EdiVoteStart EdiVoteStop Standard

EdiVoteStart EdiVoteStop Standard Il denosumab ha dimostrato nel tumore della mammella metastatico a livello osseo di: Essere non inferiore all'acido zoledronico in termini di tempo al primo SRE Essere non inferiore e anche superiore all'acido zoledronico in termini di tempo al primo SRE Essere capace di ridurre l'incidenza del primo e dei successivi SRE in misura identica all'acido zoledronico Indurre un incremento di incidenza di ONJ superiore all'acido zoledronico 25% 25% 000 25% 25% 020

EdiVoteStart EdiVoteStop Standard Il denosumab ha dimostrato nel tumore della prostata ormonorefrattario metastatico a livello osseo di: Essere non inferiore all'acido zoledronico in termini di tempo al primo SRE Essere non inferiore e anche superiore all'acido zoledronico in termini di tempo al primo SRE Essere capace di ridurre l'incidenza del primo e dei successivi SRE in misura identica all'acido zoledronico Indurre un incremento di incidenza di ONJ superiore all'acido zoledronico 25% 000 25% 25% 25% 020

Università Campus Bio-Medico
May 13, 2011 New Drugs in Cancer Therapy Director: G. Minotti Denosumab Daniele Santini Medical Oncology Università Campus Bio-Medico Rome

RANKL / RANK / OPG and bone
osteoblast/stromal cell RANK differentiation, fusion, activation and survival of osteoclasts RANKL OC precursor osteoblast/stromal cell OPG OC precursor

Pre-fusion Osteoclast Multinucleated Osteoclast
RANK Ligand Is an Essential Mediator of Osteoclast Formation, Function, and Survival CFU-M Pre-fusion Osteoclast RANKL RANK M-CSF Multinucleated Osteoclast Hormones Growth factors Cytokines Activated Osteoclast Osteoblasts Bone Formation CFU-M = colony forming unit macrophage M-CSF = macrophage colony stimulating factor Bone Resorption Adapted from Boyle WJ, et al. Nature. 2003;423: 5

Osteoprotegerin (OPG) Prevents RANK Ligand Binding to RANK and Inhibits Osteoclast Formation, Function, and Survival CFU-M Osteoclast Precursor RANKL RANK OPG Hormones Growth factors Cytokines Osteoclast Formation, Function, and Survival Inhibited Osteoblasts Bone Resorption Inhibited Bone Formation CFU-M = colony forming unit macrophage M-CSF = macrophage colony stimulating factor For Internal Use Only. Amgen Confidential. Adapted from Boyle WJ, et al. Nature. 2003;423: 6

RANK Ligand Drives an Increase in Osteoclast Activity
Alterations of the RANK Ligand / OPG ratio are critical in the pathogenesis of bone diseases that result from increased bone resorption1-3 OPG RANK Ligand The relative balance between RANK Ligand and OPG is regulated by cytokines and hormones and determines osteoclast activity. Alterations of the RANK Ligand/OPG ratio are critical in the pathogenesis of bone diseases that result in increased bone resorption. Unopposed RANK Ligand (i.e., an elevated RANK Ligand/OPG ratio) within the skeleton promotes bone loss, while restoring a balanced RANK Ligand/OPG ratio or inhibiting RANK Ligand decreases osteoclast activation and bone resorption. In many diseases involving increased bone resorption, RANK Ligand expression is upregulated by osteoclastogenic factors (growth factors, hormones, cytokines) while OPG expression is simultaneously downregulated.1-3 Hofbauer LC, et al. Clinical implications of the osteoprotegerin/RANKL/RANK system for bone and vascular diseases. JAMA. 2004;292:490-5. Lacey DL, et al. Osteoprotegerin Ligand is a Cytokine that Regulates Osteoclast Differentiation and Activation. Cell. 1998;93:165–76 Boyle WJ, et al. Osteoclast Differentiation and Activation. Nature. 2003;423: Promotes OC activation Prevents OC activation Osteoclast Activity OC = osteoclast 1Hofbauer LC, et al. JAMA. 2004;292:490-5. 2Lacey DL, et al. Cell. 1998;93: 3Boyle WJ, et al. Nature. 2003;423:

Mouse Functional Genomics Revealed OPG/RANK/RANKL as Key Regulators of Bone Mass
OPG ApoE Tg 8 weeks of age RANKL KO 4 weeks of age Normal 4 weeks of age OPG KO 8 weeks of age RANK KO 4 weeks of age

TURNOVER OSSEO IN CASO DI DEFICIT ESTROGENICO
PTH ALP NTX CTX ICTP IL-1 IL-6 > RANKL/RANK < OPG Bone Turnover

RANK Ligand Targeting and Vicious Cycle of Bone Destruction
Tumor Cells PTHrP IL-6 PGE2 TNF M-CSF BMP PDGF FGFs IGFs TGF-β RANKL Osteoblast Osteoclast Bone 10

RANK Ligand Targeting and Vicious Cycle of Bone Destruction
Tumor Cells BMP PDGF FGFs IGFs TGF-β PTHrP IL-6 PGE2 TNF M-CSF RANKL Osteoblast Osteoclast Bone 11

Pharmacologic Properties of Denosumab
Model of Denosumab Fully human monoclonal antibody IgG2 isotype High affinity for human RANK Ligand High specificity for RANK Ligand No detectable binding to TNFα, TNFβ, TRAIL, or CD40L No neutralizing antibodies detected in clinical trials to date Denosumab, an investigational fully human monoclonal antibody (IgG2), binds with high affinity and specificity to human RANK (receptor activator of nuclear factor kappa B) ligand, an essential mediator of osteoclast activity.1-3 No neutralizing antibodies have been detected in clinical trials to date.1,3 Binding of denosumab to RANK Ligand was investigated in an in-vitro study using flow cytometry and ELISA. Binding affinity was measured using BIAcore and a kinetic exclusion assay. Denosumab bound both soluble and membrane-bound forms of human RANK Ligand. This binding was inhibited by excess human RANK Ligand, but not by TNF-, TNF-, TRAIL or CD40 Ligand. The dissociation constants of denosumab were calculated to be 9.5 x 10-11M and x 10-12M using the BIAcore and kinetic exclusion assay, respectively.2 No neutralizing antibodies have been detected in clinical trials to date: In a phase 1, double-blind study, 49 healthy postmenopausal women were randomized to receive a single dose of denosumab 0.01, 0.03, 0.1, 0.3, 1.0, or 3.0 mg/kg or placebo. No anti-denosumab antibodies were detected in subjects enrolled in this study.1 In a phase 2 study, 412 postmenopausal women with low bone mineral density (BMD) were randomized to receive denosumab SC either every three months (6, 14, or 30 mg) or every six months (14, 60, 100, or 210 mg), open-label alendronate (70mg orally once weekly), or placebo. Denosumab-binding antibodies were observed in two subjects—one at 1 month and the other at 12 months. These antibodies were not neutralizing and were not detected in subsequent samples in either subject.3 The effects of denosumab on bone resorption appear reversible.3 Note: The graphic in the slide is a ribbon depiction of denosumab. Bekker PJ, et al. J Bone Miner Res. 2004;19: Elliott R, et al. Osteoporos Int. 2007;18:S54. Abstract P149. McClung MR, et al. New Engl J Med. 2006;354: Bekker PJ, et al. J Bone Miner Res. 2004;19: 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: TNF = tumor necrosis factor; TRAIL = TNFα-related apoptosis-inducing Ligand

Denosumab Binds RANK Ligand and Inhibits Osteoclast-Mediated Bone Destruction
CFU-M Pre-Fusion Osteoclast RANKL RANK Denosumab Hormones Growth factors Cytokines Osteoclast Formation, Function, and Survival Inhibited Denosumab is the first fully human monoclonal antibody in clinical development that specifically targets RANK Ligand, an essential mediator of osteoclast formation, function, and survival.1,2 Lewiecki EM, et al. Exper Opin Biol Ther. 2006;6: McClung ER, et al. New Engl J Med. 2006;354: Osteoblasts Bone Formation Bone Resorption Inhibited Provided as an educational resource. Do not copy or distribute.

