 0.0168%

P < 0.001



Fracture Risk at 36 Months

Intent-to-treat, last observation carried forward analysisThe percentage of new vertebral fractures was calculated using the number of patients with a baseline and at least one post-baseline spine x-ray evaluation.

65%P < 0.001

78%P < 0.001

61%P < 0.001

PlaceboDenosumab



New Vertebral fractures at Month 12, 24 & 36t Month 12, 24 & 36

Nonvertebral fractures were reduced by 20% (95% CI: 0.67, 0.95)*P = 0.01

Placebo, n 3,906 3,750 3,578 3,410 3,264 3,121 3,009

Denosumab, n 3,902 3,759 3,594 3,453 3,337 3,228 3,130

Number of patients at risk

Placebo

Denosumab 60 mg Q6M

Cum

ulat

ive

Inci

denc

e (%

)

Month0 6 12 24

02468

18 30 36

6.5%*8.0% 20%

†

†



First Non VF Through 36 Months

*P = 0.04

Placebo, n 3,906 3,799 3,672 3,538 3,430 3,311 3,221

Denosumab, n 3,902 3,796 3,676 3,566 3,477 3,397 3,311

Hip fractures were reduced by 40% (95% CI: 0.37, 0.97)

Number of patients at risk

Cum

ulat

ive

Inci

denc

e (%

)

Month0 6 12 24

0.018 30 36

0.4

0.8

1.2

0.7%*

1.2%Placebo

Denosumab 60 mg Q6M

40%†

†



First new Hip Fracture Through 36 Months

Adverse events, n (%) Placebo(n = 3,876)

Denosumab 60 mg Q6M(n = 3,886)

P value

All adverse events 3,607 (93.1) 3,605 (92.8) 0.91Serious adverse events 972 (25.1) 1,004 (25.8) 0.61Deaths 90 (2.3) 70 (1.8) 0.08AEs leading to study discontinuation 81 (2.1) 93 (2.4) 0.39AEs leading to discontinuing the study drug 202 (5.2) 192 (4.9) 0.55

AEs = adverse events Cummings SR, et al. N Engl J Med. 2009;361:756-765


Adverse Events (36 Months)

Serious adverse events, n (%) Placebo(n = 3,876)

Denosumab 60 mg Q6M(n = 3,886)

P value

Serious adverse eventsMalignancy 125 (3.2) 144 (3.7) 0.28Infection 133 (3.4) 159 (4.1) 0.14Cardiovascular events 178 (4.6) 186 (4.8) 0.74

Stroke 54 (1.4) 56 (1.4) 0.89Coronary heart disease 39 (1.0) 47 (1.2) 0.41Peripheral vascular disease 30 (0.8) 31 (0.8) 0.93Atrial fibrillation 29 (0.7) 29 (0.7) 0.98

Serious adverse events occurring with ≥ 0.1% incidence and P ≤ 0.01Cellulitis (includes erysipelas) 1 (< 0.1) 12 (0.3) 0.002Concussion 11 (0.3) 1 (< 0.1) 0.004



Adverse Events (36 Months)

Phase 3 The FREEDOM Trial: Summary

Cummings SR, et al.N Engl J Med.2009;361:756-765

Placebon = 166

Denosumab 60 mg SC Q6M

n = 166SCREENING

1 126 18

Phase 3Phase 3The DEFEND Trial Extension StudyThe DEFEND Trial Extension Study

Study DesignStudy Design

Day 1Visit

Study Month24

END

OF

PARENT

Study population332 postmenopausal women T-score at the lumbar spine between 1.0 and 2.5

Objective of this analysisEffects of denosumab discontinuation on bone turnover markers and BMD during 24 months of off-treatmentCalcium and Vitamin D

SC = subcutaneously; Q6M = once every 6 months; BMD = bone mineral density

RANDOMIZATION

Parent Study(On-Treatment)

No Study Medication

No Study Medication

27 3630 42Study Month

48

END

OF

EXTENSION

Calcium and Vitamin D

Extension Study(Off-Treatment)

Multicenter, double-blind, placebo-controlled study

Bone H, et al. J Bone Miner Res. 2009;24(Suppl 1)

