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Osteoanabolic Therapy for Osteoporosis

Osteoanabolic Therapy for Osteoporosis. John P. Bilezikian, MD Professor of Medicine College of Physicians and Surgeons Columbia University New York, NY USA. Skeletal Endocrinology Brescia, Italy 18 September 2015. THE HOLY GRAIL?.

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Osteoanabolic Therapy for Osteoporosis

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  1. Osteoanabolic Therapy for Osteoporosis John P. Bilezikian, MD Professor of Medicine College of Physicians and Surgeons Columbia University New York, NY USA Skeletal Endocrinology Brescia, Italy 18 September 2015

  2. THE HOLY GRAIL?

  3. WHY PARATHYROID HORMONE AS AN OSTEOANABOLIC THERAPYWHEN….. “Parathyroid hormone is bad for bones”

  4. PHPT IN THE EARLY YEARS, 1929-1970 The captain (1929-1933) and The lady (1970)

  5. * * The densitometric signature of primary hyperparathyroidism in the modern era 100 * Differs from radius, p<.05 90 Bone Mineral Density:% of Expected 80 70 Lumbar Spine Femoral Neck Radius Silverberg, Bilezikian et al. JBMR, 1989

  6. PTH dose and timing determine its effect on bone MODE EFFECT Continuous (high dose) Catabolic Daily(low dose) Anabolic Dobnig H, et al. Endocrinology 1997;138:4607-12.

  7. PTH Intermittent Anabolism Catabolism

  8. Three keys to the anabolic potential of PTH • Low dose • Intermittent administration • Pulsatility with rapid “on” and “off” kinetics Under these conditions…..

  9. PTH is anabolic: Bone Formation Markers increasebeforeBone Resorption Markers 80 70 60 50 Mean % Change in Turnover Marker 40 30 20 Osteocalcin 10 n-telopeptide 0 0 1 2 3 4 5 6 Time (Months) Lindsay R, et al. Lancet. 1997;350(9077):550-555.

  10. Quadruple Labels in Teriparatide-treated and Control Subjects Teriparatide Control Dempster et al. 2003

  11. Initial Cellular Mechanisms of PTH PTH stimulates bone formation directly first and then stimulates the remodeling process

  12. PTH as an Anabolic Agent for Bone:A Kinetic Model Bone formation markers Peak Early increase in bone formation also seen in dynamic histomorphometic indices by transiliac bone biopsy Index of Bone Turnover Months

  13. PTH as an Anabolic Agent for Bone:A Kinetic Model Bone formation markers Bone resorption markers Peak “Anabolic Window” Index of Bone Turnover Believed to limit the osteoanabolic potential of PTH Months

  14. Clinical Trials with PTH and its analogues TeriparatidePTH (1-84)Abaloparatide (PTHrP analogue)

  15. Effect of Teriparatide on Incidence of Vertebraland Non-Vertebral Fractures in Postmenopausal Women with Osteoporosis New vertebral fracture Non-vertebral fractures 20 20 P< 0.01 P< 0.01 18 18 16 16 14 14 12 12 Patients (%) with fracture Patients (%) with fracture 10 10 65% 8 8 53% 6 6 4 4 2 2 0 0 Placebo 20 g PTH Placebo 20 g PTH Neer RM, et al. N Engl J Med. 2001;344:1434-41

  16. 3-D µCT Images of iliac crest biopsies before and after either PTH(1-84) or Teriparatide Therapy PTH(1-84) Placebo Therapy Placebo Teriparatide

  17. Despite efficacy of teriparatide as a therapy for osteoporosis,there are “issues” • Animal toxicity data (osteosarcoma), still a concern to some prescribers and patients

  18. Update on Osteosarcoma (Cipriani, Irani, and Bilezikian, J Bone Miner Res, 2012) • 3-5 cases of osteosarcoma have been reported in patients who have received teriparatide since 2002 (Harper et al. JBMR, 2007) • Epidemiological considerations • >2.0 million patients have been treated with teriparatide and PTH(1-84) • The background incidence of osteosarcoma in adults- 1/250,000 • The cases reported are fewer than what would be expected on coincidental, epidemiological grounds

