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New Treatments for Osteoporosis
Professor Peter R Ebeling AODepartment of MedicineSchool of Clinical Sciences
Annual ESA Seminar Meeting
Melbourne
26th May 2017
2
▪ Research grants from NHMRC, Amgen, Eli-Lilly and Merck
▪ Honoraria from Amgen, Eli-Lilly, Gilead
▪ Advisory Board for Amgen, UCB
Disclosures
3
▪ Differentiating effects of anti-resorptive and anabolic
drugs on bone
▪ New data on old drug - teriparatide
▪ Anti-fracture efficacy of the PTHrP analogue,
abaloparatide
▪ Anti-fracture efficacy of the monoclonal antibody to
sclerostin, romosozumab
▪ An initiative to redesign RCTs for osteoporosis
▪ Some late-breaking news
New Treatments for Osteoporosis
MSC
OB precursor
HSC
OB
osteoclastosteoblasts
osteocytes
The Bone Remodelling Unit
MonashHealth
Potential Mechanisms of Anti-Resorptive Drugs
Rachner TD et al Lancet 2011 377: 1276–87.
Action of Bisphosphonates on Osteoclasts
Bind to bone mineral
Bisphosphonate (bone surface)
Osteoclast membrane
Concentrate at sites of bone resorption
BP = bisphosphonates
BP BPBPBP
BP
BP
Bone
Osteoclasts are ‘crippled’, ‘disabled’ or ‘frustrated’(but do not necessarily ‘die’ by apoptosis)
Release and intracellular uptake during resorption
BP BPBPBP
BP
BPBP BP
BP
Bone
Loss of resorptive function (via
inhibition of FPPS and prenylation of
GTP-ases)
BP BPBPBP
BP
BPBP BP
BP
BPBP
BP
BP
Bone
Selective Inhibition of the Mevalonate Pathwayby Statins and Bisphosphonates Is the Result of Selective Tissue
Targeting
HMG Co-A
Mevalonate
Farnesyl-PP
Squalene
Cholesterol
Isoprenylation of proteins
N- bisphosphonates
Bone resorption inhibited
Geranylgeranyl-PP
Osteoclasts
Cholesterol synthesis inhibited
Statins O
O
H
HCH
H3C
O
OH3C
H3C
CH3
H
Liver
MonashHealth
Therapeutic Targets in Osteoclast Physiology
Rachner TD et al Lancet 2011 377: 1276–87.
MonashHealth
Therapeutic Targets in Osteoblast Physiology
Rachner TD et al Lancet 2011 377: 1276–87.
MonashHealth
Modelling-Directed (A – Anti-Sclerostin Antibodies) versus Remodelling-Directed (B – PTH and abaloparatide) Bone Formation
Ke HZ et al., Endocrine Reviews 33: 747–783, 2012
77% romosozumab30% teriparatide
70% teriparatide15% romosozumab
MonashHealth
Effect of Anti-Sclerostin Antibodies to Increase Bone Formation and Decrease Bone Resorption in Humans