PTHrP, BMP, TGF-β, IGF, FGF, VEGF, ET1, WNT
RANKL Inhibition May Interrupt The “Vicious Cycle” of Cancer-Induced Bone Destruction RANKL RANK Denosumab Tumor Cell Formation Inhibited PTHrP, BMP, TGF-β, IGF, FGF, VEGF, ET1, WNT PDGF, BMPs TGF-β, IGFs FGFs, Ca2+ Apoptotic Osteoclast Osteoblasts

Oncology Denosumab Phase 3 Registration Programme
Hormone- Ablative Therapy- Induced Bone Loss Prolonging Metastasis-Free Survival Treatment of Bone Metastases To Prevent SREs n~11,000 patients

Denosumab Oncology Programme Overview Phase 1 Phase 2 Phase 3
BrCa & MM - PK/PD Breast cancer - PK/PD (Bisphosphonate naïve)2 Breast cancer – AI bone loss7 Solid tumours & MM - PK/PD (Bisphosphonate treated)3,4 Prostate cancer – ADT bone loss8 Giant cell tumour6 Prostate cancer – delay bone mets Multiple myeloma5 Breast cancer - SRE9 Prostate cancer – SRE 10 Solid tumours & MM – SRE 11 1Body J J, et al. Clin. Cancer Res 2006; 12: ; 2Lipton A, et al. J Clin Oncol 2007; 25: ; 3Suarez T et al. J Clin Oncol 2006;24(S18):6S:8562; 4Fizazi K, et al. J Clin Oncol 2009;27: Vij et al. Blood 2007; 110(11):3604; 6Thomas et al. CTOS, 2007:787; 7Ellis G, et al. J Clin Oncol 2008;26: ; 8Smith MR et al. N Engl J Med, 2009 9 Stopeck A. et al. JCO, Fizazi K et al. Lancet, Henry D et al, JCO, 2011 16 16

Denosumab and potential applications in medical oncology
Denosumab and SREs in metastatic disease Denosumab and CTIBL Denosumab and adjuvant setting

Study 20040113 (Phase II): Breast Cancer Pts With Bone Mets
~ 42 patients per group (N = 255) Blinded denosumab Open-label IV bisphosphonate comparator Patients naive to bisphosphonates ECOG PS: 0-2 Denosumab 30 mg SC Q4W Denosumab 120 mg SC Q4W Denosumab 180 mg SC Q4W Screening/ randomization Follow-up at Weeks 33, 45, 57 Denosumab 60 mg SC Q12W ECOG PS, Eastern Cooperative Oncology Group performance score; Q4W, every 4 weeks; Q12W, every 12 weeks. Denosumab 180 mg SC Q12W Bisphosphonate IV Q4W 25 weeks of treatment Lipton A, et al. J Clin Oncol. 2007;25:

Study 20040113 (Phase II): Breast Cancer Pts With Bone Mets
Primary endpoint % change in uNTx/Cr at Week 13 Secondary endpoints % change in uNTx/Cr at Week 25 Proportion with > 65% reduction in uNTx/Cr at Weeks 13 and 25 Proportion experiencing a SRE Time to first SRE Denosumab 30 mg SC Q4W Denosumab 120 mg SC Q4W Denosumab 180 mg SC Q4W Screening/ randomization Follow-up at Weeks 33, 45, 57 Denosumab 60 mg SC Q12W SRE, skeletal-related event; Q4W, every 4 weeks; Q12W, every 12 weeks; uNTX/Cr, urinary N-telopeptide corrected for urine creatinine. Denosumab 180 mg SC Q12W Bisphosphonates used in this study: Zoledronic acid (n = 39) Pamidronate (n = 3) Ibandronate (n = 1) Bisphosphonate IV Q4W 25 weeks of treatment Lipton A, et al. J Clin Oncol. 2007;25:

Selected phase III dose: 120 mg Q4W
Denosumab suppresses bone turnover and seems to reduce SRE risk similarly to IV BPs IV BP Denosumab 180 mg Q4W 20 Denosumab 30 mg Q4W Denosumab 60 mg Q12W Denosumab 120 mg Q4W Denosumab 180 mg Q12W All denosumab -20 Selected phase III dose: 120 mg Q4W Median (Q1, Q3) Change in uNTx/Cr (%) -40 -60 BP, bisphosphonate; Q4W, every 4 weeks; Q12W, every 12 weeks; uNTx/Cr, urinary N-telopeptide corrected for urine creatinine. -80 -100 2 5 9 13 17 21 25 Study Week Lipton A, et al. J Clin Oncol. 2007;25: Lipton A, et al. Clin Cancer Res, 2008; 14:6690-6

With Daily Supplements of Calcium and Vitamin D
Randomized Phase II trial of denosumab in patients with bone metastases from prostate cancer, breast cancer and other neoplasms after intravenous bisphosphonates Patients with bone metastases and elevated uNTx levels despite ongoing IV bisphosphonate therapy Screening/ Randomization n = 38 Denosumab 180 mg SC Q4W 25 Weeks of Treatment With Daily Supplements of Calcium and Vitamin D n = 36 Denosumab 180 mg SC Q12W n = 37 IV BP Q4W Extension/ Follow-up Study Design ( ) Fizazi K et al., J Clin Oncol, 10:15-64, 2009

The decrease of uNTx was higher in the denosumab group
IV BP Q4W (n= 35) Total SC Denosumab (n = 69) SC Denosumab 180 mg Q12W (n = 33) SC Denosumab 180 mg Q4W (n = 36) Visit Week 2 5 9 13 17 21 25 -100 -80 -60 -40 -20 20 40 60 80 100 Median Percent Change From Baseline in uNTx Corrected by Creatinine Fizazi K et al., J Clin Oncol, 10:15-64, 2009

The incidence of SRE was higher in the bisphosphonate group
IV BP Q4W 30 Pooled SC Denosumab Group Proportion of Patients With a First On-Study SRE SC Denosumab 180 mg Q4W 25 SC Denosumab 180 mg Q12W 20 15 10 5 20 40 60 80 100 120 140 160 180 Study Day Fizazi K et al., J Clin Oncol, 10:15-64, 2009

