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We Need Drugs That… 7/5/2016 Disclosures New Osteoporosis Treatments Mary L. Bouxsein, PhD Advisory Board: Merck, Eli Lilly, Radius Department of Orthopedic Surgery Harvard Medical School, Boston, MA Research funding: Merck, Amgen Consulting fees: Acceleron Pharma, Agnovos What we have today We need drugs that… • Treatments that reduce the risk of vertebral • Maintain or promote bone formation fractures by 50 to 80% • Strengthen cortical bone —> reduce Non‐VFx • Treatments that reduce the risk of non‐vertebral fractures by 20‐25% – Non‐vertebral fracture remain major source of disability • Are convenient for patient • Are cost‐effective % of days of disability due to different • Are safe types of fractures Results from FIT II Cummings et al, JAMA 2006 1 7/5/2016 New treatments, new mechanisms of action Cathepsin K and Bone Resorption • CatK is a lysosomal protease highly expressed in osteoclasts, where it is • Cathepsin K inhibitors released during bone resorption Odanacatib (ODN) • CatK is the major protease responsible for degradation of type I collagen • Anti‐sclerostin antibody Romozosumab • Novel PTH Analogs Abaloparitide (BA‐058) Rodan SB et al. IBMS BoneKey. 2008;5:16–24. Global deletion of Cathepsin K in mice decreases bone resorption but increases bone formation Distal femur Serum CTx WT How can cathepsin K inhibition lead to increased bone formation? WT KO Revisiting the ‘coupled’ process of BFR/BS KO bone remodeling WT KO Pennypacker B. et al., Bone, 2009 2 7/5/2016 Coupling of bone formation & resorption Genetic deletion of CatK in osteoclasts Bone mass Bone resorption OPG “Clastokines” Bone formation RANKL Osteoclast # CON OC CatK KO ) * 2 # Oc MDGFs BFR * (IGF1, TGFß) BFR/TV (%/year) Image courtesy of R. Baron (/mm N.Oc/TA WT KO WT KO • Direct effects on osteoblasts? • Indirect effects via the osteoclasts and coupling? Lotinun, et al. J Clin Invest, Feb 2013 Osteoclasts have a dual function Pharmacologic inhibition of CathepsinK Odanacatib Odanacatib is a selective, and reversible nonbasic inhibitor of Cat K with minimal metabolism, which Bone supports once weekly dosing in humans. Formation F CF IC (nM) 3 H N 50 N N Cat K 0.2 H O Cat B 1,034 MeO 2S Cat L 2,995 Cat S 60 Bone IC50 = 50% inhibitory concentration; Cat = cathepsin. Duong LT. BoneKey Reports. 2012;1. Article no. 67. Resorption Gauthier JY et al. Bioorg Med Chem Lett. 2008;18:923–928. 3 7/5/2016 Human Osteoclasts ODN treatment increases avg. cortical thickness CON Effects of reducing in femur of OVX monkeys activity of CatK in Proximal Femur Central Femur # the osteoclast 4.0 # p<0.05 vs VEH VEH 3.6 • Same or increased number of 3.2 Cortical Thickness, mm Thickness, Cortical 0 osteoclasts Veh 630 ODN, mg/kg ODN-treated Femoral Neck † ODN • Shallow resorption 1.6 † p = 0.08 vs VEH pits 1.4 1.2 Cortical Thickness, mm Thickness, Cortical 0 Veh 630 Leung et al. Bone, 2011 ODN, mg/kg Cusick et al. J Bone Miner Res. 2012;27:524–537. Randomized trial (phase 2b) • Original: 2 year dose‐ranging study • Postmenopausal women 45‐85 years (N=399) Human trials • BMD T‐score < ‐2.0 but not < ‐3.5 • 50 mg odanacatib vs. placebo (once weekly, oral) • After 2 years, randomly assigned to stop or continue to 5 years Langdahl et al. JBMR 2012 4 7/5/2016 Lumbar spine BMD Femoral neck BMD 15 15 PBO/PBO (n=14) PBO/PBO (n=14) 14 14 ODN 50 mg/50 mg/50 mg (n=13) ODN 50 mg/50 mg/50 mg (n=13) 13 13 ODN 50 mg/PBO/PBO (n=14) 12 ODN 50 mg/PBO/PBO (n=14) 11.9% 12 11 11 10 50 mg 10 9.8% 9 9 50 mg 8 8 7 50 mg 7 50 mg 6 6 5 5 4 4 Mean % Mean % change Mean % change Mean % Placebo (SE) baseline from 3 3 from baseline from baseline (SE) 2 2 Placebo 1 1 0 –0.4% 0 –1 Placebo 0.8% –1 Placebo –1.6% –2 –2 –0.5% 03 12 24 36 48 60 03 12 24 36 48 60 16 18 30 42 54 16 18 30 42 54 Month Langdahl et al. JBMR 2012 Month Langdahl et al. JBMR 2012 ODN: Bone turnover markers Phase 3 Fracture Trial - LOFT (Long term odanacatib fracture trial) ODN 50 mg OW N=74-76 Placebo OW N=78-80 • Randomized, placebo-controlled CTX P1NP SEM) SEM) • ODN (50 mg/wk) vs PBO 20 10 -1.99 ± 3.03 ± 10 0 0 -10 -10 • >16,000 subjects enrolled worldwide -20 -20 * -11.06 -30 – Age > 65 yrs * -30 -40 * * -40 -50 * * – Low hip BMD, with or without prior vertebral fx -42.56 -60 -50 Geometric LS Mean Percent Mean Geometric LS Geometric LS Mean Percent Mean Geometric LS Change from BaselineChange from ( 61218 24 BaselineChange from ( 61218 24 Month Month * P<0.001 vs PBO Brixen et al, JCEM 2013 98:571-80 Per-Protocol Population 5 7/5/2016 Fracture Reduction with Odanacatib Safety and adverse events : odanacatib Presented at ASBMR, September 2014 ASBMR Sept 2014 