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Seminar 08-10-2008 - klinische highlights asbmr september 2008 montreal

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Seminar 08-10-2008 - klinische highlights asbmr september 2008 montreal

  1. 1. J. Coen NetelenbosJ. Coen Netelenbos 8 oktober 2008, IWO, Utrecht8 oktober 2008, IWO, Utrecht Klinische Highlights ASBMR September 2008 Montreal •SERMS •Calcilytica •Bisfosfonaten •Cathepsine K remmer •Ab RANKL •Ab Scerostin
  2. 2. ““We Are Experiencing a Seismic Event inWe Are Experiencing a Seismic Event in the Treatment of Osteoporosis”the Treatment of Osteoporosis” Reuters 22 mei 2008Reuters 22 mei 2008 Bisphosphonates - Reclast/Aclasta (zoledronic acid; Novartis) - Fosamax (alendronate;Bisphosphonates - Reclast/Aclasta (zoledronic acid; Novartis) - Fosamax (alendronate; Merck/Watson/Teva) - Fosavance (alendronate + Vitamin D; Merck) - BonivaMerck/Watson/Teva) - Fosavance (alendronate + Vitamin D; Merck) - Boniva (ibandronate; Roche / GSK) - Actonel (risedronate; P&G/Sanofi-Aventis) MAb(ibandronate; Roche / GSK) - Actonel (risedronate; P&G/Sanofi-Aventis) MAb Antiresorptives - Denosumab (Amgen) Cathepsin K Inhibitors - Odanacatib (MK-Antiresorptives - Denosumab (Amgen) Cathepsin K Inhibitors - Odanacatib (MK- 0822; Merck) - Balicatib (AAE-581; Novartis) SERMs - Evista (raloxifene; Lilly) -0822; Merck) - Balicatib (AAE-581; Novartis) SERMs - Evista (raloxifene; Lilly) - Viviant (bazedoxifene; Wyeth) - Aprela (bazedoxifene + estrogen; Wyeth) - FablynViviant (bazedoxifene; Wyeth) - Aprela (bazedoxifene + estrogen; Wyeth) - Fablyn (a.k.a Oporia; lasofoxifene; Pfizer/Ligand) - Arzoxifene (Lilly) Other Antiresorptives -(a.k.a Oporia; lasofoxifene; Pfizer/Ligand) - Arzoxifene (Lilly) Other Antiresorptives - Protelos (Strontium; Servier) - SMC-021 (Oral Calcitonin; Novartis / NordicProtelos (Strontium; Servier) - SMC-021 (Oral Calcitonin; Novartis / Nordic Biosciences / Unigene / Emisphere) Anabolics - Sclerostin / SOST / Wnt / Dkk1 -Biosciences / Unigene / Emisphere) Anabolics - Sclerostin / SOST / Wnt / Dkk1 - AMG-785 (CDP-7851; Anti-Sclerostin MAb; Amgen / UCB) - BHQ880 (anti-Dkk1AMG-785 (CDP-7851; Anti-Sclerostin MAb; Amgen / UCB) - BHQ880 (anti-Dkk1 MAb Novartis/Galapagos) PTH - Forteo (teriparatide / sub-q PTH 1-34; Lilly) - PTHMAb Novartis/Galapagos) PTH - Forteo (teriparatide / sub-q PTH 1-34; Lilly) - PTH Fc (1-34; Amgen) - Preos / Preotact (sub-q PTH 1-84; Nycomed/NPS) - Inhaled PTHFc (1-34; Amgen) - Preos / Preotact (sub-q PTH 1-84; Nycomed/NPS) - Inhaled PTH 1-34 (Lilly / Alkermes) - Nasal Transmucosal PTH (1-34); Nastech/P&G - Ostabolin-C1-34 (Lilly / Alkermes) - Nasal Transmucosal PTH (1-34); Nastech/P&G - Ostabolin-C (PTH 1-31; Zelos/Nektar) - BA-058 (PTHrP Analog; Radius Pharmaceuticals / Teijen /(PTH 1-31; Zelos/Nektar) - BA-058 (PTHrP Analog; Radius Pharmaceuticals / Teijen / Ipsen / Novartis) Prostaglandin Agonists - CP-533536 (Pfizer) Calcilytics - ronacaleretIpsen / Novartis) Prostaglandin Agonists - CP-533536 (Pfizer) Calcilytics - ronacaleret (SB-751689; GSK / NPS Pharmaceuticals) Activin Receptor Agonists - ACE-011(SB-751689; GSK / NPS Pharmaceuticals) Activin Receptor Agonists - ACE-011
  3. 3. Effect of SERMEffect of SERM LasofoxifeneLasofoxifene through 3 yearsthrough 3 years (PEARL) on fracture endpoints (1288)(PEARL) on fracture endpoints (1288)
