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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
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THE HOLY GRAIL?
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WHY PARATHYROID HORMONE AS AN OSTEOANABOLIC THERAPY WHEN…..
“Parathyroid hormone is bad for bones”
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PHPT IN THE EARLY YEARS, 1929-1970
The captain ( ) and The lady (1970)
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Bone Mineral Density: % of Expected Silverberg, Bilezikian et al.
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
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PTH dose and timing determine its effect on bone
MODE EFFECT Continuous (high dose) Catabolic Daily (low dose) Anabolic The dual actions of PTH as a function of dosing and amount were teased apart, which led to the idea that continuous high-dose PTH is catabolic primarily for cortical bone, whereas the daily low dose was associated with anabolic effects. Dobnig H, Turner RT. The effects of programmed administration of human parathyroid hormone fragment (1-34) on bone histomorphometry and serum chemistry in rats. Endocrinology 1997;138: Dobnig H, et al. Endocrinology 1997;138:
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PTH Intermittent Anabolism Catabolism
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Three keys to the anabolic potential of PTH
Low dose Intermittent administration Pulsatility with rapid “on” and “off” kinetics Under these conditions…..
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Mean % Change in Turnover Marker
PTH is anabolic: Bone Formation Markers increase before Bone Resorption Markers 80 70 60 50 Mean % Change in Turnover Marker 40 30 20 Osteocalcin 10 n-telopeptide 1 2 3 4 5 6 Time (Months) Lindsay R, et al. Lancet. 1997;350(9077):
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Quadruple Labels in Teriparatide-treated and Control Subjects
Dempster et al. 2003
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Initial Cellular Mechanisms of PTH
However, the results from the marker studies have led to the hypothesis that PTH treatment increases bone mass rapidly by directly stimulating bone formation, i.e., bone formation without prior resorption. PTH stimulates bone formation directly first and then stimulates the remodeling process
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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
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PTH as an Anabolic Agent for Bone: A Kinetic Model
Bone formation markers Peak Bone resorption markers “Anabolic Window” Index of Bone Turnover Believed to limit the osteoanabolic potential of PTH Months
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Clinical Trials with PTH and its analogues Teriparatide PTH (1-84) Abaloparatide (PTHrP analogue)
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Effect of Teriparatide on Incidence of Vertebral and 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 8 65% 8 53% 6 6 4 4 2 2 Placebo 20 g PTH Placebo 20 g PTH Neer RM, et al. N Engl J Med. 2001;344:
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3-D µCT Images of iliac crest biopsies before and after either PTH(1-84) or Teriparatide
Therapy PTH(1-84) Placebo Biopsy studies have provided compelling evidence of the anabolic effects of Preotact® on trabecular bone Iliac crest biopsies were obtained from postmenopausal osteoporotic women enrolled in the TOP study after 18 months of daily sc injections of placebo or 100 μg Preotact ® Treatment with Preotact® increases trabecular bone volume and improves connectivity It also improves trabecular morphology, from the rod-like structure associated with elderly postmenopausal women to a more mechanically competent plate-like structure typically seen in premenopausal women Also note the increase in cortical thickness after treatment with Preotact® These results are consistent with an increase in bone strength and the marked reduction in vertebral fracture incidence observed in the TOP study. Therapy Placebo Teriparatide
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Despite efficacy of teriparatide as a therapy for osteoporosis, there are “issues”
