Presenter: 翁家嫻 Venue date:

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1 FOR THE TREATMENT OF OSTEOPOROSIS IN POSTMENOPAUSAL WOMEN AT INCREASED RISK OF FRACTURES 1 Presenter: 翁家嫻 Venue date: PMO: postmenopausal osteoporosis. 1. Prolia (denosumab), Summary of Product Characteristics, July Prescribing information is available at the end of this presentation. Date of preparation: November 2015 PR-TWN-MKT-P JUN

2 The 2009 TIME 100: TOP 10 MEDICAL BREAKTHROUGHS

3 Osteoporosis affects over 200 million women worldwide 1 30% of all postmenopausal women have osteoporosis 2 The major complication of osteoporosis is hip fracture 2 Lifetime risk for hip, vertebral and wrist fractures, estimated at 40%, is similar to the risk of cardiovascular disease International Osteoporosis Foundation. Available at: Accessed November Reginster J-Y, Burlet N. Bone 2006; 38: S4 S9. 3. Gullberg B et al. Osteoporos Int 1997; 7:

4 The social and economic burden of some fractures have more impact than others 1 Less than 50% of survivors regain the level of function they had prior to hip fracture 1 Recovery from a hip fracture is slow and many patients end up permanently institutionalised in nursing homes Ström O et al. Arch Osteoporos 2011; 6: Kanis JA et al. Osteoporos Int 2013; 24:

5 Osteoporotic fractures are caused by both cortical and trabecular bone loss 1 Most cortical bone loss occurs between 65 and 79 years of age 1 Targeting both cortical and trabecular bone is important to help reduce fracture risk for PMO patients 1,3 5 PMO: postmenopausal osteoporosis. 1. Zebaze RMD et al. Lancet 2010; 375: Dempster DW. Chapter 2. Anatomy and Functions of the Adult Skeleton. In: Favus M, editor. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. 6th Ed p Roux J-P et al. J Bone Miner Res 2010; 25:

6 Increased cortical porosity leads to bone fragility 1 These micrographs are from anterior subtrochanteric specimens. A Elsevier Ltd. Adapted with permission from: Zebaze RMD, Ghasem-Zadeh A, Bohte A, et al. Supplementary web appendix to: Intracortical remodelling and porosity in the distal radius and post-mortem femurs of women: a cross-sectional study. The Lancet 2010; 375: [online] Available at: lancet/article/piis (10) B. Zebaze RMD and Seeman E, Melbourne, Australia. High-resolution peripheral CT. C Elsevier Ltd. Adapted with permission from: Zebaze RMD, Ghasem-Zadeh A, Bohte A, et al. Intracortical remodelling and porosity in the distal radius and post-mortem femurs of women: a cross-sectional study. The Lancet 2010; 375: *Prolia is indicated for the treatment of osteoporosis in postmenopausal women at increased risk of fractures Zebaze RMD et al. Lancet 2010; 375: Prolia (denosumab), Summary of Product Characteristics, July 2015.

7 The incidence of hip fracture increases exponentially with age 1 Vertebral fracture is prevalent among postmenopausal women. Hip fracture is agedependent and increases significantly and exponentially with age. 1 *Radiographic confirmed fractures Sambrook P and Cooper C. Lancet 2006; 367:

8 Fracture rates are significantly higher for patients with lower BMD T-scores 1 8 BMD: bone mineral density. 1. Office of the Surgeon General (US). Report of the Surgeon General's Workshop on Osteoporosis and Bone Health. December 12 13, 2002.

9 A Wide Variety of Therapies Are Currently Available f or Osteoporosis Current Clinical Prescription THERAPIES APPROVED FOR OSTEOPOROSIS Category Therapy name (brand name) Mode and frequency of administration 9 RANK Ligand Inhibitor Denosumab (Prolia ) Subcutaneous injection, every 6 months Bisphosphonates Selective oestrogen receptor modulator (SERM) Parathyroid hormone (PTH) Other Alendronate (Fosamax ) Ibandronate (Bonviva ) Zoledronate (Aclasta ) Raloxifene (Evista ) Teriparatide (Forteo ) Strontium ranelate (Protos ) Oral, daily or weekly Oral, monthly IV injection, every 3 months IV infusion, yearly Oral, daily Injection, daily Oral, daily

