9/29/2016. John P. Bilezikian, M.D. Disclosures: ADVANCES IN BASIC SCIENCE: New Knowledge. Regulatory Molecules Hormone Action

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1 The Therapeutics of Osteoporosis: Application of Bone Science to Clinical Practice John P. Bilezikian, MD Silererg Professor of Medicine Vice-Chair, International Education and Research Department of Medicine College of Physicians and Surgeons Columia University New York, NY USA th EFF-ASBMR Forum On Osteoporosis and Other Metaolic Bone Diseases Atlanta, Georgia Septemer 1-15, 16 John P. Bilezikian, M.D. Disclosures: Amgen (Consultant, Advisory Board) Merck (Consultant, Advisory Board) Shire Pharmaceuticals (Research Grant) Radius Pharmaceuticals (Advisory Board) 11//15 ADVANCES IN BASIC SCIENCE: New Knowledge Regulatory Molecules Hormone Action New Therapeutic Concepts in Osteoporosis 1

2 Antiresorptive Therapy How antiresorptive agents improve one strength Bone density + Bone quality = Bone strength 1. Bone turnover. Architecture 3. Mineralization. Bone size and shape 5. Damage accumulation 6. Matrix quality Adapted from NIH Consensus Development Panel on Osteoporosis. JAMA 85 (1): Effects of Anti-resorptive Therapies on Bone Turnover And Bone Density Biochemical Markers of Turnover Change from Baseline Bone Turnover 1 Resorption Formation Months Mean % Change in BMD BMD Lumar spine Femoral neck P <.1 for all 3 skeletal sites Month 1 Chesnut CH, et al. Am J Med. 1995;99:1-5. Bone HG, et al. N Engl J Med. ;35:

3 Antiresorptive Agents: Efficacy Data Based upon Pivotal Clinical Trials Agent Verteral Nonvert Hip Estrogen Alendronate Risedronate Zoledronic acid Iandronate + - * - Denosuma Raloxifene Calcitonin Bisphosphonate Basics R 1 R C Bisphosphonate Structures O P P O OH OH OH OH O O O- O - P O P O O- O- H O - P C P O O- H O- O- Pyrophosphate Simplest BP O- R 1 O - O P C P O General BP structure O- R Y O- R 1 : many options possile (usually -OH) R : very large numer of options possile 3

4 The irth of isphosphonates Science Vol 165, 1969 Graham Russell, Herie Fleisch, Dave Francis Mevalonate pathway. Multiple sites of inhiition y BPs HMG-CoA Statins inhiit here MEVALONATE phosphomevalonate mevalonate diphosphate IPP isomerase dimethylallyl diphosphate isopentenyl diphosphate x CHOLESTEROL squalene synthase x squalene x FPP synthase (main site of action of N-BPs) farnesyl diphosphate xgpp synthase Ra GGTase geranylgeranyl diphosphate geranylgeranylated x Ra proteins CENTRAL MECHANISM OF ACTION OF THE BISPHOSPHONATES Inhiition of one resorption y impairing osteoclast function

5 Safety Osteoporosis Therapy: Bisphosphonates Adverse Effects Randomized controlled trials: no increase in UGI issues Class warning regarding UGI symptoms Class warning regarding infrequent one, joint and/or muscle pain Influenza-like symptoms may occur after first monthly oral dose or IV injection Class warning regarding jaw osteonecrosis Class warning regarding atypical fractures of sutrochanteric regions of the femur 1 of 57 Prescriing information: Perception has interfered with Reality Common perceptions aout the isphosphonates are that they.. cause the stomach to hurt (UGI distress) cause the jaw to fall out (ONJ) cause fractures (Atypical Femoral Fractures) cause cancer (esophageal) 5