  4. 4. Effect of SERMEffect of SERM Lasofoxifene through 5 yearsLasofoxifene through 5 years onon Breast Cancer, VTE, Stroke and CHD (1288)Breast Cancer, VTE, Stroke and CHD (1288) OutcomeOutcome Hazard RatioHazard Ratio (95% CI)(95% CI) ER+ Breast CancerER+ Breast Cancer 0.17 (0.05-0.57)0.17 (0.05-0.57) VTEVTE 2.06 (1.17-3.61)2.06 (1.17-3.61) StrokeStroke 0.64 (0.41-0.99)0.64 (0.41-0.99) CHDCHD 0.68 (0.50-0.93)0.68 (0.50-0.93) FDA Sept 8, 2008FDA Sept 8, 2008
  5. 5. Lasofoxifene effect on all cause mortality; FDALasofoxifene effect on all cause mortality; FDA advisory committee sept 8, 2008advisory committee sept 8, 2008 Advies aan FDA:Advies aan FDA: *Benefits outweigh the risks*Benefits outweigh the risks *Restricted to patients with high risk of fracture*Restricted to patients with high risk of fracture FDA beslist in oktober 2008FDA beslist in oktober 2008 NB regio 2NB regio 2 (Mexico, Centr. en Zuid Amerika)(Mexico, Centr. en Zuid Amerika)
  6. 6. Anabolic CalcilyticaAnabolic Calcilytica (cinacalcet) (ronacalaret)
  7. 7. Ronacalaret (1174)Ronacalaret (1174) GSK ends NPS's osteoporosis drug studyGSK ends NPS's osteoporosis drug study Sep 26 2008 - 9:20amSep 26 2008 - 9:20am Bad news for NPS Pharmaceuticals: the company announced lateBad news for NPS Pharmaceuticals: the company announced late Thursday that its partner GlaxoSmithKline would abandon a Phase IIThursday that its partner GlaxoSmithKline would abandon a Phase II study of Ronacalaret, an osteoporosis drug. According to SEC filingsstudy of Ronacalaret, an osteoporosis drug. According to SEC filings cited by thecited by the AssociatedAssociated Press, GSK is halting the study becausePress, GSK is halting the study because Ronacalaret is not effective.Ronacalaret is not effective. NPS shares fall as Glaxo pulls out of drug studyNPS shares fall as Glaxo pulls out of drug study 15 september 200815 september 2008 Fase 1 studie: orale toediening: stijging PTH, BAP, PINP en OcFase 1 studie: orale toediening: stijging PTH, BAP, PINP en Oc zonder stijging CTX!zonder stijging CTX! Veel Belovend!!Veel Belovend!!
  8. 8. Biology of the Osteoclast in Bone MetabolismBiology of the Osteoclast in Bone Metabolism Deftos LJ.Deftos LJ. NEJM 2005;353:872-5NEJM 2005;353:872-5 Denosumab OdanaOdanacatib Bisphosphonates
  9. 9. Significante reductie fracturen enSignificante reductie fracturen en mortaliteit door jaarlijks zolendronaatmortaliteit door jaarlijks zolendronaat infuus na heupfractuurinfuus na heupfractuur www.nejm.orgwww.nejm.org on line September 17, 2007; NEJM 2007;357on line September 17, 2007; NEJM 2007;357
  10. 10. Reduction in mortality with ZoledronicReduction in mortality with Zoledronic acid after hip fractureacid after hip fracture [25% (CI 3-42%)][25% (CI 3-42%)] (1030)(1030) • Kon niet verklaard worden uit lager aantal latere fracturenKon niet verklaard worden uit lager aantal latere fracturen • Mannen hoger voordeel mbt mortaliteit (6.4 vs 2.8% vooral CHD)Mannen hoger voordeel mbt mortaliteit (6.4 vs 2.8% vooral CHD) • Verpleeghuispatiënten hadden geen vermindering sterfteVerpleeghuispatiënten hadden geen vermindering sterfte Zolendronaat heeft gunstig effect op :Zolendronaat heeft gunstig effect op : ““physiological reserve and ability to recover from acute illnessses”physiological reserve and ability to recover from acute illnessses” vgl met placebo groep bleek minder sterfte door:vgl met placebo groep bleek minder sterfte door: - pneumonie- pneumonie - kanker- kanker - cardiovasculaire ziekten- cardiovasculaire ziekten
