Denosumab Treatment for 5 Years of Postmenopausal Women With Osteoporosis:

Results From the First Two Years of the FREEDOM Trial Extension

Henry G Bone1, Roland Chapurlat2, Maria Luisa Brandi3, Jacques P Brown4, Edward Czerwinski5, Nadia S Daizadeh6, Andreas Grauer6,

Mark-Antoine Krieg7, Cesar Libanati6, Zulema Man8, Dan Mellstrom9, Sebastiao Radominski10, Jean-Yves Reginster11, Heinrich Resch12,

Jose Andres Román13, Christian Roux14, Steven R Cummings15, Socrates Papapoulos16

1Michigan Bone and Mineral Clinic, Detroit, MI, USA ; 2Hôpital Edouard Herriot, Lyon, France; 3University of Florence, Florence, Italy; 4CHUQ Research Centre, Laval University, Quebec City, QC, Canada; 5Krakow Medical Center, Krakow, Poland; 6Amgen

Inc., Thousand Oaks, CA, USA; 7University Hospital of Lausanne, Lausanne, Switzerland; 8Centro TIEMPO, Buenos Aires, Argentina; 9Sahlgrenska University Hospital, Göteburg, Sweden; 10Universidade Federal do Paraná, Curitiba, Brazil; 11University

of Liège, Liège, Belgium; 12St. Vincent's Hospital, Vienna, Austria; 13Hospital Universitario La Fe, Valencia, Spain; 14Paris Descartes University, Paris, France; 15San Francisco Coordinating Center, CPMC Research Institute, San Francisco, CA, USA;

16Leiden University Medical Center, Leiden, The Netherlands

AACE; San Diego, CA; April 13-17, 2011

Disclosures

• HG Bone: Research grants and/or consulting or speaking fees from Amgen, Eli Lilly, Merck, Nordic Bioscience, Novartis, Takeda, Tarsa, and Zelos

• R Chapurlat: Research grants and/or consulting fees from Amgen, Merck, Novartis, Roche, sanofi-aventis, Servier, and Warner Chilcott

• ML Brandi: Research grants and/or consulting fees from Amgen, Eli Lily, GSK, MSD, NPS, Nycomed, Roche, Servier, and Stroder

• JP Brown: Research grants and/or consulting or speaking fees from Abbott, Amgen, Bristol-Myers Squibb, Eli Lilly, Novartis, Merck, Pfizer, Roche, and Warner Chilcott

• E Czerwinski: Research grants from Amgen, AstraZeneca, Danone Research, Eli Lilly, Merck Sharp & Dohme, Merck Serono, Novartis, Pfizer, Roche, SantoSolve AS, and Servier

• NS Daizadeh, A Grauer, C Libanati: Employed by Amgen and own Amgen stocks or stock options

• M-A Krieg, D Mellstrom, H Resch: None

• Z Man: Lecture fees and/or consulting fees from Merck, Novartis, Roche, and sanofi-aventis; Novartis steering committee member

• S Radominski: Research grants from Amgen, Aventis, Bristol-Myers Squibb, Novartis, Pfizer, and Roche

• J-Y Reginster: Research grants, consulting fees, and/or lecture fees from Amgen, Analis, Bristol-Myers Squibb, Ebewe Pharma, Genevrier, GSK, IBSA, Eli Lilly, Merck Sharp & Dhome, Negma, Novartis, Novo-Nordisk, Nycomed, NPS, Roche, Rottapharm, Servier, Teijin, Teva, Theramex, UCB, Wyeth, and Zodiac

• JA Román: Research grants from Roche

• C Roux: Research grants and/or consulting fees from Amgen, MSD, Novartis, Roche, and Servier

• SR Cummings: Research grants and/or consulting fees from Amgen, Eli Lilly, Merck, and Novartis

• S Papapoulos: Consulting fees from Amgen, GSK, Merck, Novartis, Procter & Gamble, and Wyeth

• FREEDOM (Fracture REduction Evaluation of Denosumab in Osteoporosis Every 6 Months) assessed the efficacy and safety of 3 years of denosumab treatment compared with placebo in postmenopausal women with osteoporosis.1

• FREEDOM was extended to evaluate the safety and efficacy of long-term denosumab treatment (up to 10 years of continuous exposure).

• The first 2 years of the FREEDOM open-label extension are reported in this analysis (up to of 5 years of continuous denosumab exposure).