6 Efficacy and Safety No drug is safe No action in life is safe (e.g. crossing the street in Atlanta!) All actions (and drugs) have to e considered along with the risks The isphosphonates: enefits and risks The enefits of the isphosphonates are clear: ALN, RIS, and ZOL all reduce fracture risk at all sites ONJ and AFF are rare events Bisphosphonates cause more good than harm New York Times Front Page Story y Gina Kolata June, 16 - in, osteoporosis patients taking the drugs (including alendronate, iandronate, risedronate and zoledronate) have sustained roken thigh ones. Fewer than one in, have had the jawone prolem. You only need to treat 5 people to prevent a fracture, ut you need to treat, to see an atypical fracture 6

7 The isphosphonates: pulic perception versus reality OUR CHALLENGES To emphasize the importance of osteoporosis To place enefits front and center while properly and reasonaly placing the matter of SAEs in the right perspective New approaches ased upon advances in one cell iology Antiresorptives Anaolics Comination Therapy New Classes of Therapeutics Antiresorptives Denosuma RANKL Stimulates Osteoclast-mediated Bone Resorption RANK Ligand Is Essential for Osteoclast Formation, Function, and Survival CFU-M RANKL RANK Pre-Fusion Osteoclast Growth Factors Hormones Cytokines Multinucleated Osteoclast Mature Osteoclast Bone CFU-M = colony forming unit macrophage Adapted from Boyle WJ et al. Nature. 3;3:

8 Osteoprotegerin controls actions of RANKL on osteoclast function Osteoclast Formation, Function and Survival Inhiited y OPG OPG RANKL RANK CFU-M Pre-Fusion Osteoclast Growth Factors Hormones Cytokines Multinucleated Osteoclast Mature Osteoclast Bone Adapted from Boyle WJ et al. Nature. 3;3:337-. Denosuma, a human IgG antiody to RANKL, controls osteoclast differentiation, activation and survival Growth Factors Hormones Cytokines Y Denosuma RANKL RANK CFU-M Pre-Fusion Osteoclast Multinucleated Osteoclast Osteolast BONE Activated Osteoclast The FREEDOM Trial Study design: Primary endpoint: Secondary endpoints: Randomized, placeo-controlled 6 mg denosuma or placeo sucutaneously every 6 months for 36 months Plus -8 IU vitamin D and 1 g of calcium New verteral fracture (y X-ray over 36 months) Nonverteral fracture and hip fracture Cummings et al. N Engl J Med 9; 361[8]:

9 The effect of Denosuma on all Fractures The Freedom Trial 3-yr RCT 788 postmenopausal women age 6-9 with osteoporosis (T-score -.5) 3% with verteral fracture (severe fractures excluded) Fx incidence at 36 mos % 68% % % Cummings et al. N Engl J Med 9; 361[8]: Ferrari et al. Relationship Between Total Hip BMD T-Score and the Incidence of Non-Verteral Fracture with up to 8 Years of Denosuma Treatment (ASBMR, 15) FREEDOM Extension R A N D O M I Z A T I O N Year Denosuma 6mg Denosuma 6 mg Long-term SC Q6M SC Q6M Denosuma (N = 39) (N = 33) Treatment Year Placeo SC Q6M (N = 396) Calcium and Vitamin D Denosuma 6 mg SC Q6M (N = 7) Cross-over Denosuma Treatment 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 International, multicenter, open-lael, single-arm study Long-term Denosuma Treatment Continuously Increases Total Hip BMD and Results in Reduced Nonverteral Fracture Incidence Placeo Denosuma Percentage Change From Baseline 8 6 Total Hip BMD Nonverteral Fractures FREEDOM EXTENSION 8.3% FREEDOM EXTENSION *.9% * * * * * * * Yearly Incidence of Nonverteral Fractures (%) Study Year Years of Denosuma Treatment Papapoulos S et al. Osteoporos Int 15. DOI.7/s LS Means and 95% confidence intervals. *P <.5 vs FREEDOM aseline; P <.1 vs FREEDOM aseline and extension aseline. Percentages for nonverteral fractures are Kaplan-Meier estimates. 9