0102030405060708090

100110

0 1 6 10 12 14 18 24 27 30 36 42 480 1 6 10 12 14 18 24 27 30 36 42 48

0.10.20.30.40.50.60.70.80.9

1.11.2

00.10.20.30.40.50.60.70.80.91.01.11.2

Serum CTX*

Med

ian

CTX

(ng/

mL)

On-treatment Off-treatment

Med

ian

PINP

(µg/

L)

On-treatment Off-treatmentSerum PINP*

Placebo (n = 128) Denosumab (n = 128)

*Values were median and interquarti le range. Solid line indicated on-treatment; dashed line indicated off-treatment

Study Month


Bone Turnover MarkersBone Turnover Markers


*Values were least-square mean percentages and 95% CIs. Solid line indicated on-treatment; dashed line indicated off-treatment.†P < 0.002; ‡P ≤ 0.007CI = confidence interval

Study Month

Placebo (n = 128) Denosumab (n = 128)

Leas

t-Squ

are

Mea

n Pe

rcen

tage

Cha

nge

From

Bas

elin

e

On-treatment Off-treatment

–3%–2%–1%

0%1%2%3%4%5%6%7%8%9%

0 1 6 12 24 30 36 42 48

†

Lumbar Spine BMD*

–3%

–2%

–1%

0%

1%

2%

3%

4%

5%

1 6 12 24 30 36 42 480

Total Hip BMD*On-treatment Off-treatment

†

†

†

†

†† †

‡

‡

‡

‡

‡

‡‡ ‡

Phase 3Phase 3The DEFEND Trial Extension StudyThe DEFEND Trial Extension StudyLumbar Spine and Total Hip BMDLumbar Spine and Total Hip BMD


Incidence, n* (%)Placebo

(n = 128)†

Denosumab(n = 128)†

Nonvertebral fracturesFootFibulaRadiusFemoralHumerus

4 (3.1)2 (1.6)1 (0.8)1 (0.8)

01 (0.8)

4 (3.1)1 (0.8)1 (0.8)1 (0.8)1 (0.8)

0Vertebral fracture 0 1 (0.8)

*Number of subjects reporting ≥ 1 event and Included only fractures during the off-treatment phase†Number of subjects who enrolled in the off-treatment phase and received ≥ 1 dose of study medication during the on-treatment phase.


Confirmed Osteoporotic Fractures During OffConfirmed Osteoporotic Fractures During Off--Treatment PhaseTreatment Phase


Multicenter, double-blind, double-dummy, active-controlled study

END

OF

TREATMENT

Denosumab 60 mg every 6 months (Q6M)+Placebo for alendronate once weekly (QW)

1 63 9

Placebo for denosumab Q6M + Alendronate 70 mg QW

Day 1Visit

Study Month

12

12 months

Study Visit(month)

Phase 3Phase 3The DECIDE TrialThe DECIDE Trial

Study DesignStudy Design

Calcium (≥ 500 mg/d) and vitamin D (≥ 400 IU/d)

Study population1189 Postmenopausal naifwomen with low bone mass T-score ≤ −2.0 at LS or total hip

Primary endpointChange in BMD at total hip at month 12

Secondary endpointsChange in BMD at lumbar spine, femoral neck, trochanter, and 1/3 radius at month 12

LS = lumbar spine.

RANDOMIZATION

SCREENING

Brown JP, et al. J Bone Miner Res. 2009;24:153-161.

*P ≤ 0.0001..

Perc

ent C

hang

e Fr

om B

asel

ine

(%) i

n BM

DLe

ast S

quar

es M

ean

(95%

CI)

Denosumab 60 mg Q6M

1.1%*

Total Hip Lumbar Spine 1/3 RadiusFemoral NeckTrochanter0

1

2

3

4

5

6

1.0%*

0.6%*

0.6%*

1.0%*Alendronate 70 mg QW


Phase 3Phase 3The DECIDE TrialThe DECIDE TrialBMD at Month 12 BMD at Month 12

*P ≤ 0.0001.