1Cummings SR et al., NEJM 2009;361:756-65

Background

• Describe the effects of up to 5 years of continuous denosumab exposure on:

– Changes in bone turnover and bone density

– Safety and tolerability

– Incidence of new vertebral and nonvertebral fractures

Study Objectives

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

Key Inclusion Criteria:• Must have completed the FREEDOM study (received denosumab or placebo)• Not receiving any other osteoporosis medications

FREEDOM EXTENSION

1 2 3Year 0 5 6 74 8 9 10

1 2 30 5 6 74Year

RANDOMIZATION

Denosumab 60 mgSC Q6M

(N = 3902)

Denosumab 60 mgSC Q6M

(N = 2343)

PlaceboSC Q6M

(N = 3906)

Denosumab 60 mgSC Q6M

(N = 2207)

Calcium and Vitamin D

FREEDOM Extension Study Design

Long-termDenosumab

Cross-overDenosumab

 

Long-term DMAb Treatment EXTENSION Subjects

N = 2343

Cross-over DMAb Treatment EXTENSION

SubjectsN = 2207

FREEDOM Baseline

EXTENSION Baseline

FREEDOM Baseline

EXTENSION Baseline

Age (years) 71.9 74.9 71.8 74.8

Age groups (%)

≥ 65 years 94.3% 97.9% 93.7% 97.4%

≥ 75 years 28.3% 53.7% 28.3% 52.2%

Prevalent vertebral fractures (%)

23.9% 24.5% 22.0% 25.0%

LS BMD T-score –2.83 –2.14 –2.84 –2.81

TH BMD T-score –1.85 –1.50 –1.85 –1.93

CTX* (ng/mL) 0.524 0.183 0.554 0.568

P1NP* (µg/L) 46.72 17.49 54.24 48.80N = number of subjects enrolled in the EXTENSION. Data are mean unless otherwise noted.*Includes data from 65 subjects (long-term) and 36 subjects (cross-over); values are medians.

Baseline Characteristics

Percent Change in Serum CTX and P1NP

Median (IQR)

60

40

20

0

-20

-40

-60

-80

-100

80

Pe

rce

nt

Ch

an

ge

Fro

m B

as

eli

ne

1 2 3 4 50

Year

FREEDOM EXTENSION

60

40

20

0

-20

-40

-60

-80

-100

80

Pe

rce

nt

Ch

an

ge

Fro

m B

as

eli

ne

1 2 3 4 50

Year

FREEDOM EXTENSION

sCTX P1NP

Placebo Denosumab

Percent Change in Lumbar Spine and Total Hip BMD

LS Mean (95% CI)*p < 0.05 vs FREEDOM baseline; ^p < 0.05 vs FREEDOM and EXTENSION baseline; †p < 0.05 vs year 4.

Placebo Denosumab

* * *

*

^

^

FREEDOM EXTENSION10

8

6

4

2

0

-20 0.5 1 2 3 4 5

*

^

^

FREEDOM EXTENSION16

14

12

10

8

6

4

2

0

-2

0 0.5 1 2 3 4 5

Pe

rce

nt

Ch

an

ge

Fro

m B

as

eli

ne

Pe

rce

nt

Ch

an

ge

Fro

m B

as

eli

ne

Lumbar Spine Total Hip

Year Year

^†

^†

^†

^†

Exposure-adjusted Subject Incidence of Adverse Events (Rates per 100 Patient-years)

Placebo Denosumab

FREEDOM

Years 1-3N = 3883Rate (n)

FREEDOM

Years 1-3N = 3879Rate (n)

EXTENSIONLong-termYears 4-5N = 2343Rate (n)

EXTENSIONCross-overYears 1-2N = 2206Rate (n)

All AEs 156.1 154.3 113.2 111.4

Infections 30.7 29.3 25.1 27.4

Malignancies 1.6 1.8 2.0 1.6

Eczema 0.6 1.1 1.1 0.9

Hypocalcemia < 0.1 (3) 0 < 0.1 (1) 0.1 (5)

Pancreatitis < 0.1 (3) < 0.1 (7) < 0.1 (1) < 0.1 (1)

Serious AEs 10.4 10.6 10.8 11.1

Infections 1.3 1.5 1.2 1.5

Cellulitis or Erysipelas < 0.1 (1) 0.1 (12) < 0.1 (3) < 0.1 (1)

ONJ 0 0 0 < 0.1 (2)