Delay/Prevention of SRE (Skeletal Related Events):
Denosumab VS Zoledronic Acid Phase 3 Clinical Trials in Patients With Advanced Cancer ECCO Meeting 2009 Delay/Prevention of SRE (Skeletal Related Events): : A Randomized, Double-blind, Multicenter, Phase 3 Study of Denosumab Compared With Zoledronic Acid (Zometa®) in the Treatment of Bone Metastases in Advanced Breast Cancer (n=1960) : A Randomized, Double-blind, Multi-Center Phase 3 Trial of Denosumab versus Zoledronic Acid for Bone Metastases in Advanced Solid Tumors and Multiple Myeloma (n=1690) The slide above outlines two out of three of the Denosumab Phase 3 clinical trials in patients with advanced cancer across tumor types. The third study will be described by Dr. Smith in the following presentation. clinicaltrials.gov

Study Design Key Inclusion Adults with advanced breast cancer and confirmed bone metastases Key Exclusion Current or prior intravenous bisphosphonate administration N = Zoledronic acid 4 mg IV* and SC placebo every 4 weeks N = Denosumab 120 mg SC and Placebo IV* every 4 weeks Supplemental Calcium and Vitamin D This slide is animated due the complexity A total of 2046 eligible adult subjects who were naïve to intravenous bisphosphonates were randomized in a double-blind, double-dummy design to receive subcutaneous denosumab 120 mg or intravenous zoledronic acid (ZA) 4 mg adjusted for creatinine clearance every 4 weeks The key inclusion criterion was that there was evidence of bone metastasis based on x-ray, CT, or MRI The key exclusion criterion was no prior IV bisphosphonate. Prior oral bisphosphonate use for osteoporosis was allowed Zoledronic acid was administered per Zometa® prescribing information. IV product dose that was either zoledronic acid or placebo was calculated according to baseline creatinine clearance. Subsequent doses were withheld if there was elevation of the serum creatinine and the IV product was only reinstituted once the serum creatinine had returned to within 10% of baseline levels. This dose and schedule is per the Zometa® label. Subjects with creatinine clearance < 30 mL/min were excluded per the Zometa® label There was no modification of the subcutaneous product, which included denosumab or placebo either at baseline or on study Subjects were stratified by previous SRE, prior oral bisphosphonate, current chemotherapy, and geographic region (Japan vs others) All subjects were strongly recommended to take daily supplemental calcium (500 mg) and vitamin D (400 IU) No crossover was allowed during the treatment phase The median time on study was 17 months for both treatment arms The median time on treatment was 16.5 months for both treatment arms The study duration was 34 months The primary endpoint was time to first on-study SRE, defined as pathologic fracture, radiation therapy or surgery to bone, or spinal cord compression. Secondary endpoints included a superiority test for time to first and time to first-and-subsequent on-study SRE. Subject Disposition 46% of subjects in the denosumab arm and 45% of subjects in the zoledronic arm remained on study through the primary data analysis cut-off date The main reasons for study discontinuation were deaths, disease progression, and consent withdrawn Reference Stopeck A et al. European Journal of Cancer Supplements, Vol. 7, No 3, September 2009, Page 2. Abstract 2LBA and Oral Presentation. 1° Endpoint 2° Endpoints Time to first on-study SRE (non-inferiority) Time to first on-study SRE (superiority) Time to first and subsequent on-study SRE (superiority) *IV product dose adjusted for baseline creatinine clearance and subsequent dose intervals determined by serum creatinine (per Zometa® label) Stopeck A. et al. JCO, 2010

Baseline Characteristics
Characteristics, n (%) or median Zoledronic Acid (N = 1020) Denosumab (N = 1026) Women 1011 (99) 1018 (99) Age (years) 56 57 ECOG status of 0 or 1 932 (91) 955 (93) Hormone receptor positive 726 (71) 740 (72) Time from first bone metastasis to randomization (months) 2 Previous SRE 373 (37) 378 (37) Presence of visceral metastases 525 (51) 552 (54) Baseline characteristics were generally balanced Although 99% of subjects were women there was small population of men that was also enrolled Median age of 56 and 57 years is expected for this population Over 90% of subjects on each arm had an ECOG of 0 or 1 Median time from first bone metastasis to randomization was 2 months 37% of subjects in each treatment arm had experienced an SRE prior to study entry Just over 50% of the population had evidence of visceral metastases at study entry with slightly more subjects in the denosumab arm Reference Stopeck A et al. European Journal of Cancer Supplements, Vol. 7, No 3, September 2009, Page 2. Abstract 2LBA and Oral Presentation. Stopeck A. et al. JCO, 2010

Time to First On-Study SRE
1.00 HR 0.82 (95% CI: 0.71, 0.95) P < (Non-inferiority) P = 0.01 (Superiority)* * Adjusted for multiplicity 0.75 Proportion of Subjects Without SRE 0.50 KM Estimate of Median Months 0.25 The primary endpoint is represented on a Kaplan Meier curve Denosumab was superior to zoledronic acid and reduced the risk of a first on-study SRE by 18% with a confidence interval from 0.71 to The P value was less than for noninferiority and equal to 0.01 for superiority The median time to first on-study SRE was not reached for denosumab and was 26.5 months for zoledronic acid The 2 most common components of SREs were fractures and radiation to bone Approximately 30-37% of subjects experienced an on-study SRE Reference Stopeck A et al. European Journal of Cancer Supplements, Vol. 7, No 3, September 2009, Page 2. Abstract 2LBA and Oral Presentation. Denosumab Not reached Zoledronic acid 26.5 3 6 9 12 15 18 21 24 27 30 Months Subjects at risk Zoledronic Acid 1020 829 676 584 498 427 296 191 94 29 Denosumab 1026 839 697 602 514 437 306 189 99 26 Stopeck A. et al. JCO, 2010

Time to First and Subsequent On-Study SRE* (Multiple Event Analysis)
* Events that occurred at least 21 days apart 1.5 Total # of Events Denosumab 474 Zoledronic acid 608 1.0 Cumulative Mean Number of SRE For the secondary endpoint of time to first and subsequent SRE, otherwise known as the multiple event analysis, denosumab was also superior to zoledronic acid and reduced the risk of multiple events by 23% (rate ratio: 0.77; 95% CI: 0.66–0.89; P=0.001) Reference Stopeck A et al. European Journal of Cancer Supplements, Vol. 7, No 3, September 2009, Page 2. Abstract 2LBA and Oral Presentation. 0.5 Rate Ratio 0.77 (95% CI: 0.66, 0.89) P = 0.001† 3 6 9 12 15 18 21 24 27 30 Months Stopeck A. et al. JCO, 2010 † Adjusted for multiplicity

