Denosumab CONFLICTS OF INTEREST: A Lecture at Amgen Two Years Ago - - PowerPoint PPT Presentation

7/25/2014 1

Denosumab

Clifford J Rosen MD Maine Medical Center Research Institute rosenc@mmc.org

CONFLICTS OF INTEREST: A Lecture at Amgen Two Years Ago

Bone remodeling is a cellular process

Osteoblasts Osteoclast Osteocytes Bone Lining Cells

Bone Remodeling

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. Osteoprotegerin Prevents RANKL Binding to RANK and Inhibits Osteoclast Activity

Activated Osteoclast Osteoclast Precursor Multinucleated Osteoclast Osteoblasts

Bone Resorption

RANKL RANK OPG

X X

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

Colony-Forming Unit-Macrophage

Hormones Growth Factors Cytokines

X RANKL Signaling Denosumab

• Denosumab is a “fully-

human” monoclonal antibody that binds to RANKL

RANKL - a ligand for RANK (receptor found on

• steoclasts) which promotes

function, formation and

• survival. Found on T cells,

marrow stromal cells and precursors to osteoblasts Osteoprotegerin is the endogenous modulator of RANKL, blocking its effects Denosumab mimics

• steoprotegerin

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• 7688 women enrolled;

6478 completed 36 mos; 5979 received all injections

• 3902 in denosumab

group; 3906 placebo

Denosumab Fracture Study

Results

• Denosumab

increased BMD at L- Spine (9.2%) and total hip (6.0%) relative to placebo

• Also significantly

decreased CTX and PINP levels vs. placebo

– “CTX is released directly from bone as a result of

• steoclastic resorption”

– PINP is an osteoblast marker – a marker of bone formation

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Results Results

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FREEDOM - Summary

• Denosumab 60mg SC twice yearly x 36 most

significantly reduced the risk of new vertebral fracture compared to placebo

• Also reduced incidence of nonvertebral and

hip fractures

• Sig increase BMD at L-spine and total hip
• Sig decrease Bone turnover markers
• Safety signals are minimal at three years

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Serum CTX

Serum CTX percent change (%) (median) Month

• 90
• 80
• 70
• 60
• 50
• 40
• 30
• 20
• 10

10 20 BL D3 6 D3 12 18 24

Alendronate 60 mg Placebo

Lewiecki EM et al. J Bone Miner Res. 2007 Dec;22(12):1832-41.

Serum BSAP

Month Bone-specific alkaline phosphatase percent change (%) (median)

BL 6 12 18 24

Alendronate 60 mg Placebo

• 80
• 70
• 60
• 50
• 40
• 30
• 20
• 10

10 20

Lewiecki EM et al. J Bone Miner Res. 2007 Dec;22(12):1832-41.

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Adverse Events

• No significant difference incidence of

serious adverse events

• Specifically no diff in incidence of

cancer, CV events, serious infection, delayed fracture healing

• 1 pt developed osteonecrosis of jaw
• Several cases of skin rashes and

erysipelas

FREEDOM Extension Study Design

International, multicenter, open-label, single-arm study

Key Inclusion Criteria for the Extension:

• Completed the FREEDOM study (completed their 3-year visit, did not discontinue

investigational product, and did not miss > 1 dose).

• Not receiving any other osteoporosis medications.

FREEDOM EXTENSION

1 2 3 Year 5 6 7 4 8 9 10 1 2 3 5 6 7 4 Year

R A N D O M I Z A T I O N

DMAb 60 mg SC Q6M (N = 3902) Placebo SC Q6M (N = 3906)

Long-term DMAb Treatment Cross-over DMAb Treatment

DMAb 60 mg SC Q6M (N = 2343) DMAb 60 mg SC Q6M (N = 2207) Calcium and Vitamin D

Percentage Change in BMD at the Lumbar Spine and Total Hip

LS means and 95% confidence intervals. n = number of subjects with values at baseline and the time point of interest. *P < 0.05 vs FREEDOM baseline; †P < 0.0001 vs FREEDOM baseline and extension baseline.

^Represents subjects from the FREEDOM DXA substudy.