  19. Update on Osteosarcoma (Andrews et al, J Bone Miner Res, 2012) • 15-year FDA-mandated surveillance “Osteosarcoma Surveillance Study” • The report covers the first 7 years • 1448 cases of osteosarcoma identified (62% of all US cases over this period) • 549 patients or proxies interviewed (representative of the entire cohort) • No history of teriparatide use in any patient

  20. Safety of PTH • No oncogenic signals after 12 years of human use, worldwide • The likelihood that osteosarcoma is a human toxicity when used in the way it is being used would appear to be remote. • Surveillance (and the black box) continues

  21. Antiresorptive Combination therapy with an antiresorptive and osteoanabolic agent Teriparatide • Rationale is clear but the results… • Raloxifene: possible small benefit • Estrogen: possible small benefit • Alendronate: reduced benefit • Risedronate (in men): possible hip BMD benefit • Zoledronic acid: early benefit primarily • Denosumab: promising (Tsai et al, Lancet, 2013; Leder, JCEM, 2014, J BMR, 2015)

  22. New approaches and delivery systems for teriparatide and PTH(1-84) • PTHrP(1-36) and analogues (Horwitz et al, JCEM, 2010; Miller Endo Soc, 2015) • Endogenous stimulation of PTH (Fitzpatrick et al. J Bone Miner Res, 2011) • Transdermal route • (Cosman et al, JCEM, 2010) • “Chip” Technology (Sci Trans Med, 2012) • Weekly administration (Approved in Japan, 2012)

  23. Horwitz M, Tedesco MB, Garcia-Ocaña A, Sereika SM, Prebehala L, Bisello A, Hollis BW, Gundberg CM, Stewart AF, Parathyroid Hormone-Related Protein for the Treatment of Postmenopausal Osteoporosis: Defining the Maximal TolerableDose. J Clin Endocrinol Metab 2010 95:1279-1287 Bone Formation Bone Resorption

  24. Functional optimization of PTHrP: Abaloparatide, an analogue 27 hPTH1-34 (Forteo™) regulates CA homeostasis and bone metabolism hPTHrP1-34 PTHrP (BA058) 22 30 34 100% hPTHrP 38% hPTHrP based on amino acid replacements between residues 22-34

  25. Odea et al. 2010: Percentage Change in Spine BMD3,6,and 12 Month Data: BA058, in subjects with osteoporosis or at risk for osteoporosis (T<-2.0) 28 CONFIDENTIAL

  26. 200 150 100 50 0 Abaloparatide vs TeriparatideChange in Biomarkers at 6 Months Phase 2 study ABALO-80 TPTD-20 Women with postmenopausal osteoporosis Interventions: rPTHrP 20, 40 or 80 ugm QD TPTD 20 ugm QD Placebo % Change from baseline P1NP CTX Hattersley R et al. Endocrine Society. OR-08, 2012.

  27. Abaloparatide vs TeriparatideChange in BMD over 12 Months Placebo ABALO-80 TPTD-20 % Change from baseline Lumbar Total spine hip Hypercalcemia (%) Placebo 4% TPTD 40% PTHrP 80 ugm 18% Hattersley R et al. Endocrine Society. OR-08, 2012. Leder BZ et al. J Clin Endocrinol Metab. 2015;100:697-706.