  11. 11. OsteoNecrosis of the Jaw (ONJ); ExperienceOsteoNecrosis of the Jaw (ONJ); Experience with Zoledronic Acid 5 mg yearly in a variety ofwith Zoledronic Acid 5 mg yearly in a variety of osteoporosis indications (sept 2008 ASBMR)osteoporosis indications (sept 2008 ASBMR) 44 studies met 11 000 patienten - 7714 Horizon 1 (PMP osteoporose)studies met 11 000 patienten - 7714 Horizon 1 (PMP osteoporose) - 2111 Horizon 2 (na heupfx)- 2111 Horizon 2 (na heupfx) - 833 GIOP- 833 GIOP - 302 Mannen met osteoporosis- 302 Mannen met osteoporosis ONJ :ONJ : • niet meer gevonden dan de twee eerder beschreven patienten (1 uitniet meer gevonden dan de twee eerder beschreven patienten (1 uit placebo en 1 uit zolendronaat groep)placebo en 1 uit zolendronaat groep) • geen verband ONJ met serum CTX spiegelgeen verband ONJ met serum CTX spiegel
  12. 12. Global Longitudinal study ofGlobal Longitudinal study of Osteoporosis in Women (GLOWOsteoporosis in Women (GLOW)) • Scientific Advisory CommitteeScientific Advisory Committee J. AdachiJ. Adachi A. LaCroixA. LaCroix S. AdamiS. Adami R. LindsayR. Lindsay F. AndersonF. Anderson M. McClungM. McClung S. BoonenS. Boonen J.C. NetelenbosJ.C. Netelenbos J. CompstonJ. Compston J. PfeilschifterJ. Pfeilschifter C. CooperC. Cooper C. RouxC. Roux P. DelmasP. Delmas K. SaagK. Saag A. Diez-PerezA. Diez-Perez P. SambrookP. Sambrook S. GehlbachS. Gehlbach S. SilvermanS. Silverman S. GreenspanS. Greenspan E. SirisE. Siris N. WattsN. Watts • Center for Outcomes Research (COR) at the University ofCenter for Outcomes Research (COR) at the University of MassachusettsMassachusetts • The Alliance for Better Bone HealthThe Alliance for Better Bone Health – Procter & Gamble Pharmaceuticals and sanofi-aventisProcter & Gamble Pharmaceuticals and sanofi-aventis ASBMR 6 PostersASBMR 6 Posters Onderzoek bij bijna 60 000 PMP vrouwenOnderzoek bij bijna 60 000 PMP vrouwen in eerste lijn op drie continentenin eerste lijn op drie continenten
  13. 13. Why need to understand more aboutWhy need to understand more about osteoporosis?osteoporosis? Osteoporosis remains under-diagnosed andOsteoporosis remains under-diagnosed and undertreatedundertreated •Patients who fracture are not being treatedPatients who fracture are not being treated •Patients at high risk of fracture (asymptomatic) are not beingPatients at high risk of fracture (asymptomatic) are not being identified and treatedidentified and treated •When interventions are initiated, adherence is suboptimalWhen interventions are initiated, adherence is suboptimal
  14. 14. Self-Perceived Fracture Risk Compared toSelf-Perceived Fracture Risk Compared to Women of the Same AgeWomen of the Same Age
  15. 15. OPTAMISE Study; Doel en Design (OPTAMISE Study; Doel en Design (M349, F396M349, F396 en JCEM on lineen JCEM on line [Miller PD et al. doi:10.1210/jc.2008-0353][Miller PD et al. doi:10.1210/jc.2008-0353] )) 2-wk screening period2-wk screening period PriorPrior BisphosphonateBisphosphonate Therapy ≥2 yearsTherapy ≥2 years Daily TPTD for 12Daily TPTD for 12 monthsmonths Prior Risedronate 5 mg/d or 30-35 mg/wk Prior Alendronate 10 mg/d or 70 mg/wk Teriparatide Only 20 μg/d SQ Vraag: verstoort Risedronaat de effecten van Teriparatide inVraag: verstoort Risedronaat de effecten van Teriparatide in dezelfde mate als Alendronaat?dezelfde mate als Alendronaat?
