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

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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!