Med

ian

(Q1,

Q3)

Cha

nge

From

Bas

elin

e (%

)

Study Month

sP1NPsCTx-1

Study Month

Med

ian

(Q1,

Q3)

Cha

nge

From

Bas

elin

e (%

)-100

-80

-60

-40

-20

0

20

0 1 3 6 9 12-100

-80

-60

-40

-20

0

20

0 1 3 6 9 12

* * * *

Denosumab 60 mg Q6MAlendronate 70 mg QW

*

* * * *


Phase 3Phase 3The DECIDE TrialThe DECIDE Trial

Bone Turnover Markers

SCREENING

Denosumab 60 mg Q6M

1 63 9

Alendronate 70 mg QW

Day 1Visit

Study Month12

STUDY

END

Study Visit(month)

RANDOMIZATION

ALN

≥6

MONTHS

Run-in phase ALN 70 mg QW + 1 g calcium + 400 IU vit. D

N = 504

n = 253

n = 251

5 10 15

Days5 10 15

Days

Phase 3The STAND Trial

Study Design

Kendler DL, et al. J Bone Miner Res. 25: 72-81; 2010.

Study population504 postmenopausal women previously treated with alendronate 70 mg QW or equivalent for ≥ 6 monthsT-score ≤ –2.0 and ≥ –4.0 at lumbar spine or total hip

Primary endpointChange in BMD at total hip at month 12

Secondary endpointsChange in lumbar spine BMD at month 12Change in serum CTX-I at month 3

-0.2

0.00.2

0.4

0.60.8

1.0

1.2

1.4

1.6

1.82.0

2.2

Perc

ent C

hang

e Fr

om B

asel

ine

(Lea

st S

quar

es M

ean

±95

% C

I)

Study Month

BL 6 12

Alendronate 70 mg QW (n = 241)

Denosumab 60 mg Q6M (n = 246)

**

*P ≤ 0.01.n = number of subjects who have a baseline and ≥ 1 postbaseline evaluation. Kendler DL, et al. J Bone Miner Res. 25: 72-81; 2010.

Phase 3The STAND Trial Femoral Neck BMD

Perc

ent C

hang

e Fr

om B

asel

ine

(Lea

st S

quar

es M

ean

±95

% C

I)

Study Month

*

†

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

0 6 12

Alendronate 70 mg QW (n = 241)

Denosumab 60 mg Q6M (n = 246)

*P ≤ 0.01.†P < 0.0001.n = number of subjects who have a baseline and ≥ 1 postbaseline evaluation. Kendler DL, et al. J Bone Miner Res. 25: 72-81; 2010.

Phase 3The STAND Trial Lumbar Spine BMD

Alendronate Denosumab

*P < 0.0001.Dotted line is lower limit of premenopausal reference range.Values are medians; error bars represent the interquartile range.De Papp AE, et al. Bone. 2007;40:1222-1230..

Study Month

0.34

6

Seru

m C

Tx-

1 (n

g/m

L)

BL 1 3 9 12

0.320.300.280.260.240.220.200.180.160.140.120.100.080.060.04

Study Month

34

6

Seru

m P

1NP

(ng/

mL)

BL 1 3 9 12

323028262422201816141210

8* *

**

* *

* * **

CTx-1 P1NP

Kendler DL, et al. J Bone Miner Res. 25: 72-81; 2010.

Phase 3The STAND Trial

Biochemical Bone markers

Adherence Encompasses Both Persistence and Compliance

Payer J, et al. Biomed Pharmacother 2007.

Adherence

Persistence Compliance+

Reflects a combination of behaviours determining the extent to which patients take medications as prescribed

The length of time from beginning to completion or discontinuation of therapy

The consistency and accuracy with which a prescribed regimen is followed

Siris et al. A.J of Medicine 2009Siris et al. A.J of Medicine 2009

Osteoporosis Therapies and Osteoporosis Therapies and Patient AdherencePatient Adherence

Less than 50% of patients persist with their osteoporosis therapy for more than 1 year