Animal toxicity data (osteosarcoma), still a concern to some prescribers and patients
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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
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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
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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
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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)
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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)
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Bone Formation Bone Resorption
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 Tolerable Dose. J Clin Endocrinol Metab : Bone Formation Bone Resorption
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Functional optimization of PTHrP: Abaloparatide, an analogue
27 Functional optimization of PTHrP: Abaloparatide, an analogue hPTH1-34 (Forteo™) regulates CA homeostasis and bone metabolism hPTHrP1-34 PTHrP (BA058) 100% hPTHrP 38% hPTHrP based on amino acid replacements between residues 22-34 27
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28 Odea et al. 2010: Percentage Change in Spine BMD 3,6,and 12 Month Data: BA058, in subjects with osteoporosis or at risk for osteoporosis (T<-2.0) CONFIDENTIAL 28
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Abaloparatide vs Teriparatide Change in Biomarkers at 6 Months
Phase 2 study ABALO TPTD-20 200 150 50 100 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. 29
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Abaloparatide vs Teriparatide Change in BMD over 12 Months
% Change from baseline Lumbar Total spine hip ABALO TPTD-20 Placebo 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: 30
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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
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Phase 3 Trial Design of Abaloparatide Clinical Trial
Placebo Abaloparatide 80 mcg Daily SC Teriparatide 20 mcg Daily SC Randomization Months 6 12 18 N = 2463 Miller et al, 2015
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Changes in Bone Turnover Markers: Abaloparatide vs. Teriparatide vs
Changes in Bone Turnover Markers: Abaloparatide vs. Teriparatide vs. Placebo (Miller et al. Endo Soc 3-15) CTX P1NP * * * * -46% -12% -56% -69% -28% -33% * * * # * # * # Percent Change from Baseline * # Percent Change from Baseline * # # Months Months Placebo Abaloparatide Teriparatide *p < vs placebo #p < 0.01 vs teriparatide
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Changes in BMD at the Spine and Reduction in New Vertebral Fractures: All 3 Groups (Miller et al. Endo Society, 3-15) Lumbar Spine BMD % Change from Baseline Months #p < 0.01 vs TP # Abaloparatide teriparatide Placebo Abaloparatide Teriparatide
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Changes in BMD at Non-Vertebral Sites and NVF Risk Reduction: All 3 Groups (Miller et al. Endo Society, 3-15) Total Hip BMD # p < vs TP ^ ^ p = vs TP # # % Change from Baseline Months Femoral Neck BMD # p < vs TP @ @ p = vs TP # # % Change from Baseline Months
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Kaplan-Meier Time to First Event (Miller et al. Endo Society, 3-15)
Percent of Patients with Fracture Time to Event (Days) Placebo Abaloparatide Teriparatide Non-Vertebral Fractures Percent of Patients with ≥1 New Non-Vertebral Fracture Abaloparatide
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Kaplan-Meier Time to First Event (Miller et al. Endo Society, 2015)
Clinical Fractures Placebo Abaloparatide Teriparatide Percent of Patients with ≥1 New Clinical Fracture Percent of Patients with Fracture Abaloparatide Time to Event (Days)
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K-M Estimated Incidence Rate Wrist Fracture (ITT Population)
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) % Change from Baseline * Months *p < vs placebo #p = vs TP # NS Ultra-Distal Radius BMD Abaloparatide
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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)
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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)