10 Prolia has a different mechanism of action from bisphosphonates 1 10 this may explain potential differences in their effects on cortical and trabecular bone Baron R et al. Bone 2010; 48: ; 2. Prolia (denosumab), Summary of Product Characteristics, July 2015; 3. Cummings SR et al. N Engl J Med 2009; 361: ; 4. Seeman E et al. J Bone Miner Res 2010; 25: ; 5. Kostenuik PJ. Curr Opin Pharmacol 2005; 5: ; 6. Boyle WJ et al. Nature 2003; 423: ; 7. Dempster DW. Chapter 2. Anatomy and Functions of the Adult Skeleton. In: Favus M, editor. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. 6th Ed p7 11; 8. Russell RGG. Bone 2011; 49: 2 19; 9. Kimmel DB et al. J Dent Res 2007; 86: ; 10. Lin JH et al. Drug Metabolism and Disposition 1992; 20:

11 Prolia : Therapeutic indication 1 Treatment of osteoporosis in postmenopausal women at increased risk of fractures. Prolia significantly reduces the risk of hip, vertebral and non-vertebral fractures 1 The recommended dose of Prolia is 60 mg administered as a single subcutaneous injection once every 6 months into the thigh, abdomen or upper arm Prolia (denosumab), Summary of Product Characteristics, July 2015.

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13 OPG Is a Decoy Receptor That Prevents RANK Ligand Binding to RANK 16 CFU-GM Prefusion Osteoclast RANKL RANK OPG Hormones Growth Factors Cytokines Osteoclast Formation, Function, and Survival Inhibited Osteoblasts Bone Formation Bone Resorption Inhibited Adapted from: Boyle WJ, et al. Nature. 2003;423:

14 OPG: osteoprotegerin Boyle WJ, et al. Nature 2003;423: Eghbali-Fatourechi G, et al. J Clin Invest 2003;111: Reduction in Oestrogen Increases RANK Ligand Expression, Causing Increased Bone Resorption Differentiated Osteoclasts Precursors RANK RANK Ligand RANK OPG 17 RANK Decreased Oestrogen Decreased oestrogen increases RANK ligand expression Increased RANK Ligand in Postmenopausal Women Leads to Excessive Bone Resorption RANK Ligand Osteoblasts OPG Excess RANK ligand expression overwhelms Osteoblasts Activated Osteoclasts OPG Imbalanced Resoprtion and Formation

15 Denosumab in CTIBL: Proposed Mechanism of Action 18

16 FREEDOM

17 FREEDOM: Study design 1 Eligibility criteria 1 7,808 postmenopausal women between the ages of 60 and 90 years were randomised BMD T-score < 2.5 at the lumbar spine or total hip and not < 4.0 at either site Randomisation was stratified according to 5-year age groups FREEDOM study design 1 Exclusion criteria 1 Any severe or more than two moderate prevalent vertebral fractures Conditions that influence bone metabolism other than PMO Primary endpoint 1 New radiographic vertebral fracture* over 36 months Secondary endpoints 1 Non-vertebral fracture Hip fracture 20 BMD: bone mineral density; PMO: postmenopausal osteoporosis. 1. Cummings SR et al. N Engl J Med 2009; 361: *Defined as an increase of at least one grade in a vertebral body that was normal at baseline. All non-vertebral fractures. However, fractures of the skull, face, mandible, metacarpals, fingers or toes were excluded because they are not associated with decreased bone mineral density. Pathological fractures and those associated with severe trauma were also excluded.

18 Prolia helps to protect your patients where they need it the most at the hip and other key sites 1 Results at 36 months. Primary endpoint: new radiographic vertebral fracture. 1 *All non-vertebral fractures. However, fractures of the skull, face, mandible, metacarpals, fingers or toes were excluded because they are not associated with decreased bone mineral density. Pathological fractures and those associated with severe trauma were also excluded Cummings SR et al. N Engl J Med 2009; 361:

19 Prolia ensures a robust and consistently low incidence of hip fractures over the course of 8 years 1 2 Papapoulos S, Lippuner K, Roux C, et al. Eight Years of Denosumab Treatment in Postmenopausal Women With Osteoporosis: Results From the First Five Years of the FREEDOM Extension. J Bone Miner Res 2013; 28 (Suppl 1). Image adapted from Poster LB-MO26 (from abstract LB-MO26: J Bone Miner Res 2013; 28 (Suppl 1); available at accessed November 2, 2015); with permission of Papapoulos S and the American Society for Bone and Mineral Research. n: number of subjects with 1 fracture; N: number of randomised subjects who remained on study at the beginning of each period Papapoulos S et al. Eight Years of Denosumab Treatment in Postmenopausal Women With Osteoporosis: Results From the First Five Years of the FREEDOM Extension. ASBMR 2013 (poster); 2. Papapoulos S et al. Osteoporos Int. 2015; doi: /s

