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Results from FIT II Cummings et al, JAMA 2006 2
Rodan SB et al. IBMS BoneKey. 2008;5:16 24. 3
Global deletion of Cathepsin K in mice decreases bone resorption but increases bone formation Serum CTx WT Distal femur WT KO BFR/BS KO WT KO Pennypacker B. et al., Bone, 2009 4
Coupling of bone formation & resorption OPG RANKL Clastokines MDGFs (IGF1, TGFß) Image courtesy of R. Baron Direct effects on osteoblasts? Indirect effects via the osteoclasts and coupling? CON OC CatK KO Genetic deletion of CatK in osteoclasts Bone mass Bone resorption Bone formation Osteoclast # BFR/TV (%/year) BFR N.Oc/TA (/mm 2 ) # Oc WT KO WT KO Lotinun, et al. J Clin Invest, Feb 2013 5
Osteoclasts have a dual function Bone Formation Bone Resorption MeO 2 S CF 3 N H O F H N N IC 50 (nm) Cat K 0.2 Cat B 1,034 Cat L 2,995 Cat S 60 IC 50 = 50% inhibitory concentration; Cat = cathepsin. Duong LT. BoneKey Reports. 2012;1. Article no. 67. Gauthier JY et al. Bioorg Med Chem Lett. 2008;18:923 928. 6
Human Osteoclasts CON Effects of reducing activity of CatK in the osteoclast ODN-treated Same or increased number of osteoclasts Shallow resorption pits Leung et al. Bone, 2011 Cortical Thickness, mm Cortical Thickness, mm 4.0 3.6 3.2 0 1.6 1.4 1.2 Proximal Femur # p<0.05 vs VEH Veh p = 0.08 vs VEH # 6 30 ODN, mg/kg Femoral Neck 0 Veh 6 30 ODN, mg/kg Cusick et al. J Bone Miner Res. 2012;27:524 537. VEH ODN Central Femur 7
Proximal Femoral Periosteum (Rhesus monkeys @21-mo Tx) Veh. ODN TCY TCY Cusick T et al. J Bone Miner Res. 2012;27:524 537. A B C Mineralized Surface, % Mineral Apposition Rate, µm/d Bone Formation Rate, µm 3 /µm 2 /y 50 40 30 20 10 0 0.8 0.6 0.4 0.2 0 120 90 60 30 0 Veh Veh Veh 6 30 ODN, mg/kg # 6 30 ODN, mg/kg # 6 30 ODN, mg/kg MS/BS MAR BFR # P<0.05 vs Veh. Human trials 8
Randomized trial (phase 2b) Study design Years 1 & 2 (N=399) PBO 3 mg 10 mg 25 mg 50 mg PBO = placebo. a Year 6 to 10 extension in planning. Langdahl B et al. J Bone Miner Res. Nov 2012 Year 3 (N=189) PBO 50 mg 50 mg 50 mg PBO 50 mg 50 mg 50 mg PBO PBO 50 mg 50 mg PBO PBO 50 mg 50 mg PBO Years 4 & 5 a (N=141) PBO 50 mg 50 mg Women who entered the Year 4 to 5 extension n=13 n=15 n=14 n=14 n=13 n=12 n=14 n=16 n=14 n=16 9
Lumbar spine BMD Mean % change from baseline (SE) 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 0 1 2 PBO/PBO (n=14) ODN 50 mg/50 mg/50 mg (n=13) ODN 50 mg/pbo/pbo (n=14) 50 mg 50 mg Placebo Placebo 0.8% 11.9% 0.4% 0 3 1 6 12 18 24 36 48 60 30 42 54 Month Femoral neck BMD Mean % change from baseline (SE) 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 0 1 2 PBO/PBO (n=14) ODN 50 mg/50 mg/50 mg (n=13) ODN 50 mg/pbo/pbo (n=14) 50 mg 50 mg Placebo Placebo 0.5% 9.8% 1.6% 0 3 1 6 12 18 24 36 48 60 30 42 54 Month 10
ODN: Bone turnover markers ODN 50 mg OW N=74-76 Placebo OW N=78-80 Geometric LS Mean Percent Change from Baseline (±SEM) 20 10 0-10 -20-30 -40-50 -60 CTX 3.03-42.56 6 12 18 24 Month Geometric LS Mean Percent Change from Baseline (±SEM) 10 0-10 -20-30 -40-50 P1NP -1.99-11.06 6 12 18 24 Month P<0.001 vs PBO Brixen et al, JCEM 2013 98:571-80 Per-Protocol Population ODN 50 mg OW (n=5) Placebo OW (n=5) Osteoid Thickness, micron 5.06 (1.07) 5.60 (0.85) Mineral Apposition Rate, micron/day 0.58 (0.05) 0.56 (0.10) Mineralizing Surface, % 5.52 (5.88) 6.32 (4.22) Mineralization Lag Time, day 21.03 (23.88) 31.96 (36.63) Bone Formation Rate, Total Volume Referent, %/ yr 18.72 (16.29) 23.14 (13.94) Bone Formation Rate, Total Surface Referent, micron 3 / micron 2 / day 0.04 (0.03) 0.03 (0.02) Eroded Bone Surface, % 1.90 (1.32) 1.66 (1.13) Activation Frequency /yr 0.47 (0.38) 0.50 (0.30) Osteoclast bone surface, % trab surface covered by OC 0.93 (0.92) 0.35 (0.23) Brixen et al, JCEM 2013 98(2):571-80 11