1 2 3 4 5 6

† 18.4% † †

* * * * * *

† † † 13.7%

7 8

• 2

2 4 6 8 10 12 14 16 20 18 Lumbar Spine

• 2

2 4 6 8 10 Total Hip Percentage Change from Baseline Study Year Study Year FREEDOM EXTENSION FREEDOM EXTENSION Placebo Long-term Denosumab Cross-over Denosumab

Cross-over n Long-term n 1962 1457 2086 1567 118^ 139^ 120^ 140^ 2022 2149 1997 2124 2006 2132 1895 2017 2005 2111 1488 1589 119^ 139^ 122^ 140^ 120^ 140^ 122^ 141^ 2029 2148 1924 2041

* * *

1 2 3 4 5 6

* * * * *

8.3% † † † † † † 4.9%

7 8

† † † †

1463 1551 1423 1518

Papapoulos S, et al. ASBMR 2013, abstract LB-MO26

Continued Denosumab Treatment in the FREEDOM Extension for Up to 8 Years

• Maintained reduction in bone turnover
• Was associated with a low incidence of nonvertebral and clinical

vertebral fractures

• Remained well tolerated

n = number of subjects with ≥ 1 fracture. N = number of randomized subjects who remained on study at the beginning of each period. Percentages for nonvertebral fractures are Kaplan-Meier estimates.

Yearly Incidence of Nonvertebral Fractures (%) 1.0 1.5 2.0 2.5 3.0 3.5 0.5 2.6% 2.2% 3.1% 2.5% 4 6 1.4% 5 1.2% 1.6% 0.0 7 1.5% Placebo Long-term DMAb 2343 2066 3454 3487 3906 3902 83 73 116 98 33 31 2243 27 N n 1867 27

FREEDOM EXTENSION

Years of DMAb Treatment 1 2.1% 2.9% 3688 3682 103 75 2 3 Papapoulos et al, ASBMR, 2013 0.7% 1747 12 8

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Effects of Denosumab Treatment on Total Hip BMD and Nonvertebral Fractures Through 8 Years

LS means and 95% confidence intervals. *P < 0.05 vs FREEDOM baseline; †P < 0.0001 vs FREEDOM baseline and extension baseline. Percentages for nonvertebral fractures are Kaplan-Meier estimates.

Placebo Long-term Denosumab Cross-over Denosumab

Papapoulos S, et al. ASBMR 2013, abstract LB-MO26

What mechanism(s) can explain the continuous increase in bone mass and observed nonvertebral fracture incidence?

What Is the Explanation for the Continuous Gain in BMD with Long-term Denosumab Therapy, Particularly at the Hip?

Possible Answer(s):

• Increased (secondary) mineralization versus increased mass
• Dynamic effects

– “Breathing” i.e. resolution of effect at end of cycle – Repeated increases in endogenous PTH

• Remodeling-independent bone formation

LS means ± 95% CIs; *P < 0.0001

BMD

Placebo Denosumab

BMC Volume

Percent Change from Baseline

• 4
• 2

2 4 6

* *

FREEDOM QCT Substudy

Adapted from McClung MR, et al. J Clin Densitom 2012;16:250-6

Total Hip QCT BMD, BMC & Volume % Change from Baseline at Month 36

BMD

Placebo Denosumab

BMC

Percent Change from Baseline

Volume

• 4
• 2

2 4 6 8 10

* *

LS means ± 95% CIs; *P < 0.0001

FREEDOM QCT Substudy

Total Hip Cortical BMD, BMC, & Volume % Change from Baseline at Month 36

Adapted from McClung MR, et al. J Clin Densitom 2012;16:250-6

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Poole K, et al. ASBMR 2012, abstract and oral presentation 1133

Mean Regional Cortical Mass and Thickness

There is a significant increase (*) in mean cortical mass, both from baseline and from placebo (which significantly decreases) This is not just an increase in density: there is also a significant increase (*) in cortical thickness

1.7% 1.2%

• 0.3%

0.6%

• 3.6%
• 6.7%
• 5.9%
• 1.1%
• 10.0%
• 8.0%
• 6.0%
• 4.0%
• 2.0%

0.0% 2.0% 4.0% 6.0% Total Cortex Compact Cortex Outer Transitional Zone Inner Transitional Zone

