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

““We Are Experiencing a Seismic Event in We 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) - Boniva Merck/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) - Fablyn Viviant (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 / Nordic Protelos (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-Dkk1 AMG-785 (CDP-7851; Anti-Sclerostin MAb; Amgen / UCB) - BHQ880 (anti-Dkk1 MAb Novartis/Galapagos) PTH - Forteo (teriparatide / sub-q PTH 1-34; Lilly) - PTH MAb 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 PTH Fc (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-C 1-34 (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 - ronacaleret Ipsen / 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 (Acceleron)(Acceleron)

Effect of SERM Effect of SERM LasofoxifeneLasofoxifene through 3 years through 3 years (PEARL) on fracture endpoints (1288)(PEARL) on fracture endpoints (1288)

Effect of SERM Effect of SERM Lasofoxifene through 5 yearsLasofoxifene through 5 years on on Breast Cancer, VTE, Stroke and CHD (1288)Breast Cancer, VTE, Stroke and CHD (1288)

OutcomeOutcome Hazard Ratio Hazard 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

Lasofoxifene effect on all cause mortality; FDA Lasofoxifene effect on all cause mortality; FDA advisory committee sept 8, 2008 advisory 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)

Anabolic CalcilyticaAnabolic Calcilytica

(cinacalcet) (ronacalaret)

Ronacalaret (1174)Ronacalaret (1174)

GSK ends NPS's osteoporosis drug study GSK ends NPS's osteoporosis drug study Sep 26 2008 - 9:20amSep 26 2008 - 9:20am

Bad news for NPS Pharmaceuticals: the company announced late Bad news for NPS Pharmaceuticals: the company announced late Thursday that its partner GlaxoSmithKline would abandon a Phase II Thursday that its partner GlaxoSmithKline would abandon a Phase II study of Ronacalaret, an osteoporosis drug. According to SEC filings study of Ronacalaret, an osteoporosis drug. According to SEC filings

cited by the cited by the Associated Associated Press, GSK is halting the study because Press, 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 2008Fase 1 studie: orale toediening: stijging PTH, BAP, PINP en Oc Fase 1 studie: orale toediening: stijging PTH, BAP, PINP en Oc

zonder stijging CTX! zonder stijging CTX!Veel Belovend!!Veel Belovend!!

Biology of the Osteoclast in Bone MetabolismBiology of the Osteoclast in Bone Metabolism

Deftos LJ.Deftos LJ. NEJM 2005;353:872-5 NEJM 2005;353:872-5

Denosumab

OdanaOdanacatib

Bisphosphonates

Significante reductie fracturen en Significante reductie fracturen en mortaliteit door jaarlijks zolendronaat mortaliteit door jaarlijks zolendronaat

infuus na heupfractuur infuus na heupfractuur

www.nejm.org on line September 17, 2007; NEJM 2007;357 on line September 17, 2007; NEJM 2007;357

Reduction in mortality with Zoledronic Reduction in mortality with Zoledronic acid after hip fracture acid 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

OsteoNecrosis of the Jaw (ONJ); Experience OsteoNecrosis of the Jaw (ONJ); Experience with Zoledronic Acid 5 mg yearly in a variety of with Zoledronic Acid 5 mg yearly in a variety of

osteoporosis indications (sept 2008 ASBMR)osteoporosis indications (sept 2008 ASBMR)

4 4 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 uit niet 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

Global Longitudinal study of Global Longitudinal study of Osteoporosis in Women (GLOWOsteoporosis in Women (GLOW))

• Scientific Advisory CommitteeScientific Advisory CommitteeJ. AdachiJ. Adachi A. LaCroixA. LaCroix S. AdamiS. AdamiR. LindsayR. Lindsay F. AndersonF. Anderson M. McClungM. McClungS. BoonenS. Boonen J.C. NetelenbosJ.C. Netelenbos J. CompstonJ. CompstonJ. PfeilschifterJ. Pfeilschifter C. CooperC. Cooper C. RouxC. RouxP. DelmasP. Delmas K. SaagK. Saag A. Diez-PerezA. Diez-PerezP. SambrookP. Sambrook S. GehlbachS. Gehlbach S. SilvermanS. SilvermanS. GreenspanS. Greenspan E. SirisE. Siris N. WattsN. Watts

• Center for Outcomes Research (COR) at the University of Center 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 vrouwenin eerste lijn op drie continentenin eerste lijn op drie continenten

Why need to understand more about Why need to understand more about osteoporosis?osteoporosis?