10 Ferrari et al. Relationship Between Total Hip T-score and Nonverteral Fracture (ASBMR, 15) Expected 1-Year Nonverteral Fracture Incidence (%) DMA (N = 361) 95% CI On Dma, the higher the BMD the lower the non-vert fracture incidence Total Hip T-score 8 Revisiting the relationship etween a therapeutic increase in BMD and reduction in fracture Risk 35 3 Relative Risk of Fracture x -1SD Bone density (SD units) Adapted from Faulkner KG. J Bone Miner Res. ;15: Bone et al. Ten Years of Denosuma Treatment in Postmenopausal Women with Osteoporosis: Results From the Freedom Extension Trial: LUMBAR SPINE AND HIP BMD (ASBMR, 15) Placeo Long-term Denosuma Cross-over Denosuma Lumar Spine Total Hip FREEDOM Extension 1.7% c FREEDOM Extension 9.% c % 18 c % relentless 16 increase in BMD over a -year c a 6 1 period with denosuma? a 5 1 a a a 8 3 a a 6 a a 1 a a a a a a a -1 What could account for the unprecedented, Percentage Change From Baseline Study Year Percentage Change From Baseline Study Year BMD data are LS means and 95% confidence intervals. a P <.5 vs FREEDOM aseline. P <.5 vs FREEDOM and Extension aselines. c Percentage change while on denosuma treatment. d Annualized incidence: (-year incidence) /. Lateral radiographs (lumar and thoracic) were not otained at years, 7, and 9 (years 1,, and 6 of the Extension).

11 Denosuma may permit a modeling effect on one to proceed even though one resorption is markedly suppressed Evidence for modeling Superior Endocortex Fluorochrome Laels 1. Tetracycline (6 mo). Alizarin (1 mo) 3. Calcein (16 mo) Flurochrome laeling of the femoral neck over 16 mos of Dma 5 mg/kg Ominsky et al, JBMR 15 The effect of Denosuma on Intact PTH Phase : Postmenopausal Women with Low BMD Placeo, N = 6 Denosuma 1 mg, N = 53 Denosuma 6 mg, N = 6 Denosuma mg, N = 1 Denosuma mg, N = 6 Alendronate 7 mg/wk, N = 5 ULN = 6.9 pmol/l LLN = 1.1 pmol/l Time (Months) et al. N Engl McClung MR, This slide deck is intended for investigator use only. Do not duplicate. 6;35: J Med. 3 Phase 1 Study (Single Dose, Dose Escalation) Increase in endogenous PTH After Single Dose of Denosuma Placeo (n=1) Dma 1. mg/kg (n=6) Baseline.8 (.6) 5. (.59) hours.5 (.6) 7.3 (1.7) days.55 (.3).7 (1.79) 1 days.5 (.35) 1.38 (.8) 1 month.91 (.53) 8.33 (1.9) months 5.3 (.51) 8.1 (1.31) 3 months 5.1 (.6) 9.7 (1.99) 6 months.38 (.3) 5.31 (.7) 9 months.77 (1.8).3 Adapted 33from Bekker et al, NEJM 6 11

12 The Paradox PHPT PTH Cortical BMD Denosuma PTH Cortical BMD Explaining the Paradox: Hypothesis Denosuma may shift endogenous PTH pathways PTH Denosuma Runx-expressing osteolast progenitor SOST BMP Wnt camp/pka Smad P R-Smads TFs -catenin CtBP Tcf P CREB RANKL OPG Anaolism Cataolism New approaches ased upon advances in one cell iology Antiresorptives Anaolics Comination Therapy New Classes of Therapeutics Antiresorptives Cathepsin K inhiition 1