Placebo (n = 22) Denosumab (n = 28)

P = 0.0001 P = 0.0009 P = 0.0008 P = 0.0002 n = number of subjects with available data at baseline and 36 months. Data are LS means and 95% CIs. Zebaze RM, et al. ASBMR 2013, abstract and oral presentation 1065

Denosumab Decreases Cortical Porosity at the Hip

Percent Change from Baseline

Keaveny TM, et al. J Bone Miner Res 2014;29:158-65 *P < 0.0001 vs both baseline and placebo; †P < 0.0001 vs 12 months; ‡P < 0.005 vs baseline; §P < 0.05 vs 12 months.

Changes in the Hip Translate into Increased FEA Strength

*P < 0.0001 vs both baseline and placebo; †P < 0.01 vs 12 months; ‡P < 0.005 vs baseline; §P < 0.05 vs 12 months. Least‐squares means ±95% CIs.

Percentage Thickness and Mass Increase at Month 36

Poole K, et al. ASBMR 2012, abstract and oral presentation 1133

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Clinical Use of Denosumab-Pluses

• Twice per year- good for compliance
• Temporary treatment post anabolic therapy
• Can be used in renal insufficiency- Class III-IV

renal dysfunction

• SC use is relatively easy and accessible by

primary care

• Can be used in cancer patients

Potential Limitations

• Expense
• Reimbursement by third party payors
• Effect wears off after 6 months- what next?

– If compliance is poor, or if cannot take Rx – Is there increased risk of fracture when no Rx is

• ffered
• Biologic- hence long term potential risk?

Summary

• The RANKL/OPG system modulates bone turnover
• RANKL signals through multiple mechanisms-

differentiation of osteoclasts

• Monoclonal Ab of RANKL prevents bone resorption

and increases bone formation

• Denosumab reduces fractures of the spine and

major osteoporotic fractures for 8 yrs

• Relatively good safety profile to 8 yrs

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Weaknesses

• Not blinded
• No mention of race of subjects – most from

Europe

• Nonvertebral fractures not evaluated as

carefully/objectively as vertebral fractures

• Long term safety not assessed

– Skin – SBE – Cancer

• Study supported by Amgen; Most of investigators

receiving grants or consulting fees from Amgen

• What happens if people Rxed don’t show up for

follow up treatment?

Discussion

• Bisphosphonate therapy

– BPs bind calcium hydroxyapatite and disrupt the survival and function of osteoclasts, thereby reducing bone resorption – They do not block the formation of osteoclasts – Several clinical trials have shown that BP therapy leads to a 33-60% reduction in risk of fractures – SEs (esp with oral BPs which are poorly absorbed) can be intolerable: dysphagia, esophagitis, risk of

• steonecrosis of the jaw and delayed fracture

healing

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Strengths

• Relatively large sample size
• Randomized, placebo-controlled
• Groups not sig different
• Spine XRs assessed by semi-quantitative

grading scale at central imaging center

• 3 year study, follow-up still ongoing

Denosumab

• By blocking binding of RANKL and RANK,

denosumab inhibits bone resorption by

• steoclasts and inhibits formation of new
• steoclasts from osteoclast precursors

Denosumab: Overview

• Fully human monoclonal antibody-IgG2 isotype
• High affinity and specificity for human RANK

Ligand

• Pharmacokinetics (SC): similar to other fully

human IgG2 monoclonal antibodies – Absorption is rapid and prolonged (Cmax ≈1-4 wks postdose) – Long half-life ≈34 days with max dose – Distribution ≈ intravascular volume – Clearance ≈ reticuloendothelial system – No kidney filtration or excretion of intact molecule

Bekker PJ et al. J Bone Miner Res. 2004;19:1059-1066. Boyle WJ et al. Nature. 2003;423:337-342.

