il sistema rank/rankl/opg come nuovo bersaglio terapeutico ... · the rankl/rank/opg pathway is an...
TRANSCRIPT
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
Excessive Remodelling Contributes Excessive Remodelling Contributes to Osteoporosisto Osteoporosis
Increased bone remodelling
Increased fracture risk
Excessive Remodelling Contributes Excessive Remodelling Contributes to Osteoporosisto Osteoporosis
Increased bone remodelling
Increased fracture risk
Excessive Remodelling Contributes Excessive Remodelling Contributes to Osteoporosisto Osteoporosis
Increased bone remodelling
Structural deterioration
Increased fracture risk
Excessive Remodelling Contributes Excessive Remodelling Contributes to Osteoporosisto Osteoporosis
Increased bone remodelling
Structural deterioration
Increased fracture risk
Excessive Remodelling Contributes Excessive Remodelling Contributes to Osteoporosisto Osteoporosis
Increased bone remodelling
Structural deterioration
Increased skeletal fragility
Increased fracture risk
Excessive Remodelling Contributes Excessive Remodelling Contributes to Osteoporosisto Osteoporosis
Increased bone remodelling
Structural deterioration
Increased skeletal fragility
Increased fracture risk
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.
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.
RANK Ligand (RANKL)– Signalling protein expressed by osteoblasts/bone lining cells– Binds to RANK and promotes osteoclast formation, function
and survival
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.
RANK Ligand (RANKL)– Signalling protein expressed by osteoblasts/bone lining cells– Binds to RANK and promotes osteoclast formation, function
and survival
RANK– Expressed by osteoclasts and their precursors– Activated by RANK Ligand binding
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.
RANK Ligand (RANKL)– Signalling protein expressed by osteoblasts/bone lining cells– Binds to RANK and promotes osteoclast formation, function
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
OsteoclastPrecursors
RANK
DifferentiatedOsteoclast
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
OsteoclastPrecursors
RANK
DifferentiatedOsteoclast
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
OsteoclastPrecursors
RANK
DifferentiatedOsteoclast
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
OsteoclastPrecursors
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
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
OsteoclastPrecursors
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
Phase 3 The FREEDOM Trial
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%
†
†
Cummings SR, et al. N Engl J Med. 2009;361:756-765
Phase 3 The FREEDOM Trial
% 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%†
Cummings SR, et al. N Engl J Med. 2009;361:756-765
Phase 3 The FREEDOM Trial
% Change in BTM over 36 Months (160 Pts)
PlaceboDenosumab
40%P = 0.04
20%P = 0.0168%
P < 0.001
Cummings SR, et al. N Engl J Med. 2009;361:756-765
Phase 3 The FREEDOM Trial
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
Cummings SR, et al. N Engl J Med. 2009;361:756-765
Phase 3 The FREEDOM Trial
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%
†
†
Cummings SR, et al. N Engl J Med. 2009;361:756-765
Phase 3 The FREEDOM Trial
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%†
†
Cummings SR, et al. N Engl J Med. 2009;361:756-765
Phase 3 The FREEDOM Trial
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
Phase 3 The FREEDOM Trial
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
Cummings SR, et al. N Engl J Med. 2009;361:756-765
Phase 3 The FREEDOM Trial
Adverse Events (36 Months)
Phase 3 The FREEDOM Trial: Summary
Cummings SR, et al.N Engl J Med.2009;361:756-765
Phase 3 The FREEDOM Trial: Summary
Cummings SR, et al.N Engl J Med.2009;361:756-765
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
Phase 3Phase 3The DEFEND Trial Extension StudyThe DEFEND Trial Extension Study
Bone Turnover MarkersBone Turnover Markers
Bone H, et al. J Bone Miner Res. 2009;24(Suppl 1)
*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
Bone H, et al. J Bone Miner Res. 2009;24(Suppl 1)
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.
Phase 3Phase 3The DEFEND Trial Extension StudyThe DEFEND Trial Extension Study
Confirmed Osteoporotic Fractures During OffConfirmed Osteoporotic Fractures During Off--Treatment PhaseTreatment Phase
Bone H, et al. J Bone Miner Res. 2009;24(Suppl 1)
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
Brown JP, et al. J Bone Miner Res. 2009;24:153-161.
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
*
* * * *
Brown JP, et al. J Bone Miner Res. 2009;24:153-161.
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