13 Cathepsin K and Bone: Genetics Genetic deficiency - Pycnodysostosis (Gel,etal.,1996; Schilling et al 7) Short stature, high one mass with skeletal fragility Frontal ossing Cathepsin K (Cat K) deficient mice (Pennypacker et al, 9) Osteopetrosis Increased one formation Overexpression of Cat K (Kivirantaet al, 1) High one turnover and osteopenia Toulouse Lautrec THE CONCEPT OF ODANACATIB: ANOTHER WAY TO TARGET THE OSTEOCLAST Rodan & Duong. BoneKey 8 Cathepsin Odanacati K is is highly a selective, expressed non-asic in the osteoclast, inhiitor where of Cathepsin it is localized K with in the minimal lysosomes metaolism and released and during an excellent one resorption. pharmacokinetic profile Inhiition of Cathepsin K: Odanacati: Phase II- randomized, doule-lind, placeo-controlled trial Extension of Phase dosing study of Odanacati, a Cathepsin K inhiitor Doses: Placeo, 3,, 5, 5 mg Primary Hypothesis: LS BMD after 18 and months will e greater with drug than with placeo 3 women, mean age: 6 ± 7.8 Other end points: one turnover markers Data from 18 month analysis and extension period McClung MR et al. Calcif Tissue Int 8;8:S53. 13

14 % Change from Baseline (Mean ± SE) Odanacati: Bone Mineral Density: 5 Years Placeo Lumar Spine Month ODN 5 mg/ Q week Full-Analysis-Set Population / LOCF % Femoral Neck % Change from Baseline (Mean ± SE) Marked and progressive increase in BMD Month Langdahl et al. J Bone Miner Res 1 ;7: % Biochemical Markers at 18 Months Geometric Mean Percent Change from Baseline at Month u-ntx Bone Resorption s-ctx Bone Formation s-bsap s-p1np Placeo ODN 3 mg ODN mg ODN 5 mg ODN 5 mg Effects of Anti-resorptive Agents on Bone Remodeling Not a head-to-head comparison % decrease from aseline of serum CTX and serum BSAP at months Alendronate 1 Denosuma 1 Odanacati CTX-s BSAP-s - 1. Lewiecki EM et al. J Bone Miner Res. 7;: McClung MR, et al. ASBMR 8, Astract 191 1

15 Is osteoclast signaling to osteolasts maintained during odanacati exposure? PGE NO osteocytes Mineralized one Morris Manolson, Toronto, ON ICOBR, 8 Beijing, China, Oct. 3, 8 osteolast R. Schenk Osteoid (non-mineralized one) Osteoclast Odanacati: Phase 3 Clinical Trial McClung et al. (ASBMR, 1) Papapoulos et al. (ASBMR, 1) Randomized, doule-lind placeocontrolled, event-driven 5 mg weekly Primary endpoints: new morphometric verteral fractures, hip, and clinical nonverteral fractures Secondary endpoints: safety/toleraility, clinical VFx, spine and hip BMD, one turnover markers #1155: McClung et al. Odanacati Efficacy and Safety in Postmenopausal Women with Osteoporosis: 5-year Data from the Extension of the Phase 3 Long-Term Odanacati Fracture Trial (LOFT) Age: 7.8 T-score <-.7 (LS); -. (TH); -.7 (FN); prior radiographic VFx (6.5%) N= 16,71; 387 centers; countries RR Reductions in: Vert Fx 5% Hip Rx 7% Non-Vert: 3% Current Study: average follow up: (18) mos (n=67 completers) RR Reductions in: Vert Fx: 5% Hip Fx: 8% Non-Vert: 6% 15