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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)
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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)
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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!
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OSTEOANABOLIC THERAPY
THE FUTURE OF OSTEOANABOLIC THERAPY
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increased bone mass throughout skeleton. very low fracture risk
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 Effect of One Year Treatment with the Cathepsin-K Inhibitor, Balicatib, on Bone Mineral Density (BMD) in Postmenopausal Women with Osteopenia/Osteoporosis. S. Adami1, J. Supronik*2, T. Hala*3, J. P. Brown4, P. Garnero5, S. Haemmerle*6, C. E. Ortmann*6, F. Bouisset*6, U. Trechsel6. 1University Hospital, Rheumatology, Verona, Italy, 2Wojewodzki Szpital, Bialystok, Poland, 3Center for Metabolic Bone Disease, Pardubice, Czech Republic, 4Laval University, Québec, PQ, Canada, 5INSERM and Synarc, Lyon, France, 6Novartis Pharma AG, Basel, Switzerland. Cathepsin K (cathK) is a cysteine protease that is selectively, highly expressed by osteoclasts and plays a key role in bone resorption. Balicatib is an orally bioavailable, novel, specific inhibitor of human cathK, acting late in the process leading to bone resorption, and may not influence osteoclast/osteoblast interactions. Therefore, bone formation may decrease less, leading to a positive bone balance at the level of the bone remodeling unit. In this randomized, placebo-controlled trial 675 postmenopausal women (mean age 62 yrs) with lumbar spine (LS) BMD T-scores <-2, were treated with 5, 10, 25, or 50mg daily oral balicatib, or placebo, for one year. At 12 months, there was a dose-related increase in DXA BMD for LS and hip, as shown in the table below (% change from baseline from an ANCOVA model). Bone resorption markers were dose-dependent, statistically significantly decreased vs placebo with 25 and 50mg at all time points during treatment with a minimum at -61% for sCTX and -55% for uNTX/Cr (50mg, 1 month). Serum osteocalcin, bone-specific alkaline phosphatase (BSAP), and N-terminal propeptide of type I collagen (sP1NP) were not statistically significantly different from placebo at 12 months with 10, 25, and 50 mg. With 5mg there was an increase in formation markers which reached statistical significance at all time points beyond 1 month for BSAP (+23%, p<0.001, at 12 months), and sP1NP (+36%, p<0.001 at 12 months.). * Multiplicity adjusted p< versus placebo Balticatib was generally safe and well tolerated at all doses up to 25mg per day. There was a higher incidence of skin adverse events (mainly pruritus) on balicatib which were more frequent on 50mg. Additionally a small number of patients experienced scleredema/ morphea-like skin changes which improved off treatment. Conclusion: This is the first demonstration of the favorable effect of a cathK inhibitor on BMD in humans. The study confirms that this new mode of action may be an interesting target for the treatment of osteoporosis. Disclosures: S. Adami, Amgen, Eli Lilly, Regimen Placebo 5 mg 10 mg 25 mg 50 mg BMD Lumbar Spine: mean%change (SE) 0.25 (0.37) 1.20 (0.38) 3.16 (0.38)* 4.41 (0.37)* 4.46 (0.40)* BMD Total Hip: mean%change (SE) 0.29 (0.27) 0.07 (0.28) 1.77 (0.27)* 2.21 (0.27)* 2.25 (0.29)* Janssens and Van Hul. Hum Mol Genet. 2002;11:
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Increased markers of bone formation
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
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Osteoblast differentiation, proliferation, and mineralization activity
Sclerostin Wnt Wnt Sclerostin LRP5/6 LRP5/6 DKK1 DKK1 LRP 4 AXIN LRP 4 Frat1 DSH APC APC AXIN GSK3β βcatenin P DSH βcatenin GSK3β βcatenin Proteosomal Degradation βcatenin Osteoblast differentiation, proliferation, and mineralization activity Osteoblast: Reduced activity 47 47
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Wnt DKK1 Frat1 DSH Sclerostin LRP5/6 LRP4 Sclerostin Antibody APC AXIN
GSK3β βcatenin βcatenin βcatenin 48 48