Siris E.S. et al. Am. J. Med. 2009; 122: S3-S13

Patients initiating therapy

Patients continuing therapy

Adherence

Side effectsSafety concernsHealth

problemsLack of results

Lack of motivation

CostInconvenient

dosingWithdrawn by others

Kendler DL et al Osteoporos Int 2010

Kendler DL et al Osteoporos Int 2010

Significantly greater treatment adherence was observed for subcutaneous administrationof Denosumab every 6 months thanfor oral Alendronate once weekly

Postmenopausal Osteoporosis

Denosumab Is Being Investigated in Denosumab Is Being Investigated in Several Conditions of Bone Loss and Several Conditions of Bone Loss and

DestructionDestruction

*Cancer treatment-induced bone lossRA = rheumatoid arthritishttp:// www.clinicaltrials.gov. Accessed November 5, 2009. Cummings SR, et al. N Engl J Med. 2009;361:756-765.Bone HG, et al. J Clin Endocrinol Metab. 2008;93:2149-2157. Brown JP, et al. J Bone Miner Res. 2009;24:153-161.Kendler DL, et al. [Published online ahead of print July 13, 2009]. J Bone Miner Res. doi:10.1359/JBMR.090716.Cohen SB, et al. Arthritis Rheum. 2008;58:1299-1309. Ellis GK, et al. J Clin Oncol. 2008;26:4875-4882. Smith MR, et al. N Engl J Med. 2009;361:745-755.

Treatment-Induced Bone Loss*

Cancer-Related Bone Destruction Bone Erosion of RA

Denosumab in Men Receiving AndrogenDenosumab in Men Receiving Androgen--Deprivation Therapy for Prostate CancerDeprivation Therapy for Prostate Cancer

Supplemental calcium and vitamin D

Baseline 36 months

Design: Randomised, double-blind, placebo-controlled, multicentre Study protocol amended from 2 to 3 years to extend period for safety and fracture evaluation

RANDOMISE

Men with nonmetastatic prostate cancer

receiving continuous ADT (n=1468)

Stratified by• Age (<70 y vs ≥70 y)• Prior ADT duration

(≤6 mo vs >6 mo)

Denosumab 60 mg SC Q6M (× 6 doses)

(n=734)

Placebo SC Q6M (× 6 doses)

(n=734)

End points

Primary Percentage change from baseline at month 24 in lumbar spine BMDSecondary Incidence of new vertebral fractures over 36 months

Percentage change from baseline at month 36 in lumbar spine BMDPercentage change from baseline at 24 and 36 months in total hip and femoral neck BMDFracture at any site (morphometric/clinical vertebral or nonvertebral)Time to first clinical fractureSafety events Smith MR et al. N Engl J Med. 2009;361:745-755.

Secondary End PointSecondary End PointNew Vertebral FracturesNew Vertebral Fractures

0

2

4

6

1.9% 0 .3 % 3 .3 % 1 .0 % 3 .9 % 1.5 %

RR 0.15P = .004

RR 0.31P = .004

RR 0.38P = .006

Subject Incidence

26 1013 2 22 7

Inci

denc

e of

New

Ver

tebr

al

Frac

ture

RR = relative risk.

SC Denosumab (n = 679)Placebo (n = 673)

12 24 36Month

Smith MR, Egerdie B, Toriz NH, et al. N Engl J Med. 2009;361:745-755. Copyright © 2009 Massachusetts Medical Society. All rights reserved.

Nb patients

L’introduzione del Denosumab nella terapia dell’Osteoporosi deve senza dubbio essere considerato un importante elemento di progresso, non soltanto per i suoi documentati effetti sulla prevenzione delle fratture da fragilità, ma anche per la sua modalità di somministrazione, parenterale ed ogni 6 mesi, che, soprattutto in Pazienti anziani che ricevono spesso diverse prescrizioni Farmaceutiche, a cui non di rado si aggiungono numerose autoprescrizioni, puòconsentire di mantenere una maggiore aderenza al trattamento e, di conseguenza, di garantire migliori effetti terapeutici e minori costi sociali

Conclusioni

www.ema.europa.euwww.ema.europa.eu

Comitato scientificoGiancarlo Isaia, Simone Cenci, Maria Grano,

Iacopo Chiodini, Giuseppe Mossetti

X RiunioneTorino 18-19 Febbraio 2011

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