  28. Update on BA 058 (Abaloparatide) • International Phase 3 trial ended, September, 2014 • Results made available, December, 2014 • Presented by Miller et al, Endocrine Society, March, 2015

  29. Phase 3 Trial Design of Abaloparatide Clinical Trial N = 2463 Randomization Placebo Abaloparatide 80 mcg Daily SC Teriparatide 20 mcg Daily SC Months 6 12 18 Miller et al, 2015

  30. Changes in Bone Turnover Markers:Abaloparatide vs. Teriparatide vs. Placebo(Miller et al. Endo Soc 3-15) Placebo P1NP Abaloparatide * * * * * -12% -46% -28% -56% * # * * # -69% # -33% * CTX # * Percent Change from Baseline Percent Change from Baseline # * # Months Months *p < 0.0001 vs placebo #p < 0.01 vs teriparatide Teriparatide

  31. Changes in BMD at the Spine and Reduction in New Vertebral Fractures: All 3 Groups(Miller et al. Endo Society, 3-15) Placebo Abaloparatide Lumbar Spine BMD #p < 0.01 vs TP # Abaloparatide # % Change from Baseline teriparatide Months Teriparatide

  32. Changes in BMD at Non-Vertebral Sites and NVF Risk Reduction: All 3 Groups (Miller et al. Endo Society, 3-15) ^ Total Hip BMD # # % Change from Baseline Months # # p < 0.0001 vs TP p < 0.0001 vs TP ^ p = 0.0003 vs TP FemoralNeck BMD @ p = 0.0016 vs TP @ # # % Change from Baseline Months

  33. Kaplan-Meier Time to First Event(Miller et al. Endo Society, 3-15) Placebo Non-Vertebral Fractures Abaloparatide Percent of Patients with Fracture Percent of Patients with ≥1 New Non-Vertebral Fracture Abaloparatide Time to Event (Days) Teriparatide

  34. Kaplan-Meier Time to First Event(Miller et al. Endo Society, 2015) Placebo Clinical Fractures Abaloparatide Percent of Patients with ≥1 New Clinical Fracture Percent of Patients with Fracture Abaloparatide Time to Event (Days) Teriparatide

  35. Changes in Wrist BMD and Wrist Fracture Reduction: Abaloparatide vs. Teriparatide vs. Placebo(Miller et al. Endo Society 3-15) K-M Estimated Incidence Rate Wrist Fracture (ITT Population) Ultra-Distal Radius BMD Abaloparatide * * * # NS NS % Change from Baseline NS *p < 0.001 vs placebo #p = 0.0013 vs TP Months

  36. New approaches and delivery systems for teriparatide and PTH(1-84) • PTHrP(1-36) (Horwitz et al, JCEM, 2010; O’Dea et al. Int’l Soc Endo, 2010) • Endogenous stimulation of PTH (Fitzpatrick et al. J Bone Miner Res, 2011) • Transdermal route • (Cosman et al, JCEM, 2010) • “Chip” Technology (Sci Trans Med, 2012) • Weekly administration (Approved in Japan, 2012)

  37. Other Potential Applications • Historical notes • Review of therapeutic efficacy in Osteoporosis • New PTHs and delivery systems • Applications of PTH to specific conditions • GIO (to be covered in another lecture) • Accelerate Fracture healing • Atypical Fractures • Hypoparathyroidism (to be covered in another lecture)

  38. PTH to accelerate fracture healing • In animals, fracture healing is enhanced(Ellegard M et al. CTI, 2010) • In human subjects • with Colles’ Fracture, 20 ug, but not 40 ug (the primary endpoint), reduced the median time to radiographic healing(Aspenberg et al. J Bone Miner Res, 2010) • With pelvic fracture, PTH(1-84) reduced the time to radiographic healing(Peichl et al. J Bone Joint Surg 2011) • Case Reports: numerous • Reviews: (J Orthop Trauma , 2013, Borges, Freitas and Bilezikian, Arq Bras Endocinol Metab, 2013, Campbell et al. expert Opin Biol Ther, 2015). • Personal Experience: Lecoultre J et al. (Rev Med Suisee, 2015)

  39. Teriparatide in the management of ONJ or Atypical Fractures • ONJ- 2 cases “bone regeneration at extraction sites and the absence of ulcerations after 10 mos of teriparatide(Harper RP et al J Oral Maxillofac Surg, 2007; Lau et al. J Rheumatol, 2009) • Atypical Fractures • Radiographic improvement and closure 1 month after starting teriparatide (Cavalho et al. J Clin Endocrin Metab, 2011) • Increases in bone turnover markers and bone density in 5 cases (Chiang CY et al. Bone, 2013)

  40. Osteoanabolic therapy with PTH and PTHrP peptides…. Provides a therapeutic mechanism by which bone gain and reduced fracture incidence is associated with microstructural improvements…… A most worthy goal!