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Antisclerostin Antibody Rx (Li et al, JBMR, 2009)
Perio MS/BS Sham Ovx Ovx + Scl-Ab 60 50 40 30 20 10 Intracort MS/BS 100 75 25 Endocort Cortical Periosteal BFR Sham Ovx Ovx + Scl-Ab 5 4 3 2 1 Ob S/BS Sham Ovx Ovx + Scl-Ab 10 8 6 4 2 Endocortical BFR 12 8 4 Sham Ovx Ovx + Scl-Ab Oc S/BS Sham Ovx Ovx + Scl-Ab 5 4 3 2 1 Li et al, JBMR 2009
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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;
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Sclerostin Antibody Increases Cancellous Bone Volume and Bone Formation
L2 VERTEBRA PROXIMAL TIBIA VEHICLE Scl-Ab (30 mg/kg IV) VEHICLE Scl-Ab (30 mg/kg IV) E F G 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
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Human Studies Romosozumab (osteoporosis) Blosozumab (osteoporosis)
CLINICAL TRIALS AND MECHANISMS OF THERAPEUTICS: ANTISCLEROSTIN ANTIBODY Human Studies Romosozumab (osteoporosis) Blosozumab (osteoporosis) BPS804 (adult onset adult-onset hypophosphatasia- MO27)
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Phase 2 CLINICAL TRIAL: Romosozumab in Postmenopausal Women with Low Bone Density. McClung et al. N Eng J Med January, 2014, 419 Postmenopausal women, 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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Phase 2 CLINICAL TRIAL: Romosozumab in Postmenopausal Women with Low Bone Density. McClung et al. N Eng J Med January, 2014 Primary endpoint: % change from baseline in BMD at the lumbar spine after 12 months Secondary endpoints: BMD at other time points and at other sites Bone turnover markers at various time points Exploratory endpoints Comparison between romosozumab and ALN or teriparatide in BMD at various sites over 12 months
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Anti-Sclerostin Antibody (Romosozumab) BMD – Phase2- effects on BMD*
Placebo ALN TPTD Romosozumab 210 mg QM –2 2 4 6 8 10 12 3 9 11.3% *†ʌ *P < vs placebo †P < vs ALN ʌP ≤ vs TPTD Month Lumbar Spine –2 –1 1 2 3 4 5 4.1% 6 9 12 * *†ʌ *P < vs placebo †P < vs ALN ʌP < vs TPTD Month Total Hip Percentage Change From Baseline Least squae mean ± 95% CI *Distal radius- no effect of Romo on BMD McClung MR et al. NEJM, 2014.
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Romosozumab Phase 2 Study
Serum P1NP and CTX Placebo Romosozumab 210 mg QM P1NP CTX *P < 0.04 vs placebo *P < 0.02 vs placebo 250 200 150 100 50 –50 –100 250 200 150 100 50 –50 –100 * * * Percentage Change from Baseline * * * * * Except for Week 1, all values were collected pre-dose Except for Week 1, all values were collected pre-dose 3 6 9 12 3 6 9 12 Month Month Data are medians and IQRs. P values are only shown for the romosozumab 210 mg QM group. McClung MR et al. New Engl J Med 2014;370:
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Bone Mineral Density – Year 2 Continued Romosozumab Therapy
Romosozumab 210 mg QM ALN TPTD Placebo Lumbar Spine Total Hip 15 6 4.2% 11.4% 15.2% 5.5% 4 10 Percent Change from Baseline 2 5 -0.7% 0.4% -1.5% -0.1% -2 3 6 12 18 24 3 6 12 18 24 Month Month McClung MR et al. ASBMR 2014. 57
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Effects of Sclerostin Inhibition with Romosozumab in human subjects
Phase I and II studies: Early, marked but transient increase in markers of bone formation Modest, persistent reduction in bone resorption Substantial increase in BMD Phase III studies are underway Effect of One Year Treatment with the Cathepsin-K Inhibitor, Balicatib, on Bone Mineral Density (BMD) in Postmenopausal Women with Osteopenia/Osteoporosis. S. Adami1, J. Supronik*2, T. Hala*3, J. P. Brown4, P. Garnero5, S. Haemmerle*6, C. E. Ortmann*6, F. Bouisset*6, U. Trechsel6. 