Inhibición de la Esclerostina en el Tratamiento de la Osteoporosis

Transcripción

1 Inhibición de la Esclerostina en el Tratamiento de la Osteoporosis Instituto de Investigaciones Metabólicas Maestría en Osteología y Metabolismo Mineral 16 de Julio de 2014

2 Osteoporosis Treatment: Targeting Bone Remodeling Pathways Imbalance of Bone Remodeling - Lead to Osteoporosis - Offer potential targets for therapy Bone Remodeling - Resorption RANK, RANKL, OPG - Formation Wnt / LRP5 / β- catenin Abbreviations: LRP, low-density lipoprotein receptor-related protein; OPG, osteoprotegerin; RANK, receptor activator for nuclear factor kappa B; RANKL, RANK-ligand

3 Wnt/LRP5/β- catenin Pathway in Bone Formation Wnt/LRP5/β-catenin pathway is essential - Osteoblast proliferation, differentiation and survival - Activity during a phase of bone formation Natural inhibitors of the Wnt/LRP5/β-catenin pathway - Dikkopf (Dkk): made by mieloma cells - Soluble decoy receptors, proteins: WIF, sfrp - Sclerostin: product of osteocytes Abbreviations: sfrp, secreted frizzled-related protein; WIF, Wnt inhibitory factor.

4 WIF Wnt sfrp Wnt Wnt Liganded State Frizzled axin Frat-1 Dsh APC Gsk3 Cytoplasm Nucleus SMRT/ NCoR β-catenin β-catenin β-catenin Nuclear Localization OSTEOBLAST Shoback D. J Clin Endocrinol Metab. 2007;92: β-catenin Tcf/Lef p300/cbp Altered Transcription of Genes BONE FORMATION

5 Wnt/ β-catening Signaling Regulates Ostogenesis Krishnan V., et al J Clin Invest 2006, 116:

6 WIF Wnt sfrp Wnt Dkk SOST Unliganded State Wnt Liganded State Kremen LRP 5/6 LRP 5/6 LRP 5/6 axin APC Gsk3 β-catenin P Proteosomal Degradation Nucleus Frizzled Cytoplasm APC SMRT/ NCoR axin Frat-1 Gsk3 β-catenin Dsh β-catenin β-catenin Frizzled Nuclear Localization OSTEOBLAST Shoback D. J Clin Endocrinol Metab. 2007;92: β-catenin Tcf/Lef p300/cbp Altered Transcription of Genes BONE FORMATION

7 Sclerostin Secreted by Osteocytes Negatively Regulates Bone Formation Mature Osteoblasts New Bone X Sclerostin Pre-Osteoblast Lining Cells X Mesenchymal Stem Cells Osteocyte Bone Ott SM. J Clin Endocrinol Metab. 2005;90: Semenov MV, et al. J Biol Chem. 2006;281: Semënov M, et al. J Biol Chem. 2005;280: Li X, et al. J Biol Chem. 2005;280:

8 Targeted Deletion of the SOST Gene in Mice Results in Increased Bone Formation and Strength Li X et al J Bone Miner Res 2008, 23 (6):

9 Inhibition of Sclerostin by Monoclonal Antibody WITHOUT Sclerostin Antibody Mesenchymal Stem Cell Osteoprogenitor Cell WITH Sclerostin Antibody Mesenchymal Stem cell Osteoprogenitor Cell Pre-Osteoblast Pre-Osteoblast Scl-MAb Sclerostin Osteocyte Bone Osteocyte

10 Sclerostin Antibody Treatment in Aged OVX Rats (A Model of Post menopausal Osteoporosis) Six-month-old female Sprague-Dawley rats were either sham-operated or OVX and left untreated for 13 months. OVX rats injected sc with PBS (n=12) or a murine anti-sclerostin mab (n=12) at 25 mg/kg, twice a week for 5 weeks. Sham-operated rats received PBS. DXA BMD, µct, histomorphometry and strength testing