Adverse Events of Interest
Event, n (%) Zoledronic Acid (N = 1013) Denosumab (N = 1020) Infectious AEs 494 (48.8) 473 (46.4) Infectious serious AEs 83 (8.2) 71 (7.0) Acute phase reactions (first 3 days) 277 (27.3) 106 (10.4) Potential renal toxicity AEs* 86 (8.5) 50 (4.9) Renal failure 25 (2.5) 2 (0.2) Acute renal failure 7 (0.7) 1 (< 0.1) Cumulative rate of ONJ† 14 (1.4) 20 (2.0) Year 1 5 (0.5) 8 (0.8) Year 2 12 (1.2) 19 (1.9) New primary malignancy Additional safety results of note include infectious AEs and infectious serious AEs, both of which were approximately balanced on the 2 arms A prespecified analysis of adverse event terms that could represent a flu-like illness or acute phase reactions reported in the first 3 days after treatment occurred was performed. These adverse events occurred much less frequently with denosumab than with zoledronic acid In another prespecified analysis, adverse event terms that could represent renal toxicity also occurred less frequently with denosumab despite appropriate renal dosing with zoledronic acid per the prescribing information Osteonecrosis of the jaw occurred infrequently and was not significantly different between treatment arms (prespecified P value of 0.39) Reference Stopeck A et al. European Journal of Cancer Supplements, Vol. 7, No 3, September 2009, Page 2. Abstract 2LBA and Oral Presentation. *Includes blood creatinine increased, hypercreatininemia, oliguria, renal impairment, proteinuria, renal failure, urine output decreased, creatinine renal clearance decreased, renal failure acute, renal function test abnormal, anuria, blood urea increased, renal failure chronic No neutralizing anti-denosumab antibodies were detected Stopeck A. et al. JCO, 2010 † P = 0.39

Study Design Henry D et al, JCO, 2011
N = Denosumab 120 mg SC and Placebo IV* every 4 weeks Key Inclusion Adults with solid tumors and bone metastases (excluding breast and prostate) or multiple myeloma Key Exclusion Current or prior intravenous bisphosphonate administration Supplemental Calcium and Vitamin D N = Zoledronic acid 4 mg IV* and SC placebo every 4 weeks This slide is animated due the complexity A total of 1776 eligible adult subjects who were naïve to intravenous bisphosphonates were randomized in a double-blind, double-dummy design to receive subcutaneous denosumab 120 mg or intravenous zoledronic acid (ZA) 4 mg adjusted for creatinine clearance every 4 weeks The key inclusion criterion was that there was evidence of bone metastasis based on x-ray, CT, or MRI The key exclusion criterion was no prior IV bisphosphonate. Prior oral bisphosphonate use for osteoporosis was allowed Zoledronic acid was administered per Zometa® prescribing information. IV product dose which was either Zometa or placebo was calculated according to baseline creatinine clearance. Subsequent doses were withheld if there was elevation of the serum creatinine and the IV product was only reinstated once the serum creatinine had returned to within 10% of baseline levels. This dose and schedule is per the Zometa label. Subjects with creatinine clearance < 30 mL/min were excluded per the Zometa label There was no modification of the SQ product which included denosumab or placebo either at baseline or on study Subjects were stratified by tumor type, previous SRE, and systemic anti-cancer therapy All subjects were strongly recommended to take daily supplemental calcium ( 500 mg) and vitamin D ( 400 IU) No crossover was allowed during the treatment phase The median time on study was 7.3 months for both treatment arms The median time on treatment was 6.7 months for both treatment arms The study duration was approximately 34 months The primary endpoint was time to first on-study SRE, defined as pathologic fracture, radiation therapy or surgery to bone, or spinal cord compression. Secondary endpoints included a superiority test for time to first and time to first-and-subsequent on-study SRE Subject Disposition Approximately 20% of subjects in the denosumab arm and 20% of subjects in the zoledronic arm remained on study through the primary data analysis cut-off date The main reasons for study discontinuation were deaths, disease progression, and consent withdrawn Reference Henry D et al. European Journal of Cancer Supplements, Vol. 7, No 3, September 2009, Page 11. Abstract 20LBA and Oral Presentation. 1° Endpoint 2° Endpoints Time to first on-study SRE (non-inferiority) Time to first on-study SRE (superiority) Time to first and subsequent on-study SRE (superiority) *IV product dose adjusted for baseline creatinine clearance and subsequent dose intervals determined by serum creatinine (per Zometa® label) Henry D et al, JCO, 2011

Baseline Characteristics
Characteristic, n (%) or median Zoledronic Acid (N = 890) Denosumab (N = 886) Male 552 (62) 588 (66) Age (years) 61 60 Primary tumor type Non-small cell lung cancer 345 (39) 343 (39) Multiple myeloma 93 (10) 86 (10) Other 452 (51) 457 (52) ECOG performance status of 0 or 1 728 (82) 748 (84) Time from first bone metastasis to randomization (months) 2 Previous SRE 446 (50) 440 (50) Presence of visceral metastases 448 (50) 474 (53) Baseline characteristics were generally balanced Approximately two-thirds of the subjects enrolled were male The median age of subjects was approximately 60 years and is expected for this population Approximately 83% of subjects had an ECOG of 0 or 1 with approximately 17% having an ECOG of 2 Median time from first bone metastasis to randomization was 2 months 50% of subjects in each treatment arm had experienced an SRE prior to study entry Just over 50% of the population had evidence of visceral metastases at study entry with slightly more subjects in the denosumab arm Reference Henry D et al. European Journal of Cancer Supplements, Vol. 7, No 3, September 2009, Page 11. Abstract 20LBA and Oral Presentation. Henry D et al, JCO, 2011

Time to First On-Study SRE
1.00 1° - HR: 0.84 (95% CI: 0.71–0.98) P = Noninferiority 2° - Unadjusted P = 0.03 Superiority* Adjusted P = 0.06 ithout W 0.75 Proportion of Subjects Without Skeletal Related Event 0.50 KM Estimate of 0.25 Median Months Denosumab 20.6 This is the primary endpoint represented on a Kaplan Meier curve Denosumab reduced the risk of first on-study SRE by 16% compared with Zometa, with a confidence interval from 0.71 to 0.98 This was significant for noninferiority with a P= The median time to first on-study SRE was 20.6 months for denosumab and 16.3 months for zoledronic acid Although directionally favorable, the time to first on-study SRE did not meet statistical superiority for denosumab over zoledronic acid due to adjustments for multiplicity (adjusted P=0.06) The 2 most common components of SREs were fractures and radiation to bone Reference Henry D et al. European Journal of Cancer Supplements, Vol. 7, No 3, September 2009, Page 11. Abstract 20LBA and Oral Presentation. Zoledronic Acid 16.3 3 6 9 12 15 18 21 24 Study Month Subjects at Risk Zoledronic Acid 890 578 376 261 194 126 86 47 Denosumab 886 582 387 266 202 134 96 55 Henry D et al, JCO, 2011

Time to First-and-Subsequent On-Study SRE (Multiple Event Analysis)
2° - Rate Ratio: 0.90 (95% CI: 0.77–1.04) P = 0.14 For the secondary endpoint of time to first-and-subsequent SRE, otherwise known as the multiple event analysis, denosumab reduced the risk of multiple events by 10% compared with zoledronic acid in all patients (rate ratio: 0.90; 95% CI: 0.77–1.04; P=0.14). This difference did not reach statistical significance. Reference Henry D et al. European Journal of Cancer Supplements, Vol. 7, No 3, September 2009, Page 11. Abstract 20LBA and Oral Presentation. Zoledronic Acid Denosumab Total # of SREs 436 392 Henry D et al, JCO, 2011

