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

Denosumab Treatment for 5 Years of Postmenopausal Women With Osteoporosis: Results From the First Two Years of the FREEDOM Trial Extension.

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

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  1. 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

  2. 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

  3. Background • 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

  4. Study Objectives • 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

  5. FREEDOM Extension Study Design International, multicenter, open-label, single-arm study FREEDOM EXTENSION Year 0 1 2 3 4 5 6 7 8 9 10 R A N D O M I Z A T I O N Denosumab 60 mg SC Q6M (N = 3902) Denosumab 60 mg SC Q6M (N = 2343) Long-term Denosumab Calcium and Vitamin D Placebo SC Q6M (N = 3906) Denosumab 60 mg SC Q6M (N = 2207) Cross-over Denosumab Year 0 1 2 3 4 5 6 7 • Key Inclusion Criteria: • Must have completed the FREEDOM study (received denosumab or placebo) • Not receiving any other osteoporosis medications

  6. Baseline Characteristics

  7. Percent Change in Serum CTX and P1NP Placebo Denosumab sCTX P1NP 80 80 FREEDOM EXTENSION FREEDOM EXTENSION 60 60 40 40 20 20 0 0 Percent Change From Baseline Percent Change From Baseline -20 -20 -40 -40 -60 -60 -80 -80 -100 -100 0 1 2 3 4 5 0 1 2 3 4 5 Year Year Median (IQR)

  8. Percent Change in Lumbar Spine and Total Hip BMD Placebo Denosumab Lumbar Spine Total Hip 10 16 FREEDOM EXTENSION FREEDOM EXTENSION † † † † 14 ^ ^ ^ ^ 8 ^ 12 ^ 6 10 8 4 Percent Change From Baseline Percent Change From Baseline ^ 6 ^ 2 4 2 * * 0 * * 0 * -2 -2 0 0.5 1 2 3 4 5 0 0.5 1 2 3 4 5 Year Year LS Mean (95% CI) *p < 0.05 vs FREEDOM baseline; ^p < 0.05 vs FREEDOM and EXTENSION baseline; †p < 0.05 vs year 4.

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

  10. Yearly Incidence of New Vertebral Fractures: Long-term Denosumab Group Placebo Denosumab FREEDOM EXTENSION 3.5% 3.1% 3.1% 3.0% Yearly Incidence of New Vertebral Fractures 2.5% 2.2% 2.0% 1.4% 1.5% 1.1% 0.9% 1.0% 0.7% 0.5% 0.0% 59 (2-year total) n 82 32 107 24 98 35 2100 N 3691 3702 3400 3453 3186 3247 1 2 3 4 and 5* Years of Treatment Exposure n = number of subjects with ≥ 1 fracture N = number of randomized subjects who remained on study at the beginning of each period *Annualized rate

  11. Yearly Incidence of Nonvertebral Fractures: Long-term Denosumab Group Placebo Denosumab FREEDOM EXTENSION 3.5% 3.1% 2.9% 3.0% Yearly Incidence of Nonvertebral Fractures 2.6% 2.5% 2.5% 2.2% 2.1% 2.0% 1.4% 1.5% 1.1% 1.0% 0.5% 0.0% n 116 98 103 75 83 73 32 25 N 3906 3902 3688 3682 3454 3487 2343 2242 1 2 3 4 5 Years of Treatment Exposure n = number of subjects with ≥ 1 fracture N = number of randomized subjects who remained on study at the beginning of each period

  12. Yearly Incidence of New Vertebral Fractures: Cross-over Denosumab Group Placebo Denosumab Denosumab Cross-over FREEDOM EXTENSION 3.5% 3.0% Yearly Incidence of New Vertebral Fractures 2.5% 2.5% 2.0% 1.5% 0.9% 1.0% 0.7% 0.5% 0.0% n 183 53 34 N 3691 3702 1978 1 and 2* 1 and 2* Years of Treatment Exposure n = number of subjects with ≥ 1 fracture N = number of randomized subjects who remained on study at the beginning of each period *Annualized rate

  13. Yearly Incidence of Nonvertebral Fractures: Cross-over Denosumab Group Placebo Denosumab Denosumab Cross-over FREEDOM EXTENSION FREEDOM EXTENSION 3.5% 3.1% 2.9% 3.0% 2.6% Yearly Incidence of Nonvertebral Fractures 2.4% 2.5% 2.1% 2.0% 1.7% 1.5% 1.0% 0.5% 0.0% 52 103 75 35 n 116 98 2207 3688 3682 2104 N 3906 3902 1 1 2 2 Years of Treatment Exposure n = number of subjects with ≥ 1 fracture N = number of randomized subjects who remained on study at the beginning of each period

  14. 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

  15. 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

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