1 Abaloparatide: PTHrP Synthetic Analogue of Human PTHrP 1-34 PTH - PDF document

What’s New and On the Horizon for Disclosure and Conflicts of Interest Prescription Medicines I serve on the Global Advisory Boards of the following companies: Amgen, Lilly, Merck I receive honoraria from the following companies: Alexion, Amgen, GSK and Merck Images Courtesy of Dr. David Dempster North American Menopause Society Las Vegas, NV October 1, 2015 Michael McClung, MD 2015 Michael R. McClung, MD, FACP Director, Oregon Osteoporosis Center Portland, Oregon, USA OOC OOC Current Osteoporosis Treatments: Emerging Treatments Limitations Anti-resorptive agents Real or perceived intolerance • Cathepsin K inhibitors Concerns about safety, especially the long-term safety of • bisphosphonates Anabolic agents Inconvenient or awkward dosing regimens • New analogs of PTH Poor adherence to therapy • Biological activators of bone formation No agent restores skeletal structure or strength to normal • Anti-sclerostin antibody levels • i.e., no “cure” for osteoporosis Expense • M McClung. Personal opinion OOC OOC 1

Abaloparatide: PTHrP Synthetic Analogue of Human PTHrP 1-34 PTH and PTHrP bind to same PTH receptor – but kinetics of • hPTH 1-34 effects are different: much longer with teriparatide vs PTHrP 1- 36. This may account for greater effects on bone resorption and hPTHrP 1-34 calcium mobilization. PTHrP 1-36: • Phase 1 studies: PTHrP(1-36) increased markers of bone PTHrP analog • formation but had little effect on bone resorption and did not (BA058 ) cause hypercalcemia. 22 30 34 Phase 2 study – vs teriparatide: 100% hPTHrP 38% hPTHrP • Smaller increases in markers of bone formation and • Functional optimization of BA058 based on amino acids 22-34 resorption Minimal differences in BMD response • More selectively binds to R*G PTH receptor than does PTHrP Same or more hypercalcemia • OOC OOC Hattersley R et al. Endocrine Society. OR31-5, 2014. Horwitz MJ et al. J Bone Miner Res . 2013; 28:2266-76. Abaloparatide: Abaloparatide: Phase 2 Studies Pivotal Phase 3 Study Design (ACTIVE) Compared to 20 ugm teriparatide daily, 80 ugm • abaloparatide daily resulted in • Smaller increases in markers of bone formation and especially of bone resorption • Larger increases in spine and especially hip BMD • Lower frequency of hypercalcemia Daily subcutaneous dosing was well tolerated Hattersley R et al. Endocrine Society. OR-08, 2012. OOC OOC Radius Health Form 8-K: January 12, 2015 Leder BZ et al. J Clin Endocrinol Metab . 2015;100:697-706. 2

ACTIVE Trial: Abaloparatide vs Teriparatide ACTIVE Trial: Abaloparatide vs Teriparatide Bone Mineral Density – 18 Months Morphometric Vertebral Fractures (worsening and/or new) Placebo APTD-80 TPTD-20 12 2460 women with % Change from baseline ANCOVA approach postmenopausal osteoporosis Placebo Abaloparatide Teriparatide N = 820 N = 822 N = 818 8 Interventions: Evaluable patients at 18 Abaloparatide 80 ugm QD 711 690 717 months 4 P=0.016 Teriparatide 20 ugm QD Fracture rate (RRR) 1 4.36% 0.72% (83%) 0.98% (78%) Placebo 0 Lumbar spine Total hip RRR = Relative risk reduction 1. Radius Health Form 8-K: January 12, 2015 Radius Health Form 8-K: January 12, 2015 OOC OOC 2. Miller PD et al. Endocrine Society. 2015 Miller PD et al. Endocrine Society 2015 ACTIVE Trial: Abaloparatide vs Teriparatide ACTIVE Trial: Abaloparatide vs Teriparatide Non-vertebral Fractures Adverse Events of Interest Placebo Abaloparatide Teriparatide % of patients with npn-vertebral fracture N = 820 N = 822 N = 818 Placebo RRR = Relative risk reduction (%) (%) (%) RRR Teriparatide 28% Overall effect on racture risk did not Back pain 10.0% 8.6% 7.2% differ significantly between active treatment groups, but the reduction in risk appeared to occur earlier with abaloparatide Hypercalciuria 8.9% 10.9% 12.5% Abaloparatide 43% Hypercalcemia Log-rank p-values: (uncorrected 1.2% 6.0% 10.8% Abaloparatide vs PBO: 0.0489 Teriparatide vs PBO: 0.2127 serum calcium) Abaloparatide vs teriparatide: 0.4363 Radius Health Form 8-K: January 12, 2015 OOC OOC Radius Health Form 8-K: January 12, 2015 Miller PD et al. Endocrine Society. 2015 3

