THURSDAY CONCURRENT SESSION # 1 S-1 . Odanacatib Efficacy and Safety in Postmenopausal Women with Osteoporosis : 5-Year Data from the Extension of the Phase 3 Long-term Odanacatib Fracture Trial ( LOFT )

S-1. Odanacatib Efficacy and Safety in Postmenopausal Women with Osteoporosis: 5-Year Data from the Extension of the Phase 3 Long-term Odanacatib Fracture Trial (LOFT) Michael R. McClung1, Bente Langdahl2, Socrates Papapoulos3, Kenneth G. Saag4, Henry Bone5,6, Douglas P. Kiel7, Kurt Lippuner8, Toshitaka Nakamura9, Ian Reid10, Norman Heyden11, Carolyn DaSilva11, Boyd B. Scott11, Rachid Massaad12, Keith D. Kaufman11, S. Aubrey Stoch11, Arthur Santora11, Deborah Gurner11, Antonio Lombardi11. 1Oregon Osteoporosis Center, Portland, OR; 2Aarhus University Hospital, Aarhus, Denmark; 3Leiden University Medical Center, Leiden, Netherlands; 4University of Alabama at Birmgham, Birmingham, AL; 5Michigan Bone & Mineral Clinic, Detroit, MI; 6The Osteoporosis Center at St. Luke’s Hospital, Chesterfield, MO; 7Institute for Aging Research, Hebrew Senior Life, Harvard Medical School, Boston, MA; 8Bern University Hospital, Bern, Switzerland; 9University of Occupational and Environmental Health, Fukuoka, Japan; 10University of Auckland, Auckland, New Zealand; 11Merck & Co., Inc., Kenilworth, NJ; 12MSD Europe, Inc., Brussels, Belgium Objective: Odanacatib (ODN) is a selective oral inhibitor of cathepsin K in development for the treatment of osteoporosis. The randomized, double-blind, placebo (PBO)controlled, event-driven, Phase 3 Fracture Trial (Long-Term Odanacatib Fracture Trial [LOFT]; NCT00529373) evaluated efficacy and safety of ODN in postmenopausal women with osteoporosis. In a planned double-blind extension to LOFT, eligible patients continued on their originally assigned treatment for up to 5 years. We present efficacy and safety data for the entire 5-year double-blind period. Design: Women ≥65 years of age with BMD T-score ≤–2.5 at total hip (TH) or femoral neck (FN), or with radiographic vertebral fracture (VFx) and T-score ≤–1.5 at TH or FN, were randomized (1:1) to ODN 50 mg/week or PBO. All received vitamin D3 (5600 IU/week) and calcium as required. Endpoints included morphometric VFx, hip fracture, non-VFx, clinical VFx, and safety and tolerability. Specific adverse events (AEs) were adjudicated. Results: Of 16,071 patients (8043 ODN, 8028 PBO) in LOFT, 12,290 (6092 ODN, 6198 PBO) completed the study. Among these, 8,257 (4297 ODN, 3960 PBO) who were eligible and consented entered the extension and 6,047 (3432 ODN, 2615 PBO) completed it. Mean (SD) age at randomization was 72.8 (5.3) years, 46.5% had prior VFx, and mean BMD T-scores were lumbar spine (LS) –2.7, TH –2.4, and FN –2.7. Mean (SD) follow-up was approximately 44 (18) months. Compared with PBO, ODN treatment over 5 years resulted in relative risk reductions of 52% for morphometric VFx, 48% for hip fracture, 26% for non-VFx, and 67% for clinical VFx (all p<0.001). Compared with PBO, ODN treatment led to progressive mean percent increases (95% CI) in BMD of 10.9% (10.5, 11.2) at LS and 10.3% (10.0, 10.6) at TH (both p<0.001) at 5 years. Incidences of AEs and serious AEs overall were balanced for ODN vs PBO (88.3 vs 88.2% and 30.3 vs 30.4%, respectively). Deaths reported in patients being followed on study were 378 (4.7%) vs 327 (4.1%), ODN vs PBO, respectively (HR 1.12 [95% CI: 0.97, 1.30]); more complete ITT analysis of deaths among all patients, including those who discontinued from study, showed 682 (8.5%) vs 660 (8.2%), respectively (HR 1.04 [95% CI: 0.93, 1.16]). Delayed fracture union occurred in 18 patients in each group. Femoral shaft fractures occurred more often with ODN (26 patients [0.3%] vs 7 [0.1%]), of which 10 (0.1%) on ODN and none on PBO met criteria for atypical femoral shaft fractures (AFFs). No cases of osteonecrosis of the jaw (ONJ) were confirmed. Morphea-like skin lesions occurred more often with ODN (13 [0.2%] vs 3 [<0.1%]), most with onset within 2 years and all improved or fully recovered. Systemic sclerosis occurred in 2 (<0.1%) with ODN vs 1 (<0.1%) with PBO. Independent adjudication of CV events is ongoing and will be presented. Conclusion: Consistent with the results of LOFT, treatment with ODN for up to 5 years reduced the risk of hip, vertebral and non-vertebral fractures. Overall incidence of AEs, including serious AEs, was generally balanced between ODN and PBO. Femoral shaft fractures, including AFFs, and morphea-like skin lesions were uncommon but more frequent with ODN. Sources of Funding: This study was sponsored by Merck & Co., Inc., Kenilworth, NJ, USA S-2. Women’s Health Initiative Clinical Trials: The Interactive Effect of Calcium and Vitamin D Supplementation with Hormonal Therapy on Cardiovascular Events and Venous Thromboembolism Xuezhi Jiang, MD1,2, John Robbins4, Matthew Nudy3, Kayler Gabbett1, David O’Sullivan, PhD1, Anita M. Kelsey, MD, FACC, FASE8, Aaron Aragaki6, Erin S LeBlanc7, Lisa S. Martin9, JoAnn E. Manson5, James Shikany10, Karen Johnson11, Marcia Stefanick12, Martha Payne13, Jane Cauley14, Barbara Howard15, Peter F. Schnatz, DO1,2. 