11 Scl-Ab Treatment Increases areal BMD in Aged OVX Rats Data represent mean ± SE for rats/group. *p < 0.05, **p < 0.01, and ***p < vs. OVX + vehicle. ^p < 0.05 and ^^p < 0.01 vs. Sham + vehicle. Li X. et al, J Bone Miner Res 2009, 24(4):

12 Scl-Ab Treatment in OVX Rats 3-D µct Images of the Distal Femur Li X. et al, J Bone Miner Res 2009, 24(4):

13 Scl-Ab Treatment Restores Tb BMD and BV/TB Back to Sham Levels in OVX Rats Data represent mean ± SE for rats/group. ***p < vs. OVX + vehicle. Li X. et al, J Bone Miner Res 2009, 24(4):

14 Scl-Ab Treatment Increases Tb BV/TV and Bone Formation as Assessed by Histomorphometry Data represent mean ± SE for 8 rats/group. *p < 0.05 and ***p < vs. OVX + vehicle. ^^p < 0.01 and ^^^p < vs. Sham + vehicle. Li X. et al, J Bone Miner Res 2009, 24(4):

15 Osteoclast Surface is Decreased in Scl-Ab- Treated OVX Rats Data are expressed as the mean ± SE for n = 9 12/group. * p < 0.01, p < 0.001, and p < 0.05, compared with vehicle-treated OVX Group. p < 0.05 and p < compared with sham control group. Li X. et al, J Bone Miner Res 2009, 24(4):

16 Scl-Ab Treatment Increases Periosteal and Endocortical Bone Formation in OVX Rats Data represent mean ± SE for 9 12 rats/group. ***p < vs. OVX + vehicle; ^^^p < vs. Sham + vehicle. Li X. et al, J Bone Miner Res 2009, 24(4):

17 Scl-Ab Treatment Increases Bone Strength in Aged OVX Rats COMPRESSION TESTING FOUR-POINT BENDING TEST LUMBAR VERTEBRAE FEMORAL MIDSHAFT Data represent mean ± SE for 12 rats/group. **p < 0.01 and ***p < 0.001vs. OVX + vehicle. ^^p < 0.01 and ^^^p < 0.001vs. Sham + vehicle. Li X. et al, J Bone Miner Res 2009, 24(4):

18 Sclerostin Antibody Treatment in Aged OVX Rats (A Model of Post menopausal Osteoporosis) Short-term administration of a sclerostin-neutralizing antibody resulted in marked increases in bone formation, bone mass and bone strength. Bone volume was increased in both the trabecular and cortical bone compartments. Bone formation was increased on the periosteal and endocortical surfaces. Osteoclast surface was decreased, suggesting an absence of the coupling between osteoblasts and osteoclasts.

19 Sclerostin Antibody Treatment in Aged Male Rats (A Model of Male Osteoporosis) Sixteen-month-old, gonad-intact male Sprague- Dawley rats were injected subcutaneously with vehicle or Scl-Ab at 5 or 25 mg/kg twice per week for 5 weeks (9 10/group). DXA BMD, µct, histomorphometry and strength testing

20 Scl-Ab Treatment Increases areal BMD in Aged Male Rats LUMBAR VERTEBRAE 1-5 FEMUR-TIBIA Data represent mean ± SEM for 7 to 10 rats/group. a p<.05 versus vehicle. b p<.05 versus 5 mg/kg group. Li X. et al, J Bone Miner Res 2010, 25(12):

21 Scl-Ab Treatment in Aged Male Rats 3-D µct Images of the Lumbar Vertebral Body, Distal Femur and Femoral Neck Greater trabecular thickness and trabecular bone volume at all three sites in rats treated with Scl-Ab Greater cortical thickness in L5 with Scl-Ab treatment. Li X. et al, J Bone Miner Res 2010, 25(12):

