Disclosures PTH analogs, alone and in Research support from Bariatric Advantage and Tate & Lyle (supplements donated for research combination with antiresorptive s study) Anne Schafer, MD Associate Professor UCSF and the San Francisco VA Health Care System July 11, 2019 Anabolic therapy increases bone Treatment of osteoporosis remodeling Antiresorptive agents 400 Formation (P1NP) 300 Resorption (CTX) Bisphosphonates Median Change (%) 300 Denosumab 200 PTH PTH Raloxifene 200 100 Calcitonin, estrogen 100 ALN ALN 0 Anabolic agents 0 Teriparatide (PTH 1-34) -100 -100 0 3 6 9 12 0 3 6 9 12 Abaloparatide (PTHrP) Month Month Mixed anabolic and antiresorptive agent Romosozumab Black, NEJM 2003 Page 1
PTH increases bone formation before Is PTH bad or good for the bone? bone resorption Captain Martell Mode Effect Continuous Catabolic (high dose) Daily intermittent Anabolic (low dose) Canalis, NEJM 2007 PTH(1-34) (Teriparatide) Parathyroid Hormone (PTH) Fracture Prevention Trial 84 amino acid sequence 1637 postmenopausal women Most of bone activity in first 34 amino acids Randomized to placebo, PTH (1-34) 20 ug, or PTH (1-34) (teriparatide) approved @ 20 mcg/day PTH (1-34) 40 ug Requires daily subQ injection Fracture was primary endpoint Thigh or abdomen 3-year study, halted after 21 months (median) Approved for up to 2 years of use Safety problem with high doses in rodents Neer, NEJM 2001 Page 2
Effect of teriparatide on spine BMD Effect of teriparatide on total hip BMD 5 16 *** *** 4 PTH 40 mcg 14 PTH 40 mcg % Change ( ± SE) % Change ( ± SE) *** 3 *** 12 PTH 20 mcg PTH 20 mcg 10 2 *** *** *** 8 *** 1 *** 6 *** ~ 9% ~ 3% *** 4 0 *** 2 Placebo -1 Placebo 0 -2 0 3 6 12 18 0 6 12 18 24 *** p < 0.001 vs. Placebo Months *** p < 0.001 vs. Placebo Months Neer, NEJM 2001 Neer, NEJM 2001 Effect of teriparatide on non-vertebral Effect of teriparatide on incident vertebral fracture risk fracture risk RR 0.35 (95% CI, 0.22 to 0.55)* 14 12 * P < 0.001 20 mcg vs. placebo: RR=0.47 (0.25,0.88) % of Women 10 8 6 4 2 64 22 19 0 Placebo rhPTH 20mg (n=448) (n=444) No. of women who had > 1 fracture Neer, NEJM 2001 Neer, NEJM 2001 Page 3
Can a PTH analog do better? PTH-related peptide (PTHrP) R G conformation of the PTH1R R 0 conformation of the PTH1R PTHrP (1-34) (abaloparatide) approved @ 80 (Associated with a more transient (Associated with more prolonged mcg/day binding of the ligand) binding of the ligand) 125 I-M-PTH(1-15) bound (%) 100 Requires daily subQ injection 100 125 I-PTH(1-34) bound (%) Teriparatide 75 75 Thigh or abdomen Abaloparatide 50 50 Approved for up to 2 years of cumulative use of Abaloparatide Teriparatide 25 teriparatide + abaloparatide 25 0 0 -12 -11 -10 -9 -8 -11 -10 -9 -8 -7 -6 -5 [Ligand] Log M [Ligand] Log M Donovan, Br J Clin Pharmacol 2018 Effect of abaloparatide on incident PTHrP (Abaloparatide) vertebral fracture risk ACTIVE Trial 2463 postmenopausal women Randomized to placebo, PTHrP 80 ug/day, or open-label teriparatide 20 ug/day 18-month study RR 0.14 RR 0.20 Miller, JAMA 2016 Miller, JAMA 2016 Page 4
Teriparatide and abaloparatide in Effect of abaloparatide on incident nonvertebral fracture risk clinical practice Approved for up to 2 yrs, cumulative Barriers for adoption in clinical practice Cost ($1600-$3500/month wholesale price) Need for daily injections Miller, JAMA 2016 Teriparatide and abaloparatide in Combination anabolic + antiresorptive? clinical practice High risk for future fracture Combine anabolic with antiresorptives to increase formation with smaller Prevalent vertebral compression fx increase in resorption? Very low BMD ( e.g., spine T-score <-3.0) Could be synergistic: 1 + 1 = 3 Failed antiresorptive therapy Or cancel each other: 1 - 1 = 0 Incident fx or active bone loss Glucocorticoid-induced osteoporosis Page 5