  41. THE FUTURE OF OSTEOANABOLIC THERAPY

  42. Clues to a new therapeutic approach: Sclerosteosis & van Buchem’s Disease • increased bone mass throughout skeleton. • very low fracture risk • due to absence of sclerostin - an inhibitor of Wnt signaling and bone formation Janssens and Van Hul. Hum Mol Genet. 2002;11:2385-93.

  43. Heterozygous carriers of Sclerosteosis and van Buchem’s disease do not appear to have complications as seen in the homozygous subjects • Higher bone density • Increased markers of bone formation • Levels of sclerostin are intermediate • No long-term or progressive sequellae

  44. Sclerostin Wnt Wnt Sclerostin LRP5/6 LRP5/6 DKK1 DKK1 LRP 4 AXIN LRP 4 APC Frat1 DSH DSH GSK3β APC GSK3β βcatenin βcatenin P βcatenin Proteosomal Degradation AXIN βcatenin Osteoblast differentiation, proliferation, and mineralization activity Osteoblast: Reduced activity

  45. Wnt Sclerostin LRP5/6 AXIN LRP4 APC DKK1 Sclerostin Antibody Frat1 GSK3β DSH βcatenin βcatenin βcatenin

  46. Antisclerostin Antibody Rx (Li et al, JBMR, 2009) 100 75 50 25 0 Cortical Ob S/BS Endocort MS/BS 10 8 6 4 2 0 Sham Ovx Ovx + Scl-Ab Oc S/BS 5 4 3 2 1 0 Perio MS/BS 60 50 40 30 20 10 Sham Ovx Ovx + Scl-Ab Periosteal BFR 5 4 3 2 1 0 12 8 4 0 Sham Ovx Ovx + Scl-Ab 40 30 20 10 0 Intracort MS/BS Sham Ovx Ovx + Scl-Ab Sham Ovx Ovx + Scl-Ab Sham Ovx Ovx + Scl-Ab Sham Ovx Ovx + Scl-Ab Endocortical BFR Li et al, JBMR 2009

  47. Sclerostin Antibody Therapy in Rats 3D µCT images of distal femur Rats ovariectomized at age 6 months. Treatment for 5 weeks beginning at 13 months of age • increased bone mass • improved trabecular architecture • increased cortical thickness Li et al. J bone Mner Res. 2009;24.578-588.

  48. Sclerostin Antibody Increases Cancellous Bone Volume and Bone Formation PROXIMAL TIBIA L2 VERTEBRA VEHICLE Scl-Ab (30 mg/kg IV) VEHICLE Scl-Ab (30 mg/kg IV) G F E H Cynomolgus monkeys treated for 10 weeks with sclerostin Ab Marked increase in modeling-based bone formation Ominsky MS et al, J Bone Miner Res 2010;25:948-59

  49. CLINICAL TRIALS AND MECHANISMS OF THERAPEUTICS: ANTISCLEROSTIN ANTIBODY Romosozumab (osteoporosis) Blosozumab (osteoporosis) BPS804(adult onset adult-onset hypophosphatasia- MO27) Human Studies

  50. Phase 2 CLINICAL TRIAL: Romosozumab in Postmenopausal Women with Low Bone Density. McClung et al. N Eng J Med January, 2014, 419 Postmenopausal women, 55-85 yrs old BMD: T < -2.0 and > -3.5 Mean T-scores: LS: -2.29; TH: -1.53; FN: -1.93 6 sc dosing regimens monthly (70, 140, 210 mg) or q 3 mos (140, 210 mg); PLB Comparators: open label- ALN (70 mg/weekly; TPTD 20 ug daily)

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