New Treatments for Osteoporosis Professor Peter R Ebeling AO - PowerPoint PPT Presentation

New Treatments for Osteoporosis Professor Peter R Ebeling AO Department of Medicine School of Clinical Sciences Annual ESA Seminar Meeting Melbourne 26 th May 2017

Disclosures ▪ Research grants from NHMRC, Amgen, Eli-Lilly and Merck ▪ Honoraria from Amgen, Eli-Lilly, Gilead ▪ Advisory Board for Amgen, UCB 2

New Treatments for Osteoporosis ▪ 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 3

The Bone Remodelling Unit HSC MSC OB precursor osteoclast osteoblasts OB osteocytes

Potential Mechanisms of Anti-Resorptive Drugs Rachner TD et al Lancet 2011 377: 1276 – 87. Monash Health

Action of Bisphosphonates on Osteoclasts Bind to BP = bisphosphonates BP BP BP bone mineral BP BP BP Bone BP Concentrate at sites of BP BP BP bone resorption BP BP BP BP BP Bone Release and BP intracellular uptake BP BP BP BP BP BP during resorption Loss of resorptive BP BP BP BP function (via BP BP inhibition of FPPS Bone and prenylation of GTP-ases) Osteoclasts are ‘crippled’, ‘disabled’ or ‘frustrated’ Bisphosphonate (bone surface) (but do not necessarily ‘die’ by apoptosis) Osteoclast membrane

Selective Inhibition of the Mevalonate Pathway by Statins and Bisphosphonates Is the Result of Selective Tissue Targeting Liver Osteoclasts HMG Co-A Statins O Mevalonate O O H N- bisphosphonates O H 3 C H H 3 C H Farnesyl-PP CH 3 CH Geranylgeranyl-PP H 3 C Isoprenylation of proteins Squalene Cholesterol Cholesterol synthesis inhibited Bone resorption inhibited

Therapeutic Targets in Osteoclast Physiology Rachner TD et al Lancet 2011 377: 1276 – 87. Monash Health

Therapeutic Targets in Osteoblast Physiology Rachner TD et al Lancet 2011 377: 1276 – 87. Monash Health

Modelling-Directed (A – Anti-Sclerostin Antibodies) versus Remodelling-Directed (B – PTH and abaloparatide) Bone Formation 77% romosozumab 70% teriparatide 30% teriparatide 15% romosozumab Ke HZ et al., Endocrine Reviews 33: 747 – 783, 2012 Monash Health

Effect of Anti-Sclerostin Antibodies to Increase Bone Formation and Decrease Bone Resorption in Humans Monash Health

Human Parathyroid Hormone 1-34 [teriparatide] and 1-84 hPTH 1-84 (Crystal structure) 2 1 10 H 2 N- hPTH (1-34) Ser Val Ser Ile Gln Leu Met His Asn Glu Leu 20 Gly Lys His Leu Ser Glu Val Arg Glu Met Asn Trp Leu Val Asn Phe Lys Leu Gln Asp His Arg Lys 30 40 50 60 70 80 hPTH/PTHrP 1 - COOH Receptor 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.

Teriparatide in GIOP - 36 Months: Markers of Bone Turnover *** *** *** *** ***c *** *** *** ALN n= 100 99 85 76 57 ALN n= 91 79 75 71 48 TPTD n= 98 97 85 76 59 TPTD n= 84 70 66 64 49 ***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 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 Maximum registered lifetime treatment of teriparatide is 18 months. 2 1 Dempster D et al., SHOTZ study JBMR July 2016 2 Forteo Australian Product Information, 2 November 2015

Teriparatide Effects on Cortical Bone SHOTZ Study 1 6 Months 24 Months Maximum registered lifetime treatment of teriparatide is 18 months. 2 1 Dempster D et al., SHOTZ study JBMR July 2016 2 Forteo Australian Product Information, 2 November 2015

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30 Years of PTHrP University of Melbourne, Professor T Jack Martin FRS AO 19

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 & Placebo BMD Miller PJ et al., JAMA. 2016; 316(7): 722-733

Phase 3 Study – Abaloparatide versus Teriparatide & Placebo Fractures Miller PJ et al., JAMA. 2016; 316(7): 722-733

Phase 3 Study – Abaloparatide versus Teriparatide & Placebo Bone 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

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 Cosman F et al. N Engl J Med 2016;375:1532-1543.

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!