16 Odanacati: Phase 3 Clinical Trial Papapoulos et al. (ASBMR, 1) RESULTS: Safety- adjudicated: Morphea-like skin lesions (1 in odanacati group (.1%) vs 3 in placeo group (<.1%) Resolved when drug stopped Not associated with systemic reactions Atypical femoral shaft fractures 5 in odanacati group (.1%); none in placeo group. Odanacati: Phase 3 Clinical Trial Papapoulos et al. (ASBMR, 1) RESULTS Safety- adjudicated: No differences in serious respiratory infections, or delayed fractured unions. No ONJ Numerical imalances: drug/placeo in Atrial firillation, Major CV events (MACE), deaths, strokes: Readjudication currently ongoing Press Release from Merck Septemer, 16 KENILWORTH, N.J.--(BUSINESS WIRE)-- Merck today announced that it is discontinuing the development of odanacati, Merck's investigational cathepsin K inhiitor for osteoporosis, and will not seek regulatory approval for its use. Merck previously reported a numeric imalance in adjudicated stroke events in the pivotal Phase 3 fracture outcomes study in postmenopausal women. The company has decided to discontinue development after an independent adjudication and analysis of major adverse cardiovascular The further events confirmed development an increased risk of stroke. The data from the analysis will e presented at the American Society for Bone Mineral Research Odanacati (ASBMR) in Septemer. as a therapy for osteoporosis From Roger M. Perlmutter, M.D., Ph.D., president, Merck Research Laoratories. "We are very thankful to has the researchers een terminated and patients who participated in the odanacati clinical development program. We have learned that odanacati treatment reduces the risk of osteoporotic fractures. At the same time, we elieve that the increased risk of stroke in our Phase 3 trial does not support further development." 16

17 At This Meeting. The Long-Term Odanacati Fracture Trial (LOFT): Cardiovascular Safety Results Results to e presented on 9/18/16 at :3 AM What the antiresorptives don t do THE HOLY GRAIL? New approaches ased upon advances in one cell iology Antiresorptives Anaolics Comination Therapy New Classes of Therapeutics Osteoanaolics Teriparatide Aaloparatide 17

18 Human Parathyroid Hormone Intact PTH (1-8) 1 H N Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Glu Val Arg Glu Met Ser Asn Leu His Lys Trp Leu Arg Lys Lys Leu Gln Asp Val His Asn Phe 3 Teriparatide -COOH HOW CAN A HORMONE THAT IS BAD FOR BONES BE GOOD FOR BONES? 18

19 PTH Mode of Administration, Timing and Dose Determine whether PTH is anaolic or cataolic in the rat skeleton Cell Aundance (% Traecular Bone Perimeter) 3 * Osteolast Vehicle *p<.1 vs vehicle **p<.1 vs vehicle 1 hour/day Continuous ** Osteoclast Donig H, Turner RT. Endocrinology. 1997;138(11): PTH and Dose Determine Effect on Bone MODE Continuous (high dose) Daily (low dose) EFFECT Cataolic Anaolic Donig H, et al. Endocrinology 1997;138:67-1. How parathyroid hormone improves one strength Bone density + Other one qualities = Bone strength 1. Bone turnover. Bone size and shape 3. Architecture. Mineralization Adapted from NIH Consensus Development Panel on Osteoporosis. JAMA 85 (1):

20 PTH Increases Bone Formation Markers Before Bone Resorption Markers Mean % Change in Turnover Marker Osteocalcin n-telopeptide Time (Months) Lindsay R, et al. Lancet. 1997;35(977): Cellular Mechanisms PTH treatment initially stimulates one formation directly with or without the involvement of the one remodeling unit PTH as an Anaolic Agent for Bone: A Kinetic Model Peak Index of Bone Turnover Anaolic Window Bone formation markers Bone resorption markers Months

21 Effect of Teriparatide on Incidence of Verteral and Non-Verteral Fractures in Postmenopausal Women with Osteoporosis New verteral fracture Non-verteral fractures Patients (%) with fracture % P<.1 Patients (%) with fracture % P<.1 Placeo g PTH Placeo g PTH Neer RM, et al. N Engl J Med. 1;3: D µct Images of iliac crest iopsies efore and after Teriparatide Placeo Teriparatide Taking advantage of asic mechanisms to develop a PTH/PTHrP analogue that has greater osteoanaolic activity Premise: states of PTH/PTRrP receptor inding to its ligand R : leads to prolonged signaling RG: associated with more transient signaling 1

