At the beginning of this month, European Commission (EC) has approved an expanded indication for XGEVA® (denosumab) for the prevention of skeletal-related events (SRE) in adults with advanced malignancies involving bone, based on the data from the Phase 3 ‘482 (NCT01345019) study, the largest international trial ever conducted for the prevention of skeletal-related events in multiple myeloma (MM) patients. Approval from the EC grants a centralized marketing authorization with unified labeling in the 28 countries that are members of the European Union (EU). Norway, Iceland and Liechtenstein, as members of the European Economic Area, will take corresponding decisions on the basis of the decision of the EC.
About XGEVA® (denosumab)
XGEVA (denosumab) is the first fully human monoclonal antibody that is designed to target nuclear factor kappa-B (RANK) ligand (RANKL), a protein that acts as the primary signal to promote bone removal/resorption. In many bone loss conditions, RANKL overwhelms the body’s natural defense against bone destruction. Denosumab prevents RANKL from activating its receptor, RANK, on the surface of osteoclasts and their precursors. Prevention of the RANKL/RANK interaction inhibits osteoclast formation, function, and survival, thereby decreasing bone resorption and increasing bone mass and strength in both cortical and trabecular bone. Chemically, it consists of 2 heavy and 2 light chains. Each light chain consists of 215 amino acids. Each heavy chain consists of 448 amino acids with 4 intramolecular disulfides. On June 1, 2010, XGEVA was approved by the U.S. Food and Drug Administration (FDA). On Jan. 5, 2018, the U.S. Food and Drug Administration approved the supplemental Biologics License Application for XGEVA to expand the currently approved indication for the prevention of SRE in patients with bone metastases from solid tumors to include patients with MM. Additional regulatory applications for XGEVA for the prevention of SRE in patients with MM are underway and have been submitted to health authorities worldwide.
About ‘482 Study (NCT01345019)
The ‘482 study (NCT01345019) was an international, Phase 3, randomized, double-blind, multicenter trial of XGEVA compared with zoledronic acid in the prevention of skeletal-related events in adult patients with newly diagnosed multiple myeloma and bone disease. The primary endpoint of the study was non-inferiority of XGEVA versus zoledronic acid with respect to time to first on-study skeletal-related event (pathologic fracture, radiation to bone, surgery to bone or spinal cord compression). Secondary endpoints included superiority of XGEVA versus zoledronic acid with respect to time to first on-study skeletal-related event, first-and-subsequent on-study skeletal-related event, and evaluation of overall survival. In this study, XGEVA successfully met the primary endpoint, demonstrating non-inferiority to zoledronic acid in delaying the time to first on-study skeletal-related event in patients with multiple myeloma (HR=0.98, 95 percent CI: 0.85-1.14). The median time to first on-study skeletal-related event was 22.8 months for XGEVA and 24.0 months for zoledronic acid. The safety profile was consistent with known adverse events of XGEVA.
About Multiple Myeloma and Bone Complications
Multiple myeloma is the second most common hematologic cancer, and it develops in plasma cells located in the bone marrow microenvironment. It is typically characterized by osteolytic bone lesions as well as renal failure, which are both parts of diagnosis. Each year an estimated 114,000 new cases of multiple myeloma are diagnosed worldwide, resulting in more than 80,000 deaths per year. More than 90 percent of patients develop osteolytic lesions during the course of the disease. Preventing bone complications is a critical aspect of caring for patients with multiple myeloma, because these events can result in significant morbidity. Current treatment options to prevent bone complications are limited to bisphosphonates, including zoledronic acid, which is cleared through the kidneys. Approximately 60 percent of all multiple myeloma patients have developed or will develop renal impairment over the course of the disease.
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