Atypical fracture 0 0 0 0

Yearly Incidence of New Vertebral Fractures: Long-term Denosumab Group

Placebo Denosumab

2.2%

3.1% 3.1%

0.9%0.7%

1.1%

1.4%

0.0%

0.5%

1.0%

1.5%

2.0%

2.5%

3.0%

3.5%

1 2 3 4 and 5*

Years of Treatment Exposure

EXTENSIONFREEDOM

21003186 32473400 34533691N 370259 (2-year total)98 35107 2482 32n

n = number of subjects with ≥ 1 fractureN = number of randomized subjects who remained on study at the beginning of each period *Annualized rate

2.6%

2.1%2.2%

3.1%2.9%

2.5%

4 5

EXTENSION

23433454 34873688 36823906 3902 2242

1.4%

1.1%

3283 73103 75116 98 25

Yearly Incidence of Nonvertebral Fractures: Long-term Denosumab Group

0.0%

0.5%

1.0%

1.5%

2.0%

2.5%

3.0%

3.5%FREEDOM

Nn

Placebo Denosumab

n = number of subjects with ≥ 1 fractureN = number of randomized subjects who remained on study at the beginning of each period

1 2 3

Years of Treatment Exposure

Yearly Incidence of New Vertebral Fractures: Cross-over Denosumab Group

Placebo Denosumab Denosumab Cross-over

n = number of subjects with ≥ 1 fractureN = number of randomized subjects who remained on study at the beginning of each period

2.5%

0.9%0.7%

0.0%

0.5%

1.0%

1.5%

2.0%

2.5%

3.0%

3.5%

1 and 2* 1 and 2*19783691 3702

34183 53

EXTENSIONFREEDOM

Nn

Years of Treatment Exposure

*Annualized rate

Yearly Incidence of Nonvertebral Fractures: Cross-over Denosumab Group

3.1%

2.4%2.6%

0.0%

0.5%

1.0%

1.5%

2.0%

2.5%

3.0%

3.5%

1 122073906N 390252116 98n

2.9%

1.7%

2.1%

23688 3682103 75

210435

2

n = number of subjects with ≥ 1 fractureN = number of randomized subjects who remained on study at the beginning of each period

Placebo Denosumab Denosumab Cross-over

EXTENSIONFREEDOM EXTENSIONFREEDOM

Years of Treatment Exposure

Summary

• Denosumab treatment for 5 years (long-term group):

− Maintained the reduction in bone turnover

− Significantly increased BMD year over year

− Remained well tolerated with an AE profile similar in years 4 and 5 to that observed in the 3 years of the placebo-controlled FREEDOM study

− Maintained a low incidence of new vertebral and nonvertebral fractures

• Denosumab treatment for 2 years (cross-over group) largely reproduced the original findings from FREEDOM

Denosumab Treatment for 5 Years of Postmenopausal Women With Osteoporosis:

Results From the First Two Years of the FREEDOM Trial Extension

Henry G Bone1, Roland Chapurlat2, Maria Luisa Brandi3, Jacques P Brown4, Edward Czerwinski5, Nadia S Daizadeh6, Andreas Grauer6, Mark-Antoine Krieg7, Cesar Libanati6, Zulema Man8, Dan Mellstrom9, Sebastiao

Radominski10, Jean-Yves Reginster11, Heinrich Resch12, Jose Andres Román13, Christian Roux14, Steven R Cummings15, Socrates Papapoulos16

1Michigan Bone and Mineral Clinic, Detroit, MI, USA ; 2Hôpital Edouard Herriot, Lyon, France; 3University of Florence, Florence, Italy; 4CHUQ Research Centre, Laval University, Quebec City, QC, Canada; 5Krakow Medical Center, Krakow, Poland; 6Amgen

Inc., Thousand Oaks, CA, USA; 7University Hospital of Lausanne, Lausanne, Switzerland; 8Centro TIEMPO, Buenos Aires, Argentina; 9Sahlgrenska University Hospital, Göteburg, Sweden; 10Universidade Federal do Paraná, Curitiba, Brazil; 11University

of Liège, Liège, Belgium; 12St. Vincent's Hospital, Vienna, Austria; 13Hospital Universitario La Fe, Valencia, Spain; 14Paris Descartes University, Paris, France; 15San Francisco Coordinating Center, CPMC Research Institute, San Francisco, CA, USA;

16Leiden University Medical Center, Leiden, The Netherlands

AACE; San Diego, CA; April 13-17, 2011