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

7/25/2014 Denosumab CONFLICTS OF INTEREST: A Lecture at Amgen Two Years Ago Clifford J Rosen MD Maine Medical Center Research Institute rosenc@mmc.org Bone remodeling is a cellular process Bone Remodeling Osteoclast Osteoblasts Bone Lining Cells Osteocytes 1

7/25/2014 . Osteoprotegerin Prevents RANKL Binding to RANK and Inhibits Osteoclast Activity Osteoclast Precursor Colony-Forming Multinucleated Unit-Macrophage RANKL Osteoclast X RANK OPG X Hormones Activated Growth Factors Osteoclast Cytokines Osteoblasts X Boyle WJ, et al. Nature. 2003;423:337-342. Bone Resorption Denosumab RANKL Signaling • Denosumab is a “fully- human” monoclonal antibody that binds to RANKL � RANKL - a ligand for RANK (receptor found on osteoclasts) 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 osteoprotegerin 2

7/25/2014 Denosumab Fracture Study Results • Denosumab increased BMD at L- • 7688 women enrolled; Spine (9.2%) and total hip (6.0%) 6478 completed 36 relative to placebo mos; 5979 received all • Also significantly injections decreased CTX and • 3902 in denosumab PINP levels vs. placebo group; 3906 placebo – “CTX is released directly from bone as a result of osteoclastic resorption” – PINP is an osteoblast marker – a marker of bone formation 3

7/25/2014 Results Results 4

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7/25/2014 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 6

7/25/2014 Serum CTX 20 10 Serum CTX percent change (%) 0 Placebo -10 -20 -30 -40 -50 -60 Alendronate (median) -70 60 mg -80 -90 6 12 18 24 BL D3 D3 Month Lewiecki EM et al. J Bone Miner Res . 2007 Dec;22(12):1832-41. Serum BSAP Bone-specific alkaline phosphatase 20 Placebo 10 percent change (%) (median) 0 -10 -20 -30 -40 60 mg -50 Alendronate -60 -70 -80 BL 6 12 18 24 Month Lewiecki EM et al. J Bone Miner Res . 2007 Dec;22(12):1832-41. 7

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7/25/2014 FREEDOM Extension Study Design Adverse Events International, multicenter, open-label, single-arm study • No significant difference incidence of FREEDOM EXTENSION serious adverse events Year 0 1 2 3 4 5 6 7 8 9 10 • Specifically no diff in incidence of R Long-term DMAb 60 mg DMAb 60 mg A SC Q6M SC Q6M DMAb cancer, CV events, serious infection, N D (N = 3902) (N = 2343) Treatment O delayed fracture healing M I Calcium and Vitamin D • 1 pt developed osteonecrosis of jaw Z A Placebo DMAb 60 mg Cross-over T I SC Q6M SC Q6M • Several cases of skin rashes and DMAb O (N = 3906) (N = 2207) Treatment N erysipelas Year 0 1 2 3 4 5 6 7 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. Percentage Change in BMD at the Continued Denosumab Treatment in the FREEDOM Extension for Up to 8 Years Lumbar Spine and Total Hip Placebo Cross-over Denosumab Long-term Denosumab • Maintained reduction in bone turnover Lumbar Spine Total Hip 20 10 † FREEDOM EXTENSION FREEDOM EXTENSION • Was associated with a low incidence of nonvertebral and clinical Percentage Change from Baseline 18 † 18.4% † † 16 8 † 8.3% vertebral fractures † † † 14 † * • Remained well tolerated 6 12 13.7% † † * * 10 † † Placebo Long-term DMAb 4 4.9% * * 8 † FREEDOM EXTENSION † * Nonvertebral Fractures (%) * 6 3.5 † 2 3.1% Yearly Incidence of * 3.0 2.9% 4 * 2.6% 2.5% 2.5 * 2.2% 2.1% 2 * 0 * 2.0 * 1.6% 1.5% 1.4% 0 * 1.5 1.2% -2 1.0 0.7% -2 0.5 0 1 2 3 4 5 6 7 8 0 1 2 3 4 5 6 7 8 0.0 Study Year Study Year 1 2 3 4 5 6 7 8 Years of DMAb Treatment Cross-over n 119^ 122^ 120^ 122^ 2005 2029 1924 1488 1463 118^ 120^ 2022 1997 1962 2006 1895 1457 1423 n 116 98 103 75 83 73 33 27 31 27 12 Long-term n 139^ 140^ 140^ 141^ 2111 2148 2041 1589 1551 139^ 140^ 2149 2124 2086 2132 2017 1567 1518 N 3906 3902 3688 3682 3454 3487 2343 2243 2066 1867 1747 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. 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. ^ Represents subjects from the FREEDOM DXA substudy. Papapoulos S, et al. ASBMR 2013, abstract LB-MO26 Papapoulos et al, ASBMR, 2013 10