22 6 Emergence of a new osteoanaolic Aaloparatide, an analogue of PTHrP Hattersley G, Bilezikian JP, Kumar P et al. The Endocrine Society 9 th Annual Mtg Houston, 1 Teriparatide hpthrp 1-3 Aaloparatide 3 % hpthrp 38% hpthrp % hpthrp % hpthrp ased on amino acid replacements etween residues -3 Taking advantage of asic mechanisms to develop a PTH/PTHrP analogue that has greater osteoanaolic activity Hypothesis: Aaloparatide will ind more selectively ind to the transient RG configuration of the PTH/PTRrP receptor Hattersley, Dean, Corgin, Bahar and Gardella. Endocrinology 16:157:11-19 Transient State Prolonged response The inding of ABL, PTH (1 3), PTHrP (1 36) and LA-PTH to two distinct PTHR1 conformations RG (A) and R (B) was assessed y competition methods in memranes prepared from GP-.3 cells staly expressing the PTHR1. RG reactions used 15I-M-PTH (1 15) as tracer radioligand, which inds selectively to the G protein coupled receptor conformation (RG). R reactions used 5I-PTH (1 3) as tracer radioligand and contained an excess concentration (1 5 M) of GTPγS, which enriches for the G protein uncoupled receptor conformation (R). Data are means (± SEM) of six experiments, each performed in duplicate. Curve fitting parameters are reported in Tale 1. Pulished in: Gary Hattersley; Thomas Dean; Braden A. Corin; Hila Bahar; Thomas J. Gardella; Endocrinology 16, 157, DOI:.1/en Copyright 16

23 Hattersley, Dean, Corgin, Bahar and Gardella. Endocrinology 16:157:11-19 GP-.3 cells preloaded with luciferin were treated with a near-ec5 concentration of PTH (1 3) (.3nM), PTHrP (1 36) (1nM), ABL (.1nM), or LA-PTH (.3nM) and luminescence was assessed at -min intervals for 1 min (A). The cells were then removed from the plate reader, rinsed twice with media to remove unound ligand, and then fresh media containing luciferin ut lacking ligand was added and luminescence was assessed for additional 15 min (B). Data are means (± SEM) of six experiments, each performed in triplicate. Curve fitting parameters are reported in Tale 3. Update on Aaloparatide International Phase 3 trial ended, Septemer, 1 Results made availale, Decemer, 1 Presented y Miller et al, Endocrine Society, March, 15, 16 Clinical Trial Results JAMA (16) Phase 3 Trial Design of Aaloparatide Clinical Trial N = 63 Placeo Randomization Aaloparatide 8 mcg Daily SC Teriparatide mcg Daily SC Months Miller et al, Endo Soc

24 Changes in Bone Turnover Markers: Aaloparatide vs. Teriparatide vs. Placeo (Miller et al. Endo Soc 3-15) CTX 5 P1NP Percent Change from Baseline * * -6% -56% *# *# * # -69% Percent Change from Baseline 15 5 * * -1% -8% *# * # * -33% *# Months -5 Placeo Aaloparatide Teriparatide Months *p <.1 vs placeo # p <.1 vs teriparatide PTH/PTHrP analogues that stimulate one formation to a greater extent than one resorption: a time dependent model Peak Index of Bone Turnover Bone Formation Markers Anaolic window Bone Resorption Markers Months Changes in BMD at the Spine and Reduction in New Verteral Fractures: All 3 Groups (Miller et al. Endo Soc 3-15) % Change from Baseline # p <.1 vs TP Lumar Spine BMD # # Months Placeo Aaloparatide Teriparatide

25 Changes in BMD at Non-Verteral Sites and NVF Risk Reduction: All 3 Groups (Miller et al. Endo Soc 3-15) % Change from Baseline # p <.1 vs TP ^p =.3 vs TP Total Hip BMD # 6 Months 1 18 # ^ % Change from Baseline Femoral Neck BMD 3.5 #p <.1 vs p =.16 vs TP.5 # # Months 1 18 Kaplan-Meier Time to First Event (Miller et al. Endo Soc 3-15) Percent of Patients Percent with of Patients 1 New with Non-Verteral Fracture Fracture Placeo Aaloparatide Teriparatide Non-Verteral Fractures Aaloparatide 3 5 Time to Event (Days) Kaplan-Meier Time to First Event (Miller et al. Endo Soc 15) Percent Percent of Patients of Patients with 1 with New Fracture Clinical Fracture Placeo Aaloparatide Teriparatide Clinical Fractures Aaloparatide. 3 5 Time to Event (Days) 5