Combination anabolic + antiresorptive? Combination #1 3 distinct possibilities Antiresorptive Anabolic 1. Antiresorptive Anabolic Antiresorptive followed by anabolic Antiresorptive 2. • Key clinical question + Anabolic • Many patients on bisphosphonates and denosumab 3. Anabolic Antiresorptive Bisphosphonate followed by PTH Denosumab followed by PTH Patient on DMAB switches to PTH analog: may Patient taking bisphosphonate switches to have transient or sustained loss of BMD PTH analog: anabolic effect still evident and strong •Magnitude somewhat delayed and/or blunted compared to treatment-naïve pts Leder, Lancet 2015 Page 6
Combination #2 PTH and Alendronate (PaTH) Study • 238 postmenopausal women with osteoporosis Antiresorptive – Treatment naive + Anabolic • Randomized to four treatment groups x 2 years • Combination of PTH (1-84) + daily alendronate Concurrent initiation of PTH analog plus antiresorptive in treatment naïve pt N Year 1 Year 2 PLB • PTH+alendronate 59 PTH(1–84) 60 PTH(1–84) ALN • PTH+zoledronic acid 59 PTH(1–84) + ALN ALN • PTH+denosumab 60 ALN ALN Black, NEJM 2003 Black, et al. New Engl J Med 2003;349:1207–15 Changes in Trabecular Volumetric Trial of once yearly zoledronic acid + BMD by QCT (g/cm 3 ) teriparatide 40 Anabolic effect of PTH, PTH(1–34) ** particularly on trabecular Mean Change (%) 30 bone, is blunted by • 412 patients PTH(1–34) + Zol. concurrent use of 20 • Follow-up one year alendronate Zoledronic acid 10 0 Spine Total Hip PTH PTH/ALN ALN Cosman, J Bone Miner Res 2011 Black, NEJM 2003 ** p<.01 Page 7
Changes in BMD at spine (DXA) Changes in BMD at the hip Total Hip BMD Femoral Neck BMD 3 3 * † Mean % Change in BMD ‡ * * Mean % Change in BMD ‡ * * * 2.5 2 2 * * * 1.5 1 * * * 1 0 0.5 0 -1 0 13 26 39 52 0 13 26 39 52 Weeks Weeks ZOL+ TPTD TPTD alone ZOL alone * P <0.05 vs TPTD alone † P <0.05 vs ZOL alone Fractures (Only assessed as AEs) PTH + Zoledronic acid • BMD change: similar to individual agents ZOL + TPTD TPTD alone ZOL alone • Pattern of marker changes is different n (%) n (%) n (%) Category (n=137) (n=137) (n=137) – Although not clear that it’s better • Fracture results intriguing Clinical fractures (assessed as AEs 4 (2.9%) 8 (5.8%) 13 (9.5%)* – But not an official study endpoint only) Spine fractures 0 1 6 * p=0.04 vs combination (post-hoc) Cosman, J Bone Miner Res 2011 Page 8
Denosumab and Teriparatide trial Denosumab and Teriparatide trial (DATA) (DATA) PTH(1–34) • 100 patients PTH(1–34) + DMAB • Follow-up 2 years DMAB Leder, J Clin Endocrinol Metab 2014 Tsai, Lancet 2013 PTH + Denosumab Combination #3 • First combo to increase BMD more at spine Anabolic Antiresorptive and hip than either agent alone • Why does DMAB seem to interfere less with Anabolic followed by antiresorptive formation than bisphosphonates? • PaTH: 1 yr of PTH then 1 yr ALN or placebo –Mechanism of action? Potency? –Frequency? (q 6 months) N Year 1 Year 2 PLB 59 PTH(1–84) • $$$ combo, but could be considered 60 PTH(1–84) ALN 59 PTH(1–84) + ALN ALN 60 ALN ALN Black, NEJM 2005 Page 9
PaTH: Change in spine BMD (DXA) DATA-Switch: Change in BMD (DXA) over 24 months 20 Mean Change (%) 24 month change 15 PTH discontinued +12% ALN 10 PTH (1–84) 5 + 4% PLB 0 0 12 24 Month Leder, Lancet 2015 Black, NEJM 2005 Take-home point: Follow PTH analog ACTIVE-Extend: Change in BMD with some antiresorptive • PTH followed by nothing will result in some loss of BMD gains • Bisphosphonates and denosumab seem to add to BMD gains Cosman, Mayo Clinic Proc 2017 Page 10
Future of anabolic therapy Combination therapy: Conclusions • Substantial literature about combination • Combinations with abaloparatide therapy, but no fracture outcomes • Other forms of and delivery methods for • Sequential antiresorptive then PTH analog: PTH analogs (e.g., transdermal) –BP then PTH: OK - in BMD • Cyclic anabolic therapy (e.g., 3- or 6-mo at a –DMAB then PTH: ? - transient in BMD time) • If using anabolic, best to use alone • Role of anti-sclerostin Ab therapy –Or with concurrent DMAB (but $$$) • PTH analog followed by antiresorptive seems to maximize BMD gains Page 11
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