22 Scl-Ab Treatment Increases Both Trabecular and Cortical Bone Formation in Aged Male Rats Fluorescent micrographs of (A ) sections from the trabecular region of the proximal tibial metaphysis and (B) cortical bone sections from the tibiofibula junction Greater mineralizing surface at both the endocortical and periosteal surfaces in Scl-Ab-treated rats Li X. et al, J Bone Miner Res 2010, 25(12):

23 Scl-Ab Treatment Increases Bone Strength in Aged Male Rats Data are presented as mean ± SEM a p<.05 versus vehicle. b p<.05 versus 5 mg/kg. Li X. et al, J Bone Miner Res 2010, 25(12):

24 Sclerostin Ab Treatment in Aged Male Rats (A Model of Male Osteoporosis) Short-term inhibition of sclerostin using a neutralizing antibody in aged male rats increased bone formation, bone mass and bone strength. Bone formation was increased in the trabecular, endocortical and periosteal compartments. Short-term sclerostin inhibition increased bone strength at the femoral neck, a principal site of osteoporotic fracture in humans. The increase in bone formation was not associated with increases in serum CTX-1 or in osteoclast surface.

25 Bone Anabolic Effects of Scl-Ab are not Blunted by Pre- or Co-treatment with ALN in OVX Rats Experimental Design Groups (n=10) First 6 weeks Second 6 weeks Sham-vehicle Vehicle N/A OVX-vehicle Vehicle N/A OVX-ALN ALN N/A Sham-vehicle/vehicle Vehicle Vehicle OVX-vehicle/vehicle Vehicle Vehicle OVX-vehicle/Scl Ab Vehicle Scl-Ab OVX-ALN/Scl Ab ALN Scl-Ab OVX-ALN/Scl Ab + ALN ALN Scl-Ab + ALN Sprague Dawley rats were sham operated or OVX and left untreated for 3.5 months ALN: 28 mg/kg, twice weekly. Scl-Ab: 25 mg/kg, once weekly Li X. et al, Endocrinology 2011,152 (9):

26 Areal BMD Changes Induced by Scl-Ab Treatment in OVX Rats Pre- or Co-treated with ALN Data are expressed as the mean ± SEM a, P < 0.05 compared with the age-matched sham group; b, P < 0.05 compared with the age-matched OVX vehicle group; c, P < 0.05 compared with the OVX-Vehicle/Scl-Ab group. Li X. et al, Endocrinology 2011,152 (9):

27 Bone Formation Rate in OVX Rats Pre- or Cotreated with ALN BFR/BS at Trabecular Bone of 3rd Lumbar Vertebral Body Data represent mean ± SEM for 10 rats per group a, P < 0.05 compared with the respective sham control group; b, P < 0.05 compared with the respective OVX control group. Li X. et al, Endocrinology 2011,152 (9):

28 Bone Strength in OVX Rats Pre- or Co-treated with ALN Bone strength parameters for the 5 th Lumbar Vertebral body Data represent mean ± SEM a, P 0.05 compared with the respective sham control group; b, P 0.05 compared with the respective OVX control group. Li X. et al, Endocrinology 2011,152 (9):

29 Bone Anabolic Effects of Scl-Ab are not Blunted by Pre- or Co-treatment with ALN in OVX Rats Weekly treatment with a Scl-Ab resulted in similar increases in bone formation, bone mass, and bone strength in OVX rats with or without ALN pretreatment. Cotreatment of Scl-Ab with ALN demonstrated equivalent efficacy as Scl-Ab alone in OVX rats pretreated with ALN.

30 Phase I Study of AMG 785, a Sclerostin Humanized Monoclonal Antibody Phase I, randomized, double-blind, placebo-controlled, ascending, single-dose study. Seventy two healthy subjects received AMG 785 or placebo (3:1) subcutaneously (0.1, 0.3, 1, 3, 5, or 10 mg/kg), or IV (1 or 5 mg/kg). Subjects were followed for up to 85 days Primary objectives: safety and tolerability Secondary objectives: pharmacokinetics, bone turnover markers, and BMD