26 Changes in Wrist BMD and Wrist Fracture Reduction: Aaloparatide vs. Teriparatide vs. Placeo (Miller et al. Endo Soc 3-15) % Change from Baseline Ultra-Distal Radius BMD Aaloparatide * * * NS NS NS # K-M Estimated Incidence Rate Wrist Fracture (ITT Population) -1 *p <.1 vs placeo # p =.13 vs TP Months 1 18 New approaches ased upon advances in one cell iology Antiresorptives Anaolics Comination Therapy New Classes of Therapeutics Comination Therapy Antiresorptive PTH Comination therapy with an antiresorptive and osteoanaolic agent Rationale is clear ut the results Raloxifene: possile small enefit Estrogen: possile small enefit Alendronate: reduced enefit Risedronate (in men): possile hip BMD enefit Zoledronic acid: early enefit primarily Denosuma: promising (Tsai et al, Lancet, 13; Leder, JCEM, 1, Tsai, JBMR, 15) 6

27 A possile mechanism for the efficacy of comination therapy with Denosuma and Teriparatide Exogenous PTH Denosuma Runx-expressing osteolast progenitor SOST BMP Wnt camp/pka Smad P R-Smads TFs -catenin CtBP Tcf P CREB RANKL OPG Anaolism Cataolism CLINICAL TRIALS AND MECHANISMS OF THERAPEUTICS: COMBINATION THERAPY WITH DENOSUMAB AND TERIPARATIDE (Leder et al, JCEM, 1) N= divided equally among Teriparatide ( ug daily); Denosuma (6 mg q 6mos); and comination. 83 completed the study Tsai et al., J Bone Miner Res, 15 Total vbmd Tra vbmd Cort vbmd Cort Th 7

28 Bisphosphonate PTH Limitations to simultaneous comination regimens and their variations Bone density and one markers are only end points No long term data Limited data on one quality No fracture data THE FUTURE OF OSTEOANABOLIC THERAPY Clues to a new therapeutic approach: Sclerosteosis & van Buchem s Disease increased one mass throughout skeleton. very low fracture risk due to asence of sclerostin (SOST) - an inhiitor of Wnt signaling and one formation Janssens and Van Hul. Hum Mol Genet. ;11:

29 Heterozygous carriers of Sclerosteosis and van Buchem s disease do not appear to have complications as seen in the homozygous sujects Higher one density Increased markers of one formation Levels of sclerostin are intermediate No long-term or progressive sequellae Wnt Sclerostin DKK1 Wnt Sclerostin DKK1 Frat1 DSH DSH βcatenin βcatenin GSK3β βcatenin P AXIN Proteosomal Degradation βcatenin Osteolast differentiation, proliferation, and mineralization activity Osteolast: Reduced activity Wnt Sclerostin DKK1 Frat1 DSH Sclerostin Antiody βcatenin βcatenin βcatenin 9

30 Antisclerostin Antiody Rx (Li et al, JBMR, 9) Cortical Periosteal BFR Sham Ovx Ovx + Scl-A Endocortical BFR O S/BS Sham Ovx Ovx + Scl-A Oc S/BS Perio MS/BS Sham Ovx Ovx + Scl-A Endocort MS/BS Sham Ovx Ovx + Scl-A Sham Ovx Ovx + Scl-A Li et al, JBMR Sham Ovx Ovx + Scl-A 3 Intracort MS/BS Sham Ovx Ovx + Scl-A Sclerostin Antiody Increases Cancellous Bone Volume and Bone Formation L VERTEBRA PROXIMAL TIBIA VEHICLE Scl-A (3 mg/kg IV) VEHICLE Scl-A (3 mg/kg IV) E F G H Cynomolgus monkeys treated for weeks with sclerostin A Marked increase in modeling-ased one formation Ominsky MS et al, J Bone Miner Res ;5:98-59 CLINICAL TRIALS AND MECHANISMS OF THERAPEUTICS: ANTISCLEROSTIN ANTIBODY Human Studies Romosozuma (osteoporosis) Blosozuma (osteoporosis) 3