Adverse Events of Interest
Event, n (%) Zoledronic Acid (N = 878) Denosumab Infectious AEs 349 (39.7) 358 (40.8) Infectious serious AEs 118 (13.4) 128 (14.6) Acute phase reaction (first 3 days) 127 (14.5) 61 (6.9) Potential renal toxicity AEs* 96 (10.9) 73 (8.3) Renal failure 25 (2.8) 20 (2.3) Acute renal failure 16 (1.8) 11 (1.3) Cumulative rates of ONJ† 10 (1.1) Year 1 5 (0.6) 4 (0.5) Year 2 8 (0.9) New primary malignancy 3 (0.3) Additional safety results of note include infectious AEs and infectious serious AEs, both of which were approximately balanced on the 2 arms A prespecified analysis of adverse event terms that could represent a flu-like illness or acute phase reactions reported in the first 3 days after treatment occurred was performed. These adverse events occurred much less frequently with denosumab than with zoledronic acid In another prespecified analysis, adverse event terms that could represent renal toxicity also occurred less frequently with denosumab despite appropriate renal dosing with zoledronic acid per the prescribing information Osteonecrosis of the jaw occurred infrequently and was not significantly different between treatment arms Reference Henry D et al. European Journal of Cancer Supplements, Vol. 7, No 3, September 2009, Page 11. Abstract 20LBA and Oral Presentation. *Includes blood creatinine increased, renal failure, renal failure acute, proteinuria, blood urea increased, renal impairment, urine output decreased, anuria, oliguria, azotaemia, hypercreatininemia, creatinine renal clearance decreased, renal failure chronic, blood creatinine abnormal No neutralizing anti-denosumab antibodies were detected † P = 1.0 Henry D et al, JCO, 2011

Denosumab  Mortality vs ZOL in MM Patients
Dmab  the risk of death by 2.3-fold vs ZOL, and Dmab is not indicated for prevention of SREs in patients with MM (n = 180)1 P value 2.26 OS < .05 0.1 0.2 1 2 3 10 Hazard ratio (Dmab vs ZOL) In favor of Dmab In favor of ZOL Abbreviations: Dmab, denosumab; MM, multiple myeloma; SRE, skeletal-related event; ZOL, zoledronic acid. 1. Xgeva™ (denosumab) injection, for subcutaneous use [package insert]. Thousand Oaks, CA; Amgen Inc; 2010. 35 35

Phase 3 Study of Denosumab in Women Receiving Aromatase Inhibitor Therapy
Study Design: Multi-center, randomized, double-blind, placebo-controlled study conducted in the United States and Canada Women Receiving Aromatase Inhibitor Therapy For Hormone-Receptor-Positive, Non-Metastatic Breast Cancer T‑score of ‑1.0 to ‑2.5 at lumbar spine, total hip (proximal femur), or femoral neck (osteopenia) N = Denosumab 60 mg SC every 6 months (x 4 doses) N = Placebo SC every 6 months (x 4 doses) Baseline month month Ellis GK et al. J Clin Oncol, 26: , 2008

At 12 and 24 months, lumbar spine BMD increased by 5. 5% and 7
At 12 and 24 months, lumbar spine BMD increased by 5.5% and 7.6%, respectively, in the denosumab group versus placebo Placebo (N = 122) Denosumab (N = 123) 8 6 4 2 -2 7 5 3 1 -1 -3 * * * 5.5% Difference at Month 12 * Percentage Change (± 95% CI) From Baseline in Lumbar Spine Bone Mineral Density * 7.6% Difference at Month 24 1 3 6 12 24 Months * P < versus Placebo Ellis GK et al. J Clin Oncol, 26: , 2008

Total Hip (Proximal Femur)
At 12 and 24 months, total hip BMD increased by 3.7% and 4.7%, and distal radius BMD increased by 3.8% and 6.1% respectively, in the denosumab group versus placebo Months Total Hip (Proximal Femur) Percentage Change (± 95% CI) From Baseline in Bone Mineral Density 1 3 6 12 24 4 2 -2 5 -1 Placebo (N = 122) Denosumab (N = 123) * Distal 1/3 Radius Placebo (N = 106) Denosumab (N =115) -3 -4 -5 3.7% Difference at Month 12 4.7% Difference at Month 24 3.8% Difference 6.1% Difference At 12 months, the denosumab arm demonstrated a mean (least-squares) percentage increase in total hip BMD of 3.1% compared with –0.7% in the placebo group (p < ) At month 24, the mean (least-squares) percentage increase was 3.8% in the denosumab group compared with -1.0% in the placebo group At 12 months, the denosumab arm demonstrated a mean (least-squares) percentage increase in distal 1/3 radius BMD of 1.8% compared with -2.1% in the placebo group At month 24, the mean (least-squares) percentage increase was 2.1% in the denosumab group compared with -3.9% in the placebo group P<0.001 vs placebo for both endpoints Ellis G, et al. Oral presentation at: 30th Annual Meeting of the San Antonio Breast Cancer Symposium (SABCS); December 13-16, 2007; San Antonio Texas. Abstract 0047 Amgen data on file. * P < versus Placebo Ellis GK et al. J Clin Oncol, 26: , 2008 39

Presenza di frattura da fragilità
ALGORITMO DECISIONALE NELLA CTIBL AIOM 2011 IN DONNE IN POSTMENOPAUSA CON CR DELLA MAMMELLA Presenza di frattura da fragilità SI NO TERAPIA CON BP o DENOSUMAB (Secondo le indicazioni della nota 79) ETA’ < 60 aa 60-75aa > 75aa DEXA T-score < -2 BPs o denosumab T-score <- 1 + 1 fattore di rischio T-score < fattore di rischio Grado di evidenza II Raccomandazione B

HALT-PC (20040138): Denosumab in ADT-Treated Prostate Cancer
Key eligibility criteria Prostate cancer subjects on ADT Subjects ≥ 70 years of age or < 70 with T-score < -1.0 No previous IV and limited oral BP use Planned N = 1226 Denosumab 60 mg SC, Day 1 of Months 6, 12, 18, 24 30 Placebo 60 mg SC, Day 1 of Months 6, 12, 18, 24 30 F O L W U P E N D S T Y Screen/Randomize Treatment Follow-up/EOS R A M I Z Study Month 1 18 24 ADT, androgen deprivation therapy; BMD, bone mineral density. Primary Endpoint: Percentage Change in Lumbar Spine BMD at Month 24 Secondary Objectives: Efficacy of denosumab compared with placebo on: Fractures and BMD at nonvertebral sites Smith M et al. N Engl J Med, 361:745-55, 2009.

Denosumab therapy was also associated with significant increases in bone mineral density at all bone sites (P≤0.001) (P≤0.001) (P≤0.001) (P≤0.001) ADT, androgen deprivation therapy; BMD, bone mineral density. Smith M et al. N Engl J Med, 361:745-55, 2009.

Denosumab therapy was also associated with significant decreases of new vertebral fractures at 12, 24, 36 months ADT, androgen deprivation therapy; BMD, bone mineral density. Smith M et al. N Engl J Med, 361:745-55, 2009.

