Osteoporosis 2017 Breaking News. Julie L. Carkin, MD The Seattle Arthritis Clinic

Transcription

1 Osteoporosis 2017 Breaking News Julie L. Carkin, MD The Seattle Arthritis Clinic 1

2 Yes, Hopefully & No Anabolic Teriparatide Abaloparatide Romosozumab blosozumab Anti-catabolic Bisphosphonates Denosumab Estrogen SERMS Cathepsin K inhibitors odanticatib 2

3 Abaloparatide Selectively binds to RG conformation of parathyroid hormone type 1 receptor Anabolic Daily sc but transdermal also in testing FDA review deadline (PDUFA date) 6/30/17 3

4 Abaloparatide vs TPTD vs PBO ACTIVE Fracture Prevention Trial PMO 2,463 ITT, 1901 (77.9%) completed High FX risk group 44.5% had Prevalent vert FX, 46.8% had recent hx of at least 1 non-vert fx Abaloparatide (ABL) 80 mcg sc qd vs matched PBO vs TPTD 20mcg sc qd open label

5 Abal vs PBO vs TPTD Miller JAMA 2016 Abalo N=824 PBO 821 TPTD 818 RR (95% CI) New vert FX ( ) nonvert FX ( ) P value <

6 Abalo vs TPTD vs PBO cont d Major Osteoporotic Fracture=clinical FX of Shoulder, upper arm, forearm (incl wrist), hip or vertebral spine 18 months ABL decreased MOF by 67 % compared with PBO, (p=0.0014). TPTD not stat sig different from PBO (p=0.2028) ABL decreased MOF more than TPTD (p=0.0437) Good safety. Blood drawn 4 hrs after ABL. Despite this very little hypercalcemia ( <TPTD) 6

7 Abaloparatide-Active Extend Trial Cosman- Mayo Clin Proc Feb months of Abaloparatide or PBO followed by 6 months alendronate 91% of eligible pts N= 1139 enrolled in Extend Results: 80% RR reduction in vert FX and approx 50% reduction non-vert FX and of major osteop FX (MOF)

8 Sclerostin (encoded by gene SOST) Secreted by osteocytes SOST expression limited to skeletal tissue Inhibits Wnt pathway mediated Beta catenin release Downregulates osteoblasts (inhibits bone formation) 8

9 Romosozumab Humanized monoclonal anti-sclerostin Ab Anabolic 210 mg SC once monthly FDA review deadline (PDUFA) Mid-July 9

10 Percentage Change from Baseline in Bone Mineral Density McClung MR et al. N Engl J Med 2014;370:

11 Cosman F et al. N Engl J Med 2016;375: FRAME Study Design

12 Incidence of New Vertebral, Clinical, and Nonvertebral Fractures. Cosman F et al. N Engl J Med 2016;375:

13 Percentage Change from Baseline in Bone Mineral Density and Levels of Bone-Turnover Markers. Cosman F et al. N Engl J Med 2016;375:

14 Hot topics: existing treatments Sequencing- anabolic first Treat to target - is there a BMD or T score target? Exit plan -consolidation after anabolic -Denosumab special concerns 14

15 Denosumab Discontinuation After stopping Dmab bone turnover markers rise above baseline at 3 months and stay elevated for 30 months BMD gains are rapidly lost reaching baseline 2 yrs off therapy 15

16 Rebound-Associated Vertebral Fractures after Denosumab Discontinuation Normal T12 Fracture Normal L1 Fracture 16

17 Vert Fx after Dmab Discontinuation Athanasios JBMR Feb 2017 Most often multiple vert Fx. Mean #/pt 4.7 Vertebroplasty caused more fx in 5 of 5 tried Mainly case reports/case series Freedom study analysis of 1001 women who stayed in the study > 7months after last Dmab injection (Brown, JBMR 2016;3 (Suppl 1) 56 of 1001 (5.6%) suffered new vert fx Similar to the pure PBO arm but post-dmab group more had multiple vert Fx (60.7% c/w 34.5% in PBO) 17

18 Clinical Care Changes Indicated Now Patients need to understand importance of adherence and receiving Dmab on time prevalent vertebral fractures before and during treatment were the strongest predictor of FX after d/c Dmab Consider starting bisphosphonate 3-5 months after last dose of Dmab to prevent bone turnover rebound Zoledronic acid most commonly used (expert opinion/ no data) 18

19 Ortho gets the ball rolling

20 Back up slides 20

21 Original Article Romosozumab Treatment in Postmenopausal Women with Osteoporosis Felicia Cosman, M.D., Daria B. Crittenden, M.D., Jonathan D. Adachi, M.D., Neil Binkley, M.D., Edward Czerwinski, M.D., Serge Ferrari, M.D., Lorenz C. Hofbauer, M.D., Edith Lau, M.D., E. Michael Lewiecki, M.D., Akimitsu Miyauchi, M.D., Cristiano A.F. Zerbini, M.D., Cassandra E. Milmont, Ph.D., Li Chen, Ph.D., Sc.D., Judy Maddox, D.O., Paul D. Meisner, Pharm.D., Cesar Libanati, M.D., and Andreas Grauer, M.D. N Engl J Med Volume 375(16): October 20, 2016

22 Study Overview Romosozumab binds sclerostin, increases bone formation, and decreases bone resorption. Postmenopausal women with osteoporosis were assigned to romosozumab or placebo for 1 year, followed by 1 year of denosumab. Romosozumab was associated with lower vertebral and clinical fracture risk.

23 Cosman F et al. N Engl J Med 2016;375: Trial Regimens and Assessments.

24 Incidence of New Vertebral, Clinical, and Nonvertebral Fractures. Cosman F et al. N Engl J Med 2016;375:

25 Percentage Change from Baseline in Bone Mineral Density and Levels of Bone-Turnover Markers. Cosman F et al. N Engl J Med 2016;375:

26 Demographic and Clinical Characteristics of the Patients at Baseline. Cosman F et al. N Engl J Med 2016;375:

27 Adverse Events. Cosman F et al. N Engl J Med 2016;375:

28 Conclusions In postmenopausal women with osteoporosis, romosozumab was associated with a lower risk of vertebral fracture than placebo at 12 months and, after the transition to denosumab, at 24 months. The lower risk of clinical fracture that was seen with romosozumab was evident at 1 year.

29 McClung MR et al. N Engl J Med 2014;370: Baseline Characteristics of the Participants.

30 Percentage Change from Baseline in Bone Mineral Density at the Lumbar Spine at Month 12. McClung MR et al. N Engl J Med 2014;370:

31 Percentage Change from Baseline in Bone-Turnover Markers. McClung MR et al. N Engl J Med 2014;370:

32 McClung MR et al. N Engl J Med 2014;370: Adverse Events.