7/25/2014 Effects of Denosumab Treatment on Total Hip BMD and What Is the Explanation for the Continuous Gain in BMD with Nonvertebral Fractures Through 8 Years Long-term Denosumab Therapy, Particularly at the Hip? Placebo Cross-over Denosumab Long-term Denosumab Possible Answer(s): What mechanism(s) • Increased (secondary) mineralization versus increased mass can explain the continuous increase in bone mass and observed nonvertebral fracture incidence? • Dynamic effects – “Breathing” i.e. resolution of effect at end of cycle – Repeated increases in endogenous PTH • Remodeling-independent bone formation 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. Papapoulos S, et al. ASBMR 2013, abstract LB-MO26 FREEDOM QCT Substudy FREEDOM QCT Substudy Total Hip QCT BMD, BMC & Volume Total Hip Cortical BMD, BMC, & Volume % Change from Baseline at Month 36 % Change from Baseline at Month 36 Placebo Denosumab Placebo Denosumab * * 6 10 Percent Change from Baseline Percent Change from Baseline * * 8 4 6 2 4 2 0 0 -2 -2 -4 -4 BMD BMC Volume BMD BMC Volume LS means ± 95% CIs; * P < 0.0001 LS means ± 95% CIs; * P < 0.0001 Adapted from McClung MR, et al. J Clin Densitom 2012;16:250-6 Adapted from McClung MR, et al. J Clin Densitom 2012;16:250-6 11

7/25/2014 Mean Regional Cortical Mass and Denosumab Decreases Cortical Porosity at Thickness the Hip Placebo (n = 22) Denosumab (n = 28) 6.0% P = 0.0001 P = 0.0009 P = 0.0008 P = 0.0002 Percent Change from Baseline 4.0% 1.7% 2.0% 1.2% 0.6% 0.0% -0.3% -1.1% -2.0% -4.0% -3.6% -6.0% -5.9% -6.7% -8.0% There is a significant increase (*) This is not just an increase in in mean cortical mass, both from density: there is also a -10.0% Total Cortex Compact Cortex Outer Transitional Inner Transitional baseline and from placebo (which significant increase (*) in Zone Zone significantly decreases) cortical thickness n = number of subjects with available data at baseline and 36 months. Data are LS means and 95% CIs. Poole K, et al. ASBMR 2012, abstract and oral presentation 1133 Zebaze RM, et al. ASBMR 2013, abstract and oral presentation 1065 Changes in the Hip Translate Percentage Thickness and Mass into Increased FEA Strength Increase at Month 36 12 months; ‡ P < 0.005 vs baseline; § P < 0.05 vs 12 months. 12 months; ‡ P < 0.005 vs baseline; § P < 0.05 vs 12 months. * P < 0.0001 vs both baseline and placebo; † P < 0.0001 vs * P < 0.0001 vs both baseline and placebo; † P < 0.01 vs Least ‐ squares means ± 95% CIs. Keaveny TM, et al. J Bone Miner Res 2014;29:158-65 Poole K, et al. ASBMR 2012, abstract and oral presentation 1133 12

7/25/2014 Clinical Use of Denosumab-Pluses Potential Limitations • Twice per year- good for compliance • Expense • Temporary treatment post anabolic therapy • Reimbursement by third party payors • Can be used in renal insufficiency- Class III-IV • Effect wears off after 6 months- what next? – If compliance is poor, or if cannot take Rx renal dysfunction • SC use is relatively easy and accessible by – Is there increased risk of fracture when no Rx is offered primary care • Can be used in cancer patients • 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 13