1University Hospital, Rheumatology, Verona, Italy, 2Wojewodzki Szpital, Bialystok, Poland, 3Center for Metabolic Bone Disease, Pardubice, Czech Republic, 4Laval University, Québec, PQ, Canada, 5INSERM and Synarc, Lyon, France, 6Novartis Pharma AG, Basel, Switzerland. Cathepsin K (cathK) is a cysteine protease that is selectively, highly expressed by osteoclasts and plays a key role in bone resorption. Balicatib is an orally bioavailable, novel, specific inhibitor of human cathK, acting late in the process leading to bone resorption, and may not influence osteoclast/osteoblast interactions. Therefore, bone formation may decrease less, leading to a positive bone balance at the level of the bone remodeling unit. In this randomized, placebo-controlled trial 675 postmenopausal women (mean age 62 yrs) with lumbar spine (LS) BMD T-scores <-2, were treated with 5, 10, 25, or 50mg daily oral balicatib, or placebo, for one year. At 12 months, there was a dose-related increase in DXA BMD for LS and hip, as shown in the table below (% change from baseline from an ANCOVA model). Bone resorption markers were dose-dependent, statistically significantly decreased vs placebo with 25 and 50mg at all time points during treatment with a minimum at -61% for sCTX and -55% for uNTX/Cr (50mg, 1 month). Serum osteocalcin, bone-specific alkaline phosphatase (BSAP), and N-terminal propeptide of type I collagen (sP1NP) were not statistically significantly different from placebo at 12 months with 10, 25, and 50 mg. With 5mg there was an increase in formation markers which reached statistical significance at all time points beyond 1 month for BSAP (+23%, p<0.001, at 12 months), and sP1NP (+36%, p<0.001 at 12 months.). * Multiplicity adjusted p< versus placebo Balticatib was generally safe and well tolerated at all doses up to 25mg per day. There was a higher incidence of skin adverse events (mainly pruritus) on balicatib which were more frequent on 50mg. Additionally a small number of patients experienced scleredema/ morphea-like skin changes which improved off treatment. Conclusion: This is the first demonstration of the favorable effect of a cathK inhibitor on BMD in humans. The study confirms that this new mode of action may be an interesting target for the treatment of osteoporosis. Disclosures: S. Adami, Amgen, Eli Lilly, Regimen Placebo 5 mg 10 mg 25 mg 50 mg BMD Lumbar Spine: mean%change (SE) 0.25 (0.37) 1.20 (0.38) 3.16 (0.38)* 4.41 (0.37)* 4.46 (0.40)* BMD Total Hip: mean%change (SE) 0.29 (0.27) 0.07 (0.28) 1.77 (0.27)* 2.21 (0.27)* 2.25 (0.29)* 58
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Romosozumab (osteoporosis) Blosozumab (osteoporosis)
CLINICAL TRIALS AND MECHANISMS OF THERAPEUTICS: ANTISCLEROSTIN ANTIBODY Romosozumab (osteoporosis) Blosozumab (osteoporosis)
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Blosozumab Phase 2 Study Lumbar Spine and Total Hip BMD
Blosozumab 270 mg Q2W Blosozumab 180 mg Q2W Blosozumab 180 mg Q4W Placebo 25 10 Lumbar Spine Total Hip 20 17.7% 8 *** 6.7% *** 15 *** 6 *** *** 10 *** 4 *** Percent Change from Baseline (95% CI) *** *** *** *** 8.4% 5 *** 2 * Figure 3. Open in figure viewer Serum levels of total sclerostin (A, B) and percent change from baseline (C, D) post single-dose or 8-week repeated doses of blosozumab, respectively. Data are mean and standard error. BP = prior bisphosphonate exposure; iv = intravenous; Q2W = once every 2 weeks; Q4W = once every 4 weeks; sc = subcutaneous. 2.1% *** -5 -2 10 20 30 40 50 10 20 30 40 50 Weeks Weeks Recker RR et al. J Bone Miner Res. 2015;30:
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Blosozumab Phase 2 Study Serum P1NP and CTX
Blosozumab 270 mg Q2W Blosozumab 180 mg Q2W Blosozumab 180 mg Q4W Placebo 225 Serum P1NP 75 Serum CTX 200 175 50 *** 150 *** 125 25 Median Percent Change from Baseline (IQR) 100 Median Percent Change from Baseline (IQR) *** *** 75 50 ** * *** *** -25 ** 25 *** * -50 -25 -50 -75 5 10 15 20 25 30 35 40 45 50 55 5 10 15 20 25 30 35 40 45 50 55 Week Week Recker RR et al. J Bone Miner Res. 2015;30: 61
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Blosozumab (osteoporosis)
CLINICAL TRIALS AND MECHANISMS OF THERAPEUTICS: ANTISCLEROSTIN ANTIBODY Blosozumab (osteoporosis) Further develop halted on April 29, 2015 because the company could not develop a subcutaneous formulation that was not associated with local skin reactions.
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Osteoanabolic Therapy for Osteoporosis: the present and the future Teriparatide Abaloparatide Romosozumab
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Summary Osteoanabolic therapy has the potential to restore skeletal microstructure and uniquely transform osteoporotic bone towards normal.
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