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Early Studies

• Previous studies have demonstrated increased BMD

and decreased bone turnover with use denosumab

– McClung 2006: phase II trial of efficacy and safety of different doses and frequencies of denosumab over 12 months in 400+ postmenopausal women with low BMD – Compared to placebo and alendronate – Denosumab increased BMD, decreased markers of bone turnover better than placebo and as effectively as alendronate

Previous Studies

• Brown et al 2006 compared BMD and BTMs in

Denosumab vs. Alendronate

– 1100+ postmenopausal women with low BMD (T<-2.0) treated for 1 year – Sig greater increases in BMD in D vs A – BTMs decreased more in D vs A – Not powered to assess risk of fracture b/t groups Denosumab Phase 2 Study

• 1-year data: N Engl J Med 2006

McClung MR, Lewiecki EM, Cohen SB, Bolognese MA, et al. Denosumab in postmenopausal women with low bone mineral density. N Engl J Med. 2006;354:821-831.

• 2-year data: J Bone Miner Res 2007

Lewiecki EM, Miller PD, McClung MR, Cohen SB, et al. Two-year treatment with denosumab (AMG 162) in a randomized phase 2 study of postmenopausal women with low bone mineral density. J Bone Miner Res. 2007

Dec;22(12):1832-41.

• 4-year data: ASBMR Oral Presentation 2007

Miller P, Bolognese M, Lewiecki EM, McClung M, et al. Effect of denosumab on bone mineral density and bone turnover markers: 48-month results. ASBMR

• 2007. Abstract 1205.

Denosumab Phase 2 Study

• Randomized, placebo-controlled, dose-ranging study
• Postmenopausal women (n = 412) with low BMD or OP

– Spine T-score -1.8 to -4.0, or TH or FN T-score -1.8 to -3.5) – Mean Spine T-Score -2.1

• Treatment Assignments:

– 7 denosumab dosing groups (6, 14, 30 mg Q3M; 14, 60, 100, or 210 mg Q6M SQ), – 1 open label 70 mg weekly alendronate group – Placebo group

• All subjects received 1000 mg Ca and 400 IU D daily
• Primary end point: Spine BMD at 12 months
• Prespecified exploratory analysis: BMD, BTMs, safety at 24 and

48 months

Lewiecki EM et al. J Bone Miner Res. 2007 Dec;22(12):1832-41.

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Spine BMD

Month

• 2

B 6 12 18 24

Lumbar spine BMD percent change (%)

aP < 0.001 vs pbo

Aln (a) Den 60 (a) Pbo

• 1

1 2 3 4 5 6 7 8 9 10

Lewiecki EM et al. J Bone Miner Res. 2007 Dec;22(12):1832-41.

Total Hip BMD

Total hip BMD (percent change (%)

Month

BL 6 12 18 24 Aln (a) Den 60 (a, b) Pbo

aP < 0.001 vs pbo bP < 0.05 vs aln

• 3
• 2
• 1

1 2 3 4 5 6

Lewiecki EM et al. J Bone Miner Res. 2007 Dec;22(12):1832-41.

1/3 Radius BMD

Month

• 4
• 3
• 2
• 1

1 2 3 BL 6 12 18 24 Distal 1/3 radius BMD percent change (%) Aln (a) Den 60 (a, b) Pbo

aP < 0.05 vs pbo bP < 0.05 vs aln Lewiecki EM et al. J Bone Miner Res. 2007 Dec;22(12):1832-41.

Figure 2 Proposed mechanism of action for denosumab

Deal C (2008) Potential new drug targets for osteoporosis Nat Clin Pract Rheumatol doi:10.1038/ncprheum0977

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Denosumab

• Denosumab is a

“fully-human” monoclonal antibody that binds to RANKL

RANKL - a ligand for RANK (receptor found on

• steoclasts) which promotes

function, formation and

• survival. Found on T cells,

marrow stromal cells and precursors to osteoblasts Osteoprotegerin is the endogenous modulator of RANKL, blocking its effects Denosumab mimics

• steoprotegerin

Results

• Cumulative incidence of

nonvertebral fracture: 6.5% (D) vs. 8.0% (P)

– 20% RRR

• Cumulative incidence of

hip fracture: 0.7% vs. 1.2%

– 40% RRR – Diff in rates here not stat sig; small number of subjects getting hip fractures in the study