ALGORITMO DECISIONALE NELLA CTIBL AIOM 2011
IN MASCHI CON CR DELLA PROSTATA Presenza di frattura da fragilità SI NO TERAPIA: DENOSUMAB* Eventualmente BP Nota 79 ETA’ < 60 aa 60-75aa > 75aa DEXA T-score < -2 TERAPIA Denosumab o eventualmente BPs T-score <- 1 + 1 fattore di rischio T-score < fattore di rischio * Evidenza 1 Racc.: A Grado di evidenza II Raccomandazione B

confronto primitivi-metastasi considerando tutti i campioni
RANK is expressed by cancer cells both at primary tumor and at bone metastases PRIMITIVI METASTASI (p= .194) (p= .528) In animal models with intracardiac injection of human MDA-231 breast cancer cells, the ability of OPG to inhibit tumor-induced osteoclastogenesis, and osteolysis was evaluated.1 The injection of MDA-231 breast cancer cells into the left ventricle of nude mice resulted in experimental bone metastases that were associated with osteolytic lesions. Mice were treated with OPG (at the indicated doses, 3 times per week for 4 weeks) starting immediately after tumor cell inoculation. RANK Ligand inhibition with OPG dose-dependently decreased the number and area of radiographically evident lytic bone lesions.1 OPG treatment at the highest doses completely prevented the radiographic appearance of osteolytic lesions (right radiograph). In the animals treated with OPG, note the increased radio-opacity of the tibial and femoral metaphyseal growth plate region associated with OPG treatment. This increase is a normal pharmacological response to OPG treatment by growing mice, whereby resorption of the secondary spongiosa is inhibited, and trabecular bone accumulates. RANK Ligand inhibition was also observed to significantly decrease the number of osteoclasts within the tumor, with a maximal reduction of 90% at 3 mg/kg (P < 0.01). In this model of experimental bone metastases, RANK Ligand inhibition was associated with significant reductions in both the frequency and the size of skeletal tumor nests and in preventing tumor-associated osteolysis.1 Morony S, et al. Osteoprotegerin Inhibits Osteolysis and Decreases Skeletal Tumor Burden in Syngeneic and Nude Mouse Models of Experimental Bone Metastasis. Cancer Res ;61: confronto primitivi-metastasi considerando tutti i campioni b. confronto primitivi-metastasi considerando solo le coppie metastasi-tumore d’origine Santini D. J Cell Phys, 2010

RANK and OPG predict overall survival in early breast cancer patients
Figure 2 Kaplan–Meier survival curves for overall survival in 295 breast cancer patients according to RANK and OPG expression A RANK and OPG predict overall survival in early breast cancer patients B In animal models with intracardiac injection of human MDA-231 breast cancer cells, the ability of OPG to inhibit tumor-induced osteoclastogenesis, and osteolysis was evaluated.1 The injection of MDA-231 breast cancer cells into the left ventricle of nude mice resulted in experimental bone metastases that were associated with osteolytic lesions. Mice were treated with OPG (at the indicated doses, 3 times per week for 4 weeks) starting immediately after tumor cell inoculation. RANK Ligand inhibition with OPG dose-dependently decreased the number and area of radiographically evident lytic bone lesions.1 OPG treatment at the highest doses completely prevented the radiographic appearance of osteolytic lesions (right radiograph). In the animals treated with OPG, note the increased radio-opacity of the tibial and femoral metaphyseal growth plate region associated with OPG treatment. This increase is a normal pharmacological response to OPG treatment by growing mice, whereby resorption of the secondary spongiosa is inhibited, and trabecular bone accumulates. RANK Ligand inhibition was also observed to significantly decrease the number of osteoclasts within the tumor, with a maximal reduction of 90% at 3 mg/kg (P < 0.01). In this model of experimental bone metastases, RANK Ligand inhibition was associated with significant reductions in both the frequency and the size of skeletal tumor nests and in preventing tumor-associated osteolysis.1 Morony S, et al. Osteoprotegerin Inhibits Osteolysis and Decreases Skeletal Tumor Burden in Syngeneic and Nude Mouse Models of Experimental Bone Metastasis. Cancer Res ;61: C Available gene expression datasets from van de Vijver et al, obtained by microarray analysis of tumor specimens from a total of 295 patients with primary breast cancer Santini D. Plos One, 2011

Immunohistochemical results: 93 primary breast cancer specimens
D C RANK positive breast cancer RANK negative breast cancer Immunohistochemical results. Image A: RANK positive breast cancer. The normal glandular epithelium is negative (black arrow) confirming the RANK protein overexpression of the tumor tissue. Image B is a detail of A. Image C: RANK negative breast cancer. The tissue associated macrophage (black arrow) are positive for RANK staining and are used as internal positive controls. Image D is a detail of C. 93 specimens: 77 IDC samples and 15 ILC samples. RANK overexpression was found in 30 of the 77 (39%) IDC samples and in 8 of the 15 (53%) ILC samples Santini D. Plos One, 2011 48

RANK expression associates with accelerated bone metastasis
RANK negative patients: SDFS of months RANK positive patients: SDFS of 58.9 months RANK expression associates with accelerated bone metastasis (Kaplan Meyer curves of SDFS). RANK negative patients showed a SDFS of months (95% C.I: ) compared with only 58.9 months (95% C.I: ) in RANK positive patients. Santini D. Plos One, 2011 49

RANK Ligand Inhibition
RANK Ligand Inhibition Blocks Tumor-Induced Osteolysis in Breast Cancer Model 0.3 1 3 2 4 * # Lesions / Mouse MDA-231 Intracardiac Model Radiographic Lesions OPG Dose (mg/kg) In animal models with intracardiac injection of human MDA-231 breast cancer cells, the ability of OPG to inhibit tumor-induced osteoclastogenesis, and osteolysis was evaluated.1 The injection of MDA-231 breast cancer cells into the left ventricle of nude mice resulted in experimental bone metastases that were associated with osteolytic lesions. Mice were treated with OPG (at the indicated doses, 3 times per week for 4 weeks) starting immediately after tumor cell inoculation. RANK Ligand inhibition with OPG dose-dependently decreased the number and area of radiographically evident lytic bone lesions.1 OPG treatment at the highest doses completely prevented the radiographic appearance of osteolytic lesions (right radiograph). In the animals treated with OPG, note the increased radio-opacity of the tibial and femoral metaphyseal growth plate region associated with OPG treatment. This increase is a normal pharmacological response to OPG treatment by growing mice, whereby resorption of the secondary spongiosa is inhibited, and trabecular bone accumulates. RANK Ligand inhibition was also observed to significantly decrease the number of osteoclasts within the tumor, with a maximal reduction of 90% at 3 mg/kg (P < 0.01). In this model of experimental bone metastases, RANK Ligand inhibition was associated with significant reductions in both the frequency and the size of skeletal tumor nests and in preventing tumor-associated osteolysis.1 Morony S, et al. Osteoprotegerin Inhibits Osteolysis and Decreases Skeletal Tumor Burden in Syngeneic and Nude Mouse Models of Experimental Bone Metastasis. Cancer Res ;61: 0.3 1 3 60 120 180 OPG Dose (mg/kg) * # of OC / mm2 Tumor Area Control RANK Ligand Inhibition *Significantly different from 0 mg/kg OPG Reproduced from Morony S, et al. Cancer Res. 2001;61(11): with permission of the American Association for Cancer Research.