Human Parathyroid Hormone1-34 [teriparatide] and 1-84
1. Niall et al. Proc Natl Acad Sci U S A 1974;71(2):384-8. 2. Jin et al. J Biol Chem 2000;275(35):27238-44.
1 10
20
30
Ser Val Ser Glu Ile Gln Leu Met His Asn
Leu
Gly
LysHisLeuAsnSerMetGluArgValGlu
Trp
Leu
Arg Lys Lys Leu Gln Asp Val His Asn Phe
50
40
6070
80
-COOH
H2N-
hPTH 1-84
(Crystal structure)2
hPTH/PTHrP
Receptor
hPTH (1-34)
1
Teriparatide in GIOP - 36 Months: Markers of Bone Turnover
***p<.001 teriparatide vs. alendronate
1) Saag et al. Arthritis Rheum 2009;60(11):3346-55. 2) Eastell et al. Bone 46 (2010) 929–934. 3) Australian Product Information update 2 November 2015
ALN n= 100 99 85 76 57
TPTD n= 98 97 85 76 59
ALN n= 91 79 75 71 48
TPTD n= 84 70 66 64 49
******
******c
******
*** ***
Maximum registered lifetime treatment of teriparatide is 18 months 3
Teriparatide MOA Histomorphometry
Dempster D et al., SHOTZ study JBMR July 2016
Teriparatide effects on Trabecular Bone -SHOTZ Study 1
6 Months 24 Months
1 Dempster D et al., SHOTZ study JBMR July 20162 Forteo Australian Product Information, 2 November 2015
Maximum registered lifetime treatment of teriparatide is 18 months.2
Teriparatide Effects on Cortical Bone SHOTZ Study 1
6 Months 24 Months
1 Dempster D et al., SHOTZ study JBMR July 20162 Forteo Australian Product Information, 2 November 2015
Maximum registered lifetime treatment of teriparatide is 18 months.2
18
19
30 Years of PTHrP University of Melbourne, Professor T Jack Martin FRS AO
Abaloparatide
• Abaloparatide is a novel synthetic peptide analogue of
PTHrP
• Retains anabolic activity with decreased bone resorption,
less calcium-mobilizing potential, and improved room
temperature stability compared with teriparatide
• Studies performed in animals have demonstrated marked
bone anabolic activity of abaloparatide with complete
reversal of bone loss in ovariectomy-induced osteopenic
rats and monkeys
Changes in BMD Following 24 Weeks Treatment with Abaloparatide, Teriparatide or Placebo – Phase 2 Study
Leder BZ et al. J Clin Endocrinol Metab 2014
Phase 3 Study – Abaloparatide versus Teriparatide & PlaceboBMD
Miller PJ et al., JAMA. 2016; 316(7): 722-733
Phase 3 Study – Abaloparatide versus Teriparatide & PlaceboFractures
Miller PJ et al., JAMA. 2016; 316(7): 722-733
Phase 3 Study – Abaloparatide versus Teriparatide & PlaceboBone Turnover Markers
Miller PJ et al., JAMA. 2016; 316(7): 722-733
Safety and Adverse Events
Fracture Efficacy Endpoints After 18 Months
Miller PJ et al., JAMA. 2016; 316(7): 722-733
Response of Spinal, Total Hip and Femoral Neck BMD to 210 mg Monthly Romosozumab
McClung MR et al. N Engl J Med 2014. DOI: 10.1056/NEJMoa1305224
Response of Bone Formation (PINP) and Bone Resorption (b-CTX) Markers to Romosozumab
McClung MR et al. N Engl J Med 2014. DOI: 10.1056/NEJMoa1305224
Phase 2 Extension – 2 Years Romosozumab Followed By One Year Denosumab
McClung MR et al. JBMR SI 2014 A326
Phase 3 Studies of Anti-Sclerostin Antibodies for Treatment of Post-Menopausal Osteoporosis
• ARCH Study - Placebo RCT of romosozumab vs.
alendronate for 12 mths, followed by open label
alendronate for 12 months with primary end-points
of clinical and new vertebral fractures over 2 yrs
• FRAME Study - Placebo RCT of romosozumab vs.
placebo for 12 mths, followed by open label
denosumab for 12 months with primary end-points
of clinical and new vertebral fractures over 2 yrs
Cosman F et al. N Engl J Med 2016;375:1532-1543
FRAME Study - Trial Regimens and Assessments
Cosman F et al. N Engl J Med 2016;375:1532-1543.
Percentage Change from Baseline in Bone Mineral Density and Levels of Bone Turnover Markers.
Cosman F et al. N Engl J Med 2016;375:1532-1543.
Incidence of New Vertebral, Clinical, and Nonvertebral Fractures.
Cosman F et al. N Engl J Med 2016;375:1532-1543.
Adverse Events
JBMR – January 2017
Addressing the Current Crisis in Osteoporosis Treatment
• New drug development to circumvent AFF
• The Biomarkers Consortium-Bone Quality Project is
attempting to qualify a surrogate marker for fracture
prediction to be used in clinical trials, obviating the need
for multiple large randomized trials with fracture as an
endpoint
• If such a surrogate marker is approved for osteoporosis
drug development, this will provide a financial incentive
to bring new drugs to market
Late-breaking News – May 21, 2017 – ARCH Study
• Subcutaneous romosozumab for 12 mths followed by
alendronate for 12 mths vs. alendronate for 2 yrs
• 50% RR reduction in vertebral fractures and 27% RR
reduction in clinical fractures at 2 yrs (both primary study
end-points)
• 19% reduction in non-vertebral fractures at 2 yrs (key
secondary end-point)
• Nominally significant reduction in hip fractures at 2 yrs
• Positively adjudicated cardiovascular serious adverse
events were 2.5% (romosozumab) vs 1.9% (ALN) - NNH 167
Amgen/UCB Press Release
Thank You!