Phase 3 Fracture Trial Randomized, placebo-controlled ODN (50 mg/wk) vs PBO >16,000 subjects enrolled Age > 65 yrs Low hip BMD, with or without prior vertebral fx Compared to placebo, patients who received odanacatib had a: 54% relative risk reduction of new and worsening morphometric vertebral fractures (p<0.001), 47% relative risk reduction of hip fractures (p<0.001), 23% relative risk reduction of non-vertebral fractures (p<0.001), and 72% relative risk reduction of clinical vertebral fractures (p<0.001) In addition, treatment with odanacatib led to progressive increases in BMD from baseline at 5 years Lumbar spine 11.2% (p<0.001) Total hip was 9.5% (p<0.001) 12
The rates of adverse events overall in LOFT were generally balanced between patients taking odanacatib and placebo Adjudicated morphea-like skin lesions occurred more frequently on odanacatib 12 patients in the odanacatib group (0.1% incidence) and 3 patients in the placebo group (<0.1% incidence) These skin lesions resolved or improved after discontinuation of the study drug Adjudicated atypical femoral shaft fractures were reported for 5 patients in the odanacatib group (incidence of 0.1%) and not reported in patients in the placebo group There were no adjudicated cases of osteonecrosis of the jaw There were 271 deaths reported in the odanacatib group and 242 deaths in the placebo group (hazard ratio 1.13 (95% CI 0.95, 1.35)); this numeric difference does not appear to be related to a particular reported cause or causes of death In the MACE analysis, events were reported for 215 patients in the odanacatib group and 194 patients in the placebo group (hazard ratio 1.12 95% CI 0.93, 1.36) There was a numeric imbalance in adjudicated strokes with more events occurring in the odanacatib group. Based on the adjudication committee assessment, 109 patients in the odanacatib group experienced stroke (incidence 1.4%) and 86 patients (incidence 1.1%) in the placebo group (hazard ratio 1.28 (95% CI 0.97, 1.70)). Investigator-reported cerebrovascular events occurred in 305 patients in the odanacatib group (incidence 3.8%) and 290 patients taking placebo (incidence 3.6%) (hazard ratio 1.06 (95% CI 0.91, 1.25)) 13
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Courtesy of C Lowik/W Van Hul Li et al, JBMR 2008 SHAM OVX + VEH OVX + SclAb Li et al, JBMR 2009 VEH Vertebral Strength SclAb Ominsky et al, JBMR 2011 15
McClung et al, NEJM 2014 16
McClung et al, NEJM 2014 McClung et al, NEJM 2014 17
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McClung et al, ASBMR 2014 McClung et al, ASBMR 2014 19
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Abaloparatide (BA058): Introduction Abaloparatide is a novel analog of hpthrp (1-34) hpth 1 hpthrp 1 ABL 34 22 34 100% hpthrp 38% hpthrp Abaloparatide was selected to achieve Potent and rapid bone anabolic activity Limited effect on bone resorption Room temperature stability Phase 2 Clinical Study: Spine BMD at 48 Weeks 16 14 +12.9% % Change in BMD 12 10 8 6 +5.1% +9.8% +8.6% Week 12 Week 24 Week 48 4 2 +0.7% 0 Placebo ABL 20 μg ABL 40 μg ABL 80 μg Teriparatide Mean (SE) % Change in Lumbar Spine BMD from Baseline (Ext. pop, N=55) 21
Phase 2 Clinical Study: Hip BMD 3.5 +2.6% 3 % Change in BMD 2.5 2 1.5 1 +0.4% +1.4% +2.0% +0.5% Week 12 Week 24 0.5 0 Placebo ABL 20 μg ABL 40 μg ABL 80 μg Teriparatide Mean (SE) % Change in Total Hip BMD from Baseline (ITT, N=221) Bone Formation Markers % Change from Baseline Percent Change in PINP from Baseline TPTD Weeks p-value < 0.05 vs. baseline 22
Bone Resorption Markers Percent Change in CTX from Baseline TPTD % Change from Baseline Weeks Lower rise in CTX with BA058 compared with teriparatide p-value < 0.05 vs. baseline Ph III: Fracture reduction vs placebo (n=690 abaloparatide, 711 placebo, 717 TPTD) Abaloparatide Teriparatide Vertebral Fx Non-vert Fx Clinical Fx 86% (p<0.001) 80% (p<0.001) 43% (p=0.049) 18% (p=0.22) 45% (p=0.01) 29% (p=0.11) Miller et al, Endocrine Society Mtg, Mar 2015 23
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