RANK Ligand Inhibition Reduces Tumor Burden and Improves Survival in a Mouse Model of Multiple Myeloma 3.0 3.5 2.5 2.0 1.5 1.0 * *P < 0.05 Paraprotein (g/dL) Cumulative Survival 5 10 15 20 25 30 35 40 Days 1.0 0.8 0.6 0.4 0.2 OPG Control P < 0.02 Control 5T33MM + Vehicle + OPG 85 90 80 75 70 65 * % Tumor Cells To evaluate the effect of reduced tumor burden on survival with RANK Ligand inhibition, 5T33MM-bearing mice were treated with OPG in separate experiments and the time to onset of morbidity were assessed.1 5T33MM cells are used as a murine model of multiple myeloma (MM). In this experiment, 24 mice were injected with 5T33MM cells and the development of MM was monitored by measuring serum paraprotein concentrations. On the day of injection of 5T33MM cells, mice were treated with OPG at 25 mg/kg/TIW or vehicle for 4 weeks. All of the animals that were given injections of 5T33MM cells developed MM. Twenty-eight days after injection of the MM cells, mice were sacrificed, bone marrow was isolated from the hind legs, and the proportion of tumor cells determined by staining the cells with an anti-5T33MM idiotype antibody and analysis by flow cytometry. To determine the effect of RANK Ligand on survival in the 5T33MM model, a similar experiment (as described above) was performed. Twenty-four mice were given injections of 5T33MM cells; 12 were treated with vehicle and 12 with OPG from the time of tumor injection. Treatment continued until each animal showed signs of morbidity, which included hind limb paralysis or cachexia, at which point they were sacrificed. Kaplan-Meier analysis demonstrated a significant delay in the onset of morbidity (7.8 days, 25% increase, P < 0.02, OPG treated group vs. vehicle). Day 1 was the first day of onset of morbidity (4 weeks after initiation of the experiment). RANK Ligand inhibition was observed to reduce tumor burden and improve survival in this murine model as measured by paraprotein levels and tumor cell numbers.1 Vanderken K, et al. Recombinant Osteoprotegerin Decreases Tumor Burden and Increases Survival in a Murine Model of Multiple Myeloma. Cancer Research. 2003;63:287–9. Adapted from Vanderken K, et al. Cancer Res ;63:287–9.

The Effect of RANK Ligand Inhibition on Established Prostate Cancer-Induced Osteoblastic Bone Lesions in Mice Prostate Cancer LuCaP 35 HU / SCID Model, Rx Initiated at 6 Weeks1 RANK Ligand Inhibition (RANK:Fc) Serum PSA as Surrogate Marker for Prostate Tumor Burden Basal Vehicle * 40 35 30 25 †,** PSA (ng/mL) 20 X-ray 15 10 Inhibition of RANK Ligand decreases tumor burden in established lesions in a prostate cancer model with RANK-expressing LuCaP 35 cells.1 A study evaluated osteoblastic disease in mice by implanting a human bone explant (see arrows in x-ray) and then injecting a human prostate cancer tumor cell line.1 The difference between basal and vehicle is approximately 4 weeks and shows how the human bone explant becomes more dense (on radiographs and BMD measures with DXA) as a result of the prostate cancer induced osteoblastic disease. Human fetal bone were subcutaneously implanted into male SCID mice (6-weeks-old). Four-weeks later, LuCaP 35 cells (which are androgen-sensitive, PSA-producing human cancer prostate cancer xenographs) were injected and allowed to develop into tumors. Six weeks after the implant of LuCaP 35 cells, mice were palpated for the presence of the tumor and blood PSA levels were measured. Mice that had tumors and were positive for PSA were randomly assigned to one of three groups (n=9/group) Intraperitoneal injection of sRANK-Fc 200 mcg/mouse or saline vehicle three times per week. Mice were sacrificed after 6 weeks of treatment. To determine the extent of tumor burden, serum PSA levels were quantified in mice. Serum PSA levels were increased by ~157% in vehicle treated mice compared with the basal group (P < 0.001). Administration of soluble RANK-Fc resulted in only a 50% increase in PSA levels from the levels of basal mice (P < 0.01), thus diminishing the increase that occurred in the vehicle treated group by ~66% (P < 0.01). This hypothesis has not been proven in humans. Zhang J, et al. Cancer Res. 2003;63: 5 Basal Vehicle RANK-Fc Treatment *P < as compared with basal group †P < 0.01 as compared with basal group **P < 0.01 as compared with vehicle treated group Osteoblastic bone metastases 1. Adapted from Zhang J, et al. Cancer Res. 2003;63:

The Effect of RANK Ligand Inhibition on Migration/Invasion of Malignant Prostate Cancer Cells Expressing RANK (PC-3) 120 RANK Ligand (2.5 mcg/mL) RANK Ligand + OPG (10 mcg/mL) 240 * 100 180 80 Migration (% Baseline) 120 60 Invasion (%) PC3 Cells 40 60 RANK Ligand has an important role in cell migration and the tissue-specific metastatic activity of cancer cells expressing RANK.1-3 The figure on the left shows the results from a study that investigated if RANK Ligand activation of RANK has a role in epithelial cell migration.1 The results are expressed as the percentage increased migration (± SD) compared to unstimulated control cells. In vitro stimulation of two RANK-expressing prostate cancer cell lines (LNCaP, Du145) with RANKL (2.5 mcg/mL) are shown in the graph: Cell migration was concentration dependent. RANK Ligand inhibition with OPG-Fc (10 mcg/mL) blocked cell migration. The same study observed similar effects in three different human breast cancer cell lines (MDA-MB-231, Hs578T, and MCF-7), and a negligible effect on migration of a colon cancer cell line (Colo205; in which the authors failed to detect RANK expression). The figure shown on the right shows the ability of RANK Ligand to stimulate invasion of PCs cells through collagen.4 PC3 cells were seeded in the upper compartment of two-layer chamber invasion plates that were separated by an uncoated (for baseline control) or a membrane coated with collagen matrix, with RANK Ligand added to the media in the lower chamber. Cells were cultured for 48 hours and invasion was determined by the number of cells that invaded the matrix-coated membrane divided by the number of cells that migrated through the uncoated membrane (baseline migration). These results are shown in the figure: Invasion was increased significantly in the presence of RANK Ligand as compared to control (P < 0.05). RANK Ligand induced invasion occurred in a dose dependent manner. Invasion of PC3 cells through collagen was blocked by the addition of OPG (P < 0.05). Thus, RANK Ligand activation of RANK was sufficient to induce migration1,2 and invasion3 of malignant epithelial cells expressing RANK. Migration can be reduced by inhibition of RANK Ligand (by OPG-Fc).1,2 1. Jones DH, et al. Nature. 2006;440: 2. Mori K, et al. Bone. 2007; In Press. 3. Armstrong AP, et al. Cancer Res. 2007: In Review. 20 LNCaP Du145 OPG† - + + RANKL† - Prostate1 † Dosed at 100 ng/ml2 Significantly reduced migration compared to RANK Ligand (a, P < 0.02; b, P < 0.05) *Significantly different from all other treatment groups, P < 0.05 1. Adapted from Jones DH, et al. Nature. 2006;440: Armstrong AP, et al. The Prostate. 2008;68:

RANK Ligand induces migration of RANK-expressing cancer cells to bone
Jones et al. investigated the role of RANK Ligand in migration of RANK-expressing cancer cells to bone and whether inhibition of RANK Ligand by the decoy receptor, OPG, can prevent this migration.1 Expression of RANK mRNA was detected in several human prostate and breast cancer cell lines. The in vitro studies by Jones et al. show RANK Ligand induced migration of the malignant epithelial cells expressing RANK. RANK Ligand is a critical osteoclast differentiation factor that is highly expressed in the bone marrow environment.2 Since RANK has been found to be expressed on cells from multiple epithelial tumors and a malignant melanoma cell line1,3, which preferentially metastasize to bone, RANK Ligand may be one of the factors that facilitate metastasis to bone. Inhibition of RANKL/RANK signalling by OPG in vivo markedly and selectively reduced bone metastasis and tumor burden in a melanoma model that does not activate osteoclasts.1 Jones DH, et al. Nature. 2006;440: Lacey DL, et al. Cell. 1998;93: Amgen, data on file. *Cell lines used expressed RANK Jones DH, et al. Nature. 2006;440:

Prevention of Bone Metastases in PC: Phase III Denosumab Trial (AMG 147)
Primary endpoint: Time to development of bone metastasis or death Secondary endpoint: Time to development of bone metastasis (excluding death) R Prostate cancer (nonmetastatic) Hormone-refractory disease High risk of bone metastases Adequate organ function N = 1,435 Denosumab 120 mg SC every 4 weeks Placebo Event-driven study: time to bone metastasis or death Data expected Q1 2011 Abbreviations: AMG, Amgen; PC, prostate cancer; SC, subcutaneous. 55 55 55

Prevention of Bone Metastases in PC: Phase III Denosumab Trial (AMG 147)
Denosumab increased bone metastasis-free survival by 4.2 months Amgen press release, 2011 Final data will presented at next ASCO, 11 R Prostate cancer (nonmetastatic) Hormone-refractory disease High risk of bone metastases Adequate organ function N = 1,435 Denosumab 120 mg SC every 4 weeks Placebo Event-driven study: time to bone metastasis or death Data expected Q1 2011 Abbreviations: AMG, Amgen; PC, prostate cancer; SC, subcutaneous. 56 56 56

ABCSG-18 & D-CARE Trials: Dmab in Adjuvant BC
Primary Objective: Compare the effects of Dmab vs placebo on the rate of first clinical fracture in women with nonmetastatic BC receiving NSAI therapy Follow-up without treatment: 96 mo R N = 3,400 Placebo SC q6mo Denosumab 60 mg SC every q6mo Treatment duration: 48 mo D-CARE2 Primary objective: Bone-metastasis–free survival with denosumab vs placebo R N = 4,500 Placebo 120 mg SC monthly x 6 mo, q3mo x 4.5 yr Dmab 120 mg SC monthly x 6 mo, q3mo x 4.5 yr Treatment duration: 5 yr Abbreviations: ABCSG-18, Austrian Breast and Colorectal Cancer Study Group trial 18; BC, breast cancer; Dmab, denosumab; NSAI, nonsteroidal aromatase inhibitor; R, randomisation; SC, subcutaneous. Identifier: NCT 57

Approved Indications for Antiresorptive Agents in Oncology
Prevention of SREs HCM Multiple Myeloma Breast Cancer Prostate Cancera Other Solid Tumors Clodronate (oral)  Pamidronate (IV) Zoledronic acid (IV) Ibandronate (oral and IV) Denosumab – no  = European Registration  = Worldwide Registration  = US Registration Zoledronic acid is currently approved for the prevention of SREs in the metastatic breast cancer setting worldwide, including the Middle East and Asia. a In the United States, prostate cancer must have progressed despite hormone therapy. Abbreviations: HCM, hypercalcemia of malignancy; IV, intravenous; SRE, skeletal-related event. Prescribing information for pamidronate and zoledronic acid is available at: and Further information for clodronate and ibandronate is available at and Denosumab prescribing information is available at 58 58

I Punti “aperti”

I Punti “aperti” Denosumab e durata della terapia

Percentage Change (LS mean ± SE)
Rapid Rebound in Osteolysis on Stopping Dmab: Risk of SREs With Missed Doses? Rapid ↑ in osteolysis and ↓ in BMD after stopping Dmab in osteoporosis setting What can we expect in bone mets setting, wherein osteolysis rates are higher? Placebo Denosumab 48 36 24 18 12 6 –4 –2 2 4 8 10 14 Time, months Treatment Off treatment Re-treatment Percentage Change (LS mean ± SE) Placebo Denosumab Treatment Off treatment Re-treatment 25 20 15 Median µg/mL (Q1, Q3) 10 5 6 12 18 24 30 36 42 48 Time, months Abbreviations: BMD, bone mineral density; Dmab, denosumab; SRE, skeletal-related event. Reprinted from Miller PD, et al. Bone. 2008;43(2): Emphasis added. 61 61

I Punti “aperti” Denosumab e rischio di infezioni

 Infections and Other AEs With Dmab ?
Infection SAEs in osteoporosis trials1 Study or subgroup Bone 2008 Ellis 2008 Lewiecki 2007 Total 0.001 0.1 1 10 1000 Favors placebo Favors Dmab 8.41 2.83 1.96 4.45 P = 0.03 Long-term safety of Dmab not yet established; in addition to hypocalcemia2 and infections,  New malignancies with Dmab vs ZOL in OST/MM (0.6% vs 0.3%)3  Cardiovascular toxicity3 Abbreviations: AE, adverse event; Dmab, denosumab; MM, multiple myeloma; OST, other solid tumors; SAE, serious adverse event; ZOL, zoledronic acid. 1. Reprinted from Anastasilakis AD, et al. Horm Metab Res. 2009;41(10): ; 2. Xgeva (denosumab) injection [package insert]. Thousand Oaks, CA: Amgen Inc., 2010; 3. Henry D, et al. ECCO-ESMO 2009., abstract 20LBA. 63

Conclusions Denosumab prevents bone mineral loss related to AI therapy in breast and in prostate cancer Denosumab prevents vertebral fractures related to ADT in prostate cancer patients RANKL, receptor activator of nuclear factor kappa B ligand; uNTx/CR, urinary N-telopeptide corrected for urine creatinine.

Conclusions Phase III studies of denosumab vs bisphosphonates ongoing in metastatic setting show non inferiority or superior efficacy in term of time to first SRE (breast , prostate and other solid tumours) Phase III studies of denosumab are ongoing in adjuvant setting (breast and prostate cancer) RANKL, receptor activator of nuclear factor kappa B ligand; uNTx/CR, urinary N-telopeptide corrected for urine creatinine.

Thank you very much for your attention

EdiVoteStart EdiVoteStop Standard Il denosumab ha dimostrato nel tumore della mammella metastatico a livello osseo di: Essere non inferiore all'acido zoledronico in termini di tempo al primo SRE Essere non inferiore e anche superiore all'acido zoledronico in termini di tempo al primo SRE Essere capace di ridurre l'incidenza del primo e dei successivi SRE in misura identica all'acido zoledronico Indurre un incremento di incidenza di ONJ superiore all'acido zoledronico 25% 25% 000 25% 25% 020

EdiVoteStart EdiVoteStop Standard Il denosumab ha dimostrato nel tumore della prostata ormonorefrattario metastatico a livello osseo di: Essere non inferiore all'acido zoledronico in termini di tempo al primo SRE Essere non inferiore e anche superiore all'acido zoledronico in termini di tempo al primo SRE Essere capace di ridurre l'incidenza del primo e dei successivi SRE in misura identica all'acido zoledronico Indurre un incremento di incidenza di ONJ superiore all'acido zoledronico 25% 000 25% 25% 25% 020

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