Relative Risk • Evidence of greater incidence of morphea‐like skin (vs PBO) reactions (<0.1%), which resolved after discontinuing drug Hip Fx 47% Non‐Vert Fx 23% • Additional adjudication for cardiovascular events, atypical femoral fractures and other AE’s is ongoing Vert Fx (morphometric) 54% • Benefit:risk profile will be better defined with Vert Fx (clinical) 72% additional efficacy & safety data that are being acquired in blinded extension study McClung et al, ASBMR 2014 McClung et al, ASBMR 2014 Sclerostin: Osteocyte‐derived cytokine that New treatments, new mechanisms of action inhibits bone formation • Cathepsin K inhibition • Sclerosteosis, van Buchem’s disease Odanacatib (ODN) ‐‐ Due to mutations in gene SOST Courtesy of C Lowik/W Van Hul • Anti‐sclerostin antibody • Sclerostin: protein encoded by gene SOST Romozosumab – Potent inhibitor of Wnt signaling & bone formation – Deletion of SOST in mice: bone mass – Sclerostin expression localized to osteocytes Li et al, JBMR 2008 6 7/5/2016 Treatment of rats & monkeys with Sclerostin Antibody Phase 2 Study of Sclerostin Antibody (Romozosumab) in Postmenopausal Women with Low BMD SHAM OVX + VEH OVX + SclAb Li et al, JBMR 2009 Vertebral Strength VEH SclAb Ominsky et al, JBMR 2011 Phase 2 Study Design Phase 2 Study Design McClung et al, NEJM 2014 McClung et al, NEJM 2014 7 7/5/2016 Lumbar spine BMD Total hip and femoral neck BMD Romosozumab TPTD ALN PBO McClung et al, NEJM 2014 % Change in serum bone turnover markers: Romozosumab: Phase III fracture trials P1NP and CTX • FRAME (n ~ 6600) – placebo controlled P1NP CTX – Blinded (0‐12 mo): Romozosumab vs PBO – Open label (12‐24 mo): Both groups transition to dmab – 1o outcome: Vertebral Fracture (12, 24 mo) – 2o outcomes: Any fracture and BMD change (12, 24 mo) • ARCH (n ~ 4100) –ALN active comparator – Blinded (0‐12 mo): Romo + PBO (oral) vs ALN + PBO (inj) – Open label (12 –24 mo): Both groups transition to ALN – 1o outcome: Vertebral or any clinical fracture (~ 24 mo) – 2o outcomes: Any fracture , BMD change (12, 24 mo) 8 7/5/2016 Press Release, Feb 21 2016 Press Release, Feb 21 2016…(continued) • ..FRAME met the co‐primary endpoints by reducing the incidence of new vertebral fracture through months 12 and • The percentage of patients with adverse events and serious 24 in postmenopausal women with osteoporosis treated with adverse events in the 12‐month double‐blind period and 24‐ romosozumab month study period were balanced overall between the – 73 % reduction in the risk of a vertebral fracture @ 12 mo’s vs. pbo treatment groups. – 75 % reduction in the risk of a vertebral fracture @ 24 mo’s vs. pbo • There were two positively adjudicated events of • The study also met the secondary endpoint of reducing the osteonecrosis of the jaw in the romosozumab treatment incidence of clinical fractures (composite of vertebral and group, one after completing romosozumab dosing and the non‐vertebral fractures) through 12 months. other after completing romosozumab treatment and – 36 percent reduction through 12 months vs. placebo receiving the initial dose of denosumab. • However, the secondary endpoint of reducing the incidence • There was one positively adjudicated event of atypical of non‐vertebral fractures through months 12 and 24 was not femoral fracture after three months of romosozumab met. treatment. New treatments, new mechanisms of action Abaloparatide (BA058): Introduction Abaloparatide is a novel analog of hPTHrP (1-34) • Cathepsin K inhibition Odanacatib (ODN) hPTH 1 34 hPTHrP • Anti‐sclerostin antibodies 1 22 34 Romozosumab ABL Blozosumb 100% hPTHrP 38% hPTHrP Abaloparatide was selected to achieve • Novel PTH Analogs • Potent and rapid bone anabolic activity Abaloparitide (BA‐058) • Limited effect on bone resorption • Room temperature stability 9 7/5/2016 Phase 2 Clinical Study: Spine BMD at 48 Weeks Phase 2 Clinical Study: Hip BMD 16 3.5 +12.9% +2.6% 14 3 12 +9.8% +2.0% +8.6% 2.5 10 Week 12 2 +1.4% Week 12 8 Week 24 Week 24 +5.1% Week 48 1.5 6 % Change in BMD +0.5% % Change in BMD 1 +0.4% 4 +0.7% 2 0.5 0 0 Placebo ABL ABL ABL Teriparatide Placebo ABL ABL ABL Teriparatide 20 μg 40 μg 80 μg 20 μg 40 μg 80 μg Mean (SE) % Change in Lumbar Spine BMD from Baseline (Ext. pop, N=55) Mean (SE) % Change in Total Hip BMD from Baseline (ITT, N=221) Bone Formation Markers Bone Resorption Markers Percent Change in CTX from Baseline Percent Change in PINP from Baseline * * TPTD TPTD * * * * * * * * * * * * * * * * * * from Baseline % Change % Change from % Change Baseline Weeks Weeks • Lower rise in CTX with BA058 compared with teriparatide *p-value < 0.05 vs.
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