31 Phase CLINICAL TRIAL: Romosozuma in Postmenopausal Women with Low Bone Density. McClung et al. N Eng J Med January, 1 Primary endpoint: % change from aseline in BMD at the lumar spine after 1 months Secondary endpoints: BMD at other time points and at other sites Bone turnover markers at various time points Exploratory endpoints Comparison etween romosozuma and ALN or teriparatide in BMD at various sites over 1 months Anti-Sclerostin Antiody (Romosozuma) BMD Phase- effects on BMD* Percentage Change From Baseline Least squae mean ± 95% CI Placeo ALN TPTD Romosozuma mg QM Lumar Spine Total Hip *P <.1 vs placeo * ʌ *P <.1 vs placeo 5 * ʌ P <.1 vs ALN P <.1 vs ALN ʌ 11.3% ʌ P.5 vs TPTD P <.1 vs TPTD.1% * ʌ * ʌ 3 * ʌ Month *Distal radius- no effect of Romo on BMD 1 1 * Month McClung MR et al. NEJM, 1. Bone Mineral Density Year Continued Romosozuma Therapy Romosozuma mg QM ALN TPTD Placeo Percent Change from Baseline 15 5 Lumar Spine 6 Total Hip 11.%.% 15.% 5.5% -.7% -.1%.% % Month Month McClung MR et al. ASBMR 1. 31

32 Results of the Phase III Clinical Trial Announced Feruary, 16 Design: doule-lind, placeocontrolled, international trial Active arm; 1 year of Romosozuma followed y 1 year of denosuma Placeo arm: 1 year of Placeo followed y 1 year of denosuma Results of the Phase III Clinical Trial Announced Feruary, 16 Two primary endpoints: Verteral fractures at 1 months Verteral fractures at months Secondary endpoints: Non-verteral fractures at 1 months Non-verteral fractures at months Results of the Phase III Clinical Trial Announced Feruary, 16 Results: Two primary endpoints met: 73% reduction in verteral fractures at 1 months 75% reduction in verteral fractures at months Secondary endpoints: No significant reduction in non-verteral fractures at 1 months No significant reduction in non-verteral fractures at months 3

33 Summary: Therapies and their Mechanisms CLASS MECHANISM EFFECTS (Vert/Hip/Nonvert) Bisphosphonates AntiOC: FPP synthase +++ Raloxifene antioc +/-/- Calcitonin antioc +/-/- Denosuma Anti-RANK L +++ Odanacati Anti-cathepsin K +++ Teriparatide OB > OC ++/- Aaloparatide OB >>>OC ++/- (faster time course than teriparatide) Romosozuma Antisclerostin +/-/- Osteoporosis Treatment Options CATEGORY RESORPTION FORMATION Anti-remodeling agents - isphosphonates, RANKL inhiitor Anti-resorptive agent - cathepsin K inhiitors Osteoanaolics - PTH and analogues Osteoanaolic agent - sclerostin inhiitors A view of the future? Antiresorptives Osteoanaolics Mechanism uncertain Estrogen Teriparatide Strontium Raloxifene Calcitonin Bisphosphonates Denosuma Cathepsin K inhiitors PTH analogues Antisclerostin molecules 33

34 Summary New insights into one iology have led to new therapeutic approaches to the treatment of osteoporosis Emphasis on pathways that directly effect one resorption or one formation (or oth) have enhanced our therapeutic options Further advances may well lead to even more definitive therapy of osteoporosis! Hopeful! THANK YOU 3