Cathepsin K Inhibitors Abaloparatide: Future Use Odanacatib Will be used like teriparatide • Cathepsin K is major osteoclast-derived protease • Genetic deficiency causes osteocyte-rich osteosclerosis • Its specific role will be determined by • with decreased resorption but formation is present • More careful analysis of non-vertebral fracture data vs TPTD Odanacatib is a non-lysosomotropic selective inhibitor • • Convenience of dosing vs TPTD (non-refrigerated) of CatK • Cost relative to TPTD Very strong pre-clinical program • • Decreased resorption but no change or even increase in numbers of osteoclast • Increased periosteal formation • Increased cortical bone thickness and strength M McClung. Personal opinion OOC OOC Odanacatib Preserves Bone Formation while Effects of Odanacatib on Periosteal Bone Inhibiting Bone Resorption: Preclinical Evidence Formation in Ovariectomized Monkeys Odanacatib reduces the activity of cathepsin K in osteoclasts • Periosteum Calcein labelling at 12 months; • Same number of resorption pits, but shallower tetracycline at Month 21 Vehicle Allows subsequent bone formation • Bone  ODN effects on bone formation 73.8 µm TCY are site specific: OC Vehicle  Trabecular surface of spine, ODN CAL dose-dependently inhibited BFR P  At proximal femur, ODN increased ODN (30 mg/kg) endocortical and periosteal bone Odanacatib formation OC 209.3 µm P CAL Masarachia PJ, et al. J Bone Miner Res . 2012;27:509-23 Bone TCY Cat K = cathepsin K; pOC = pre-osteoclast; OC = osteoclast; Cat Ki = Cat K inhibitor; Ob = osteoblast; pOb = pre- osteoblast; P = resorption pit; RANK = receptor activator of nuclear factor kappa-B; RANKL = RANK ligand . OOC OOC Duong LT. BoneKEy Reports .2012;1. Article no. 67. Leung P et al. Bone . 2011;49:623–635. 4

Odanacatib: LOFT: Phase 3 Fracture Trial Bone Mineral Density: 5 Years Biochemical Markers of Bone Turnover Urinary NTx/Cr Serum P1NP (ng/ml) Marked and progressive 20 20 Placebo ODN 50 mg/ Q week Percent change from baseline increase in BMD (geometric LS mean ± SE) 10 10 14 % Change from Baseline 12 0 0 Lumbar Spine 11.9% % Change from Baseline Femoral Neck 12 9.8% 10 -10 -10 10 (Mean ± SE) 8 NTX is a product of CatK digestion (Mean ± SE) 8 -20 -20 of type 1 collagen 6 6 No effect on formation -30 -30 4 CTX is only a product of CatK 4 markers after 2-3 years activity 2 -40 -40 2 0 0 -50 -50 ODN 50 mg OW Placebo OW -2 -2 -60 -60 0 13 6 12 18 24 30 36 42 48 54 60 0 3 12 24 36 48 60 0 6 12 24 36 48 0 6 12 24 36 48 1 6 18 30 42 54 Month Month Time (months) Time (months) Full-Analysis-Set Population / LOCF N: 554 603 516 438 49 594 634 543 460 59 N: 569 619 516 406 52 613 650 545 433 55 OOC OOC Langdahl et al. J Bone Miner Res 2012 ;27:2251-8. McClung MR, et al. ASBMR 2014 Odanacatib: Effect on Fracture Risk Odanacatib In LOFT study of more than 16,000 women with • Final safety data are being adjudicated • postmenopausal osteoporosis, odanacatib 50 mg po once weekly significantly reduced fracture risk Results of the full 5 year blinded extension study • will be available shortly Regulatory filing anticipated soon. • Relative risk reduction % (ODN vs PBO) • • vertebral 54% (2.3% vs 7.2%) • hip 47% (0.7% vs 1.2%) • non-vertebral * 23% (6.5% vs 8.0%) * Time-dependent decrease in non-vertebral fracture risk OOC OOC McClung M et al. ASBMR 2014 5