20 Prolia continues to increase BMD over the course of 8 years 1 Change in total hip BMD may act as a predictor of the benefit of Prolia treatment on fracture risk 2 Data are least-squares means (CI 95%). *P<0.05 compared with the FREEDOM baseline; P<0.05 compared with the Extension baseline BMD: bone mineral density. 1. Papapoulos S et al. Osteoporos Int. 2015; doi: /s Bone HG et al. J Clin Endocrinol Metab 2013; 98:

21 Long-term efficacy

22 Effects of Denosumab Treatment on Total Hip BMD and Nonvertebral Fractures Through 10 Years BMD data are LS means and 95% confidence intervals. a P < 0.05 vs FREEDOM baseline. b P < 0.05 vs FREEDOM and Extension baselines. c Percentage change while on denosumab treatment. Percentages for nonvertebral fractures are Kaplan-Meier estimates. Bone, H. G., et al. "Ten years of Denosumab (DMAB) treatment in postmenopausal women with osteoporosis. Results from the FREEDOM Extension trial." Osteoporosis International 27.Supplement 1 (2016):

23 Effects of Denosumab Treatment on Lumbar Spine BMD and New Vertebral Fractures Through 10 Years BMD data are LS means and 95% confidence intervals. a P < 0.05 vs FREEDOM baseline. b P < 0.05 vs FREEDOM and Extension baselines. c Percentage change while on denosumab treatment. d Annualized incidence: (2-year incidence) / 2. Lateral radiographs (lumbar and thoracic) were not obtained at years 4, 7, and 9 (years 1, 4, and 6 of the Extension). Bone, H. G., et al. "Ten years of Denosumab (DMAB) treatment in postmenopausal women with osteoporosis. Results from the FREEDOM Extension trial." Osteoporosis International 27.Supplement 1 (2016):

24 Safety results from the FREEDOM study, over 3 years 1 SERIOUS ADVERSE EVENTS IN THE FREEDOM STUDY 1 Serious adverse event Prolia 60 mg (n=3,886) Placebo (n=3,876) P-value* Cancer 144 (3.7) 125 (3.2) 0.28 Infection 159 (4.1) 133 (3.4) 0.14 Cardiovascular event 186 (4.8) 178 (4.6) 0.74 Stroke 56 (1.4) 54 (1.4) 0.89 Coronary heart disease 47 (1.2) 39 (1.0) 0.41 Peripheral vascular disease 31 (0.8) 30 (0.8) 0.93 Atrial fibrillation 29 (0.7) 29 (0.7) 0.98 Serious adverse events occurring in 0.1% patients Cellulitis (including erysipelas) 12 (0.3) 1 (<0.1) Concussion 1 (<0.1) 11 (0.3) *P-values based on log-rank test, except for between-group comparisons of deaths and cardiovascular events, which were based on a Cox proportional hazards model with adjustment for baseline cardiovascular risk score. 1 P 0.01 for between-group comparison. Among terms listed in the Medical Dictionary for Regulatory Activities (MedDRA), the incidence of serious adverse events corresponding to 152 MedDRA-preferred terms was at least 0.1% in either study group Cummings SR et al. N Engl J Med 2009; 361:

25 Safety results over 5 years of the FREEDOM Extension study 1 ADVERSE EVENTS IN THE FREEDOM EXTENSION STUDY 1 Event Cross-over Prolia (Extension, 5 years) (n=2,206) Rate Long-term Prolia (FREEDOM + Extension, 8 years) (n=2,343) Rate All adverse events Infections Malignancies Eczema Hypocalcaemia 0.1 <0.1 Pancreatitis <0.1 <0.1 Serious adverse events Infections Cellulitis or erysipelas <0.1 <0.1 Fatal adverse events ONJ <0.1 <0.1 Atypical femoral fracture <0.1 <0.1 n: number of subjects who received 1 dose of investigational product. Treatment groups are based on the original randomised treatments received in FREEDOM. Rate: exposure-adjusted subject incidence per 100 subject-years. Adverse events coded using MedDRA v13.0. Cumulative ONJ cases: 3 cross-over, 5 long-term. Cumulative atypical femoral fracture cases: 1 cross-over, 1 long-term. 28 MedDRA: Medical Dictionary for Regulatory Activities; ONJ: osteonecrosis of the jaw. 1. Papapoulos S et al. Eight Years of Denosumab Treatment in Postmenopausal Women With Osteoporosis: Results From the First Five Years of the FREEDOM Extension. ASBMR 2013 (poster).