Background/Purpose: 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.

Methods: 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 15 of 16 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 separately.

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.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/odanacatib-efficacy-and-safety-in-postmenopausal-women-with-osteoporosis-5-year-data-from-the-extension-of-the-phase-3-long-term-odanacatib-fracture-trial/