Osteoporosis remains under-diagnosed and Osteoporosis 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 being Patients 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

Self-Perceived Fracture Risk Compared to Self-Perceived Fracture Risk Compared to Women of the Same AgeWomen of the Same Age

OPTAMISE Study; Doel en Design (OPTAMISE Study; Doel en Design (M349, F396 M349, F396 en JCEM on line en 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

Prior Prior Bisphosphonate Bisphosphonate Therapy ≥2 yearsTherapy ≥2 years

Daily TPTD for 12 Daily TPTD for 12 monthsmonths

Prior Risedronate5 mg/d or 30-35 mg/wk

Prior Alendronate10 mg/d or 70 mg/wk

Teriparatide Only20 μg/d SQ

Vraag: verstoort Risedronaat de effecten van Teriparatide in Vraag: verstoort Risedronaat de effecten van Teriparatide in

dezelfde mate als Alendronaat?dezelfde mate als Alendronaat?

Comparison change P1NP bone marker Comparison change P1NP bone marker OPTAMISE study (M349, JCEM on line)OPTAMISE study (M349, JCEM on line)

Comparison change QCT Spine & Hip Comparison change QCT Spine & Hip OPTAMISE study (M349, JCEM on line)OPTAMISE study (M349, JCEM on line)

QCT SPINEQCT SPINE

QCT HIPQCT HIP

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 gedurende Odanacatib 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 voor kwamen niet vaker voor

zoals bij andere cathepsine-K remmer zoals bij andere cathepsine-K remmer BalicatibBalicatib waarvan ontwikkeling is gestopt waarvan ontwikkeling is gestopt

Werking Denosumab

Botafbrekende celBotafbrekende cel

Botafbrekende stofantilichamenantilichamen

Denusomab vs Alendronate Head to Head trial Denusomab 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

Denusomab vs Alendronate Head to Head trial Denusomab vs Alendronate Head to Head trial Bone Markers (1285 & JBMR Sept. on line)Bone Markers (1285 & JBMR Sept. on line)

CTXCTX P1NPP1NP

Denusomab vs Alendronate Head to Head trial Denusomab vs Alendronate Head to Head trial baseline CTX and effect on Hip BMD (1285)baseline CTX and effect on Hip BMD (1285)

Denusomab vs Alendronate Head to Head trial Denusomab vs Alendronate Head to Head trial Adverse events (1285 & JBMR Sept. on line )Adverse events (1285 & JBMR Sept. on line )

Denusomab FREEDOM Trial (1286)Denusomab FREEDOM Trial (1286)

3jaar bij 7868 PMP osteoporotische 3jaar bij 7868 PMP osteoporotische vrouwen (T-score vrouwen (T-score ≤ -2.5 en ≥ -4)≤ -2.5 en ≥ -4)

wervelFx 68%wervelFx 68%heupFx 40%heupFx 40%nonVertFX 20%nonVertFX 20%

Denusomab (M372): Denusomab (M372): Preference and Satisfaction with Preference and Satisfaction with a 6-monthly subcutaneous injection vs a weekly tablet a 6-monthly subcutaneous injection vs a weekly tablet

Denusomab (1285): Denusomab (1285): Preference and Satisfaction with a Preference and Satisfaction with a 6-monthly subcutaneous injection vs a weekly tablet 6-monthly subcutaneous injection vs a weekly tablet

Overall bother with treatment

Sclerostin and Wnt Signaling Sclerostin and Wnt Signaling

Buchem diseaseBuchem disease &&Sclerostosis met Sclerostosis met mutaties SOST gene, mutaties SOST gene, waardoor tekort aan waardoor tekort aan sclerostinsclerostin

First Case (1955)First Case (1955)

Antilichamen tegenAntilichamen tegenSclerostin (Scl-Ab)Sclerostin (Scl-Ab)

Phase 1 studyPhase 1 study: : BMD , BFR , BRRBMD , BFR , BRR =

Weekly s.c. antibody to sclerostin elevates BMD Weekly s.c. antibody to sclerostin elevates BMD reversibly in OVX rats (1211)reversibly in OVX rats (1211)

Dank voor uw aandacht