1ObGyn, The Reading Hospital, West Reading, PA; 2OBGYN, Sidney Kimmel Medical School of Thomas Jefferson University, Philadelphia, PA; 3Internal Medicine, Hershey Medical Center, Hershey, PA; 4Internal Medicine, UC Davis Medical Center, Sacramento, CA; 5Preventive medicine, Brigham and Women’s Hospital/Harvard Medical School, Boston, MA; 6Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA; 7Center for Health Research NW, Kaiser Permanente, Portland, OR; 8Cardiology, Saint Francis Medical Group, Inc., Hartford, CT; 9Internal Medicine, George Washington University School of Medicine and Health Sciences, Washington, DC; 10Preventive medicine, University of Alabama at Birmingham, School of Medicine, Birmingham, AL; 11Preventive medicine, University of Tennessee Health Science Center, Memphis, TN; 12Medicine, Stanford University School of Medicine, Stanford, CA; 13the Office of Research, Duke University Medical Center, Durham, NC; 14Epidemiology, University of Pittsburgh, Graduate School of Public Health, Pittsburgh, PA; 15MedStar Health Research Institute, Washington, DC Objective: Evidence from limited data suggests that calcium and vitamin D (CaD) at moderate to high doses may reduce cardiovascular disease (CVD) risk. Using randomized trial data we analyzed if the effect of menopausal hormone therapy (HT) on various cardiovascular disease events is enhanced by calcium and vitamin D (CaD) supplementation. Design: A prospective, randomized, double-blind, placebo controlled trial was implemented among Women’s Health Initiative (WHI) postmenopausal women. A total of 27,347 women were randomized to the HT trials (0.625 mg/d of conjugated equine estrogens [CEE] alone for women without a uterus or 0.625 mg of CEE in addition to 2.5 mg of medroxyprogesterone acetate daily [CEE+MPA] for women with a uterus versus placebo). After 1 year, 16, 089 women in the HT trial were randomized to the CaD trial to receive either 1,000 mg of elemental calcium carbonate plus 400 IU of vitamin D3 daily or placebo. The mean (SD) duration of follow-up after CaD randomization were 6.2(1.3) and 4.6(1.1) years, respectively. CVD events analyzed in this subgroup analysis include coronary heart disease (CHD), stroke, pulmonary embolism, all-cause mortality, plus select secondary endpoints (total myocardial infarction, coronary revascularization, deep venous thrombosis, cardiovascular death, and all CVD events). The time-to-event methods were used and models were fit with a Cox proportional hazards regression model. Results: In the CEE trial, CaD did not significantly modify the effect of CEE on most CVD outcomes but did modify its effect on cardiovascular death (p-interaction = 0.03). In the CaD-placebo group, the effect of CEE on cardiovascular death was somewhat harmful (HR [95%CI] = 1.47[0.86, 2.53]); in the CaD-supplement group, the effect of CEE was somewhat beneficial (HR [95%CI] = 0.57[0.29, 1.10]), see figure 1. Similar results were found for CHD deaths, which account for the majority of the cardiovascular deaths (52 of 92; p-interaction=0.04). We did not observe significant CEE x CaD interactions for CHD, total CVD events, or any of the remaining endpoints. Contrary to the CEE trial, there was no evidence that the effect of CEE+MPA on cardiovascular death or other CVD endpoints was modified by the CaD-supplementation (p-interaction = 0.24), see figure 2. Moreover, hazard ratios were in the opposite direction of those observed in the CEE trial. Conclusion: Calcium and vitamin D supplementation did not consistently modify the effect of CEE therapy on CVD events, but did appear to modify its effect on CVD death. The effect of CEE (active vs. placebo) on CVD death was favorable among women randomized to CaD supplement use but unfavorable among those randomized to CaD-Placebo. While CaD significantly modified the effect of CEE on cardiovascular death (p-interaction = 0.03), these differences were not individually significant. CaD did not significantly modify the effect of CEE+MPA on CVD death or any CVD events. Additional research on potential interactions between CaD and HT is warranted. Sources of Funding: None