資料來源：https://www.prnewswire.com/news-releases/fda-accepts-amgens-supplemental-biologics-license-application-to-expand-indication-for-xgeva-denosumab-to-include-multiple-myeloma-patients-300475662.html

Amgen announced that the U.S. Food and Drug Administration (FDA) has accepted the XGEVA® (denosumab) supplemental Biologics License Application (sBLA) that seeks to expand the currently approved indication for the prevention of fractures and other skeletal-related events in patients with bone metastases from solid tumors to include patients with multiple myeloma. The FDA has set a Prescription Drug User Fee Act (PDUFA) action date of Feb. 3, 2018.

"Multiple myeloma patients with fractures and other bone complications have a very poor prognosis. Bisphosphonates are the only approved class of agents for the prevention of skeletal-related events in this patient population. However, these agents have several limitations, including kidney toxicity and acute phase reactions," said Sean E. Harper, M.D., executive vice president of Research and Development at Amgen. "Based on the data we have submitted to the FDA, we look forward to potentially making XGEVA available as a novel option for patients with multiple myeloma."

XGEVA is the first fully human monoclonal antibody that binds to and neutralizes RANK ligand (RANKL) – a protein essential for the formation, function and survival of osteoclasts, which break down bone – thereby inhibiting osteoclast-mediated bone destruction. XGEVA is not cleared by the kidneys. XGEVA is indicated for the prevention of skeletal-related events in patients with bone metastases from solid tumors and is the number one prescribed agent by oncologists for this indication in the U.S. In the U.S., XGEVA currently has a limitation of use noting that it is not indicated for the prevention of skeletal-related events in patients with multiple myeloma.

The sBLA, submitted on April 3, 2017, is based on the efficacy and safety data from the pivotal Phase 3 '482 study, the largest international multiple myeloma trial ever conducted, which successfully demonstrated that XGEVA is non-inferior to zoledronic acid in delaying the time to first on-study skeletal-related event in patients with multiple myeloma. The secondary endpoints of superiority in delaying time to first on-study skeletal-related event and delaying time to first-and-subsequent skeletal-related event were not met in this study. Progression-free survival was an exploratory endpoint. The hazard ratio of XGEVA versus zoledronic acid for progression-free survival was 0.82 (95 percent CI: 0.68, 0.99; descriptive p=0.036) and the median difference in progression-free survival between arms was 10.7 months in favor of XGEVA. Data from the '482 study are also the basis of an application for a variation to the marketing authorization submitted to the European Medicines Agency (EMA).

About '482 Study (NCT01345019)

The '482 study 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. In the study, a total of 1,718 patients (859 on each arm) were randomized to receive either subcutaneous XGEVA 120 mg and intravenous placebo every four weeks, or intravenous zoledronic acid 4 mg (adjusted for renal function) and subcutaneous placebo every four weeks.

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 over zoledronic acid with respect to time to first on-study and first-and-subsequent on-study skeletal-related event and evaluation of overall survival. The hazard ratio of overall survival was 0.90 for XGEVA as compared to zoledronic acid (95 percent CI: 0.70, 1.16). The hazard ratio of XGEVA versus zoledronic acid for progression-free survival, an exploratory endpoint, was 0.82 (95 percent CI: 0.68, 0.99; descriptive p=0.036). The median difference in progression-free survival between arms was 10.7 months in favor of XGEVA. The safety and tolerability of XGEVA were also compared with zoledronic acid in the study. The most common adverse events (greater than or equal to 25 percent) in both arms were diarrhea and nausea.

About Multiple Myeloma and Bone Complications (Skeletal-Related Events)

Multiple myeloma is the second most common hematologic cancer, and it develops in plasma cells located in the bone marrow microenvironment.1,2 It is typically characterized by osteolytic bone lesions and renal impairment, which are both part of diagnosis (CRAB criteria).3,4 Each year an estimated 114,000 new cases of multiple myeloma are diagnosed worldwide, resulting in more than 80,000 deaths per year.1

More than 90 percent of patients develop osteolytic lesions during the course of the disease.3 Current treatment options for bone complications are limited to bisphosphonates, including zoledronic acid; these are cleared by the kidneys and are associated with renal toxicity which is a common complication among multiple myeloma patients.5 The majority (approximately six out of 10) of all multiple myeloma patients have or will develop renal impairment over the course of the disease.6 Preventing bone complications is a critical aspect of caring for patients with multiple myeloma, because these events can cause significant morbidity.7

About XGEVA® (denosumab)

XGEVA targets the RANKL pathway to prevent the formation, function and survival of osteoclasts, which break down bone. As a monoclonal antibody, XGEVA is not cleared by the kidneys. XGEVA is indicated for the prevention of skeletal-related events in patients with bone metastases from solid tumors. In the U.S., XGEVA currently has a limitation of use noting that it is not indicated for the prevention of skeletal-related events in patients with multiple myeloma. XGEVA is also indicated for the treatment of adults and skeletally mature adolescents with giant cell tumor of bone that is unresectable or where surgical resection is likely to result in severe morbidity. XGEVA is also indicated in the U.S. for the treatment of hypercalcemia of malignancy refractory to bisphosphonate therapy.