31 Phase I Study of AMG 785 Adverse Events Padhi D. et al, J Bone Miner Res 2011, 26 (1): 19-26

32 Phase I Study of AMG 785 Pharmacokinetics Serum concentration-time profiles of AMG 785. Profiles shown are following a single subcutaneous (s.c.) dose Data are mean and SD Padhi D. et al, J Bone Miner Res 2011, 26 (1): 19-26

33 Phase I Study of AMG 785 Bone Turnover Markers Mean percent change from baseline on markers of bone turnover following a single subcutaneous dose of placebo or AMG 785. P1NP= N-terminal propeptide of type 1 procollagen sctx= serum C-telopeptide Padhi D. et al, J Bone Miner Res 2011, 26 (1): 19-26

34 Phase I Study of AMG 785 Bone Mineral Density Mean percent change from baseline in lumbar spine or total hip BMD following a single subcutaneous dose of placebo or AMG 785 Data are mean and SE. a, p<.05; b p<.01. Padhi D. et al, J Bone Miner Res 2011, 26 (1): 19-26

35 Phase I Study of AMG 785 In this first-in-human clinical study AMG 785 was generally well tolerated. AMG 785 increased the bone-formation marker P1NP, but not he bone-resorption marker sctx. These effects were associated with potentially clinically relevant increases in lumbar spine and total hip BMD. The results support clinical investigation of AMG 785 in human conditions that could benefit from an increase in bone formation such as osteoporosis.

36 Estudio Fase II de Romosozumab en Mujeres Postmenopausicas con Baja Masa Osea Estudio de Fase II, multicentrico, internacional, randomizado, de 8 grupos paralelos. 419 mujeres postmenopausicas entre 58 y 85 años con un score T menor a -2 y mayor a -3.5 en columna lumbar o cadera. Se trataron durante 12 meses con romosozumab subcutaneo mensual (3 dosis) o cada 3 meses (2 dosis), placebo subcutaneo o controles a etiqueta abierta, alendronato 70 mg semanal o teriparatida 20 ug/dia. El objetivo primario fue el cambio a 12 meses en BMD de columna lumbar. Objetivos secundarios fueron cambios en BMD en otros sitios y BTM.

37 Esquema del Estudio McClung et al N Engl J Med Jan 30;370(5):412-20

38 Características Basales McClung et al N Engl J Med Jan 30;370(5):412-20

39 Cambios en BMD McClung et al N Engl J Med Jan 30;370(5):412-20

40 Cambios en BTM McClung et al N Engl J Med Jan 30;370(5):412-20

41 Eventos Adversos McClung et al N Engl J Med Jan 30;370(5):412-20

42 Conclusiones Estudio Fase II de Romosozumab La administración subcutánea de romosozumab por 12 meses produjo rápidos pero transitorios aumentos de marcadores de formación ósea; moderada y sostenida disminución de marcadores de resorción ósea y un aumento rápido e importante de la BMD en columna lumbar y regiones de la cadera. Los aumentos de BMD con romosozumab fueron significativamente superiores a los cambios con placebo, alendronato y teriparatida. Estos resultados aseguran continuar la evaluación de romosozumab como tratamiento para la osteoporosis.

43 Resumen I La inhibición de esclerostina aumenta la formación, masa y resistencia ósea en modelos animales de osteoporosis. Estos efectos no son bloqueados por pre- o cotratamiento con ALN. Una dosis única de un mab anti-esclerostina aumenta la formación ósea y la BMD en humanos. El aumento en la formación ósea no esta acoplado a un aumento de la resorción, resultando en una mayor ventana anabólica.

44 Resumen II Tratamiento por 12 meses con un mab anti esclerostina produjo un aumento de la BMD en columna lumbar y cadera superiores a ALN y teriparatida. Por lo tanto el tratamiento basado en la inhibición de la esclerostina puede ser eficaz en la prevención de Fx. Sin embargo, la seguridad a largo plazo de la inhibición de esclerostina no ha sido estudiada. En este momento hay en marcha 2 amplios estudios de Fase III.

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