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 THERAPY WHEN…..
“Parathyroid hormone is bad for bones”

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

5. 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

6. 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:

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. 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):

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

11. 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

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
Peak
Bone resorption
markers
“Anabolic Window”
Index of Bone Turnover
Believed to limit
the osteoanabolic
potential of PTH
Months

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

15. 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:

16. 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

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. 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. 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

24. Functional optimization of PTHrP: Abaloparatide, an analogue27
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

25. 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

26. 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

27. 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

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
Placebo
Abaloparatide 80 mcg Daily SC
Teriparatide 20 mcg Daily SC
Randomization
Months 6 12 18
N = 2463
Miller et al, 2015

30. 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

31. 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

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 #
p < vs TP ^ ^
p = vs TP # #
% Change from Baseline
Months
Femoral Neck BMD #
p < vs TP @ @
p = vs TP # #
% Change from Baseline
Months

33. 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

34. 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)

35. 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

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. OSTEOANABOLIC THERAPY
THE FUTURE OF
OSTEOANABOLIC THERAPY

42. 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:

43. 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

44. 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

45. Wnt DKK1 Frat1 DSH Sclerostin LRP5/6 LRP4 Sclerostin Antibody APC AXIN
GSK3β
βcatenin
βcatenin
βcatenin 48 48

46. 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

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;

48. 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

49. 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)

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, 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)

51. 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

52. 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.

53. 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:

54. 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

55. 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

56. Romosozumab (osteoporosis) Blosozumab (osteoporosis)
CLINICAL TRIALS AND MECHANISMS OF THERAPEUTICS: ANTISCLEROSTIN ANTIBODY
Romosozumab (osteoporosis)
Blosozumab (osteoporosis)

57. 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:

58. 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

59. 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.

60. Osteoanabolic Therapy for Osteoporosis: the present and the future Teriparatide Abaloparatide Romosozumab

61. Summary
Osteoanabolic therapy has the potential to restore skeletal microstructure and uniquely transform osteoporotic bone towards normal.

62. THANK YOU!