  16. 16. Comparison change P1NP bone markerComparison change P1NP bone marker OPTAMISE study (M349, JCEM on line)OPTAMISE study (M349, JCEM on line)
  17. 17. Comparison change QCT Spine & HipComparison change QCT Spine & Hip OPTAMISE study (M349, JCEM on line)OPTAMISE study (M349, JCEM on line) QCT SPINEQCT SPINE QCT HIPQCT HIP
  18. 18. Odanacatib (1291), Cathepsin-K inhibitorOdanacatib (1291), Cathepsin-K inhibitor Odanacatib's phase lll trial is just getting under way Fase II trial. PM osteoporose (T-score<-2)Fase II trial. PM osteoporose (T-score<-2) Odanacatib oraal 1x per week gedurendeOdanacatib oraal 1x per week gedurende 2 jaar vs placebo2 jaar vs placebo * 50mg dose -stijging LBMD 5.5% en BMDTHip 3.2%* 50mg dose -stijging LBMD 5.5% en BMDTHip 3.2% -daling NTX 52% en BAP 13%-daling NTX 52% en BAP 13% --huiduitslagenhuiduitslagen kwamen niet vaker voorkwamen niet vaker voor zoals bij andere cathepsine-K remmerzoals bij andere cathepsine-K remmer BalicatibBalicatib waarvan ontwikkeling is gestoptwaarvan ontwikkeling is gestopt
  19. 19. Werking Denosumab Botafbrekende celBotafbrekende cel Botafbrekende stofantilichamenantilichamen
  20. 20. Denusomab vs Alendronate Head to Head trialDenusomab vs Alendronate Head to Head trial BMD (1285 & JBMR Sept. on line)BMD (1285 & JBMR Sept. on line) Lumbar Spine BMDLumbar Spine BMD Fem. Neck BMDFem. Neck BMD
  21. 21. Denusomab vs Alendronate Head to Head trialDenusomab vs Alendronate Head to Head trial Bone Markers (1285 & JBMR Sept. on line)Bone Markers (1285 & JBMR Sept. on line) CTXCTX P1NPP1NP
  22. 22. Denusomab vs Alendronate Head to Head trialDenusomab vs Alendronate Head to Head trial baseline CTX and effect on Hip BMD (1285)baseline CTX and effect on Hip BMD (1285)
  23. 23. Denusomab vs Alendronate Head to Head trialDenusomab vs Alendronate Head to Head trial Adverse events (1285 & JBMR Sept. on line )Adverse events (1285 & JBMR Sept. on line )
  24. 24. Denusomab FREEDOM Trial (1286)Denusomab FREEDOM Trial (1286) 3jaar bij 7868 PMP osteoporotische3jaar bij 7868 PMP osteoporotische vrouwen (T-scorevrouwen (T-score ≤ -2.5 en ≥ -4)≤ -2.5 en ≥ -4) wervelFx 68%wervelFx 68% heupFx 40%heupFx 40% nonVertFX 20%nonVertFX 20%
  25. 25. Denusomab (M372):Denusomab (M372): Preference and Satisfaction withPreference and Satisfaction with a 6-monthly subcutaneous injection vs a weekly tableta 6-monthly subcutaneous injection vs a weekly tablet
  26. 26. Denusomab (1285):Denusomab (1285): Preference and Satisfaction with aPreference and Satisfaction with a 6-monthly subcutaneous injection vs a weekly tablet6-monthly subcutaneous injection vs a weekly tablet Overall bother with treatment
  27. 27. Sclerostin and Wnt SignalingSclerostin and Wnt Signaling Buchem diseaseBuchem disease && Sclerostosis metSclerostosis met mutaties SOST gene,mutaties SOST gene, waardoor tekort aanwaardoor tekort aan sclerostinsclerostin First Case (1955)First Case (1955) Antilichamen tegenAntilichamen tegen Sclerostin (Scl-Ab)Sclerostin (Scl-Ab) Phase 1 studyPhase 1 study:: BMD , BFR , BRRBMD , BFR , BRR =
  28. 28. Weekly s.c. antibody to sclerostin elevates BMDWeekly s.c. antibody to sclerostin elevates BMD reversibly in OVX rats (1211)reversibly in OVX rats (1211)
  29. 29. Dank voor uw aandacht

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