2014年12月9日讯 /生物谷BIOON/ --安进近日宣布，FDA已批准单抗药物Xgeva（denosumab）第3个适应症，用于双磷酸盐疗法难治性由恶性肿瘤引发的高钙血症（HCM）的治疗。之前，FDA已授予Xgeva治疗HCM的孤儿药地位。
恶性肿瘤高钙血症（HCM）是发生于晚期癌症患者（包括血液系统恶性肿瘤）的一种严重并发症，预后很差。该病由肿瘤驱动骨吸收增加所致。如果不及时治疗，可导致肾功能衰竭、进行性智力障碍、昏迷和死亡。
Xgeva的获批，是基于一项开放标签单组研究的积极结果。该研究在近期经双磷酸盐治疗的晚期癌症并伴有持续性高钙血症的患者中开展，数据显示，该项研究达到了实现白蛋白校正的血清钙（CSC）的主要终点，在第10天缓解率为63.6%。预测的实现缓解（CSC 11.5mg/dL）的平均时间为9天，总的完全缓解率（CR）为63.6%，平均缓解持续时间为104天。
XXgeva结合RANK配体（RANKL），该蛋白对于骨细胞（osteoclast）的形成、功能及生存至关重要，骨细胞负责骨吸收。骨巨细胞瘤由表达RANKL的基质细胞及表达RANK受体的骨细胞样巨细胞组成。通过RANK受体的信号促进骨溶解和肿瘤的生长。Xgeva能阻止RANKL激活位于骨细胞、前体细胞及骨细胞样巨细胞表面的受体RANK。
Xgeva是安进公司最重要的药物之一，于2010年获批用于实体瘤骨转移患者，预防骨折相关事件的发生，Xgeva不适用于在多发性骨髓瘤（MM）患者预防骨骼相关事件。在2013年，FDA批准Xgeva(denosumab)一个新适应症，用于手术不可切除性或手术切除可能导致严重并发症的骨巨细胞瘤（GCTB）成人患者及骨骼发育成熟的青少年患者的治疗，该药也是FDA批准的首个和唯一一个GCTB治疗药物。骨巨细胞瘤（GCTB）为骨原发的骨破坏性良性侵袭性肿瘤，通常影响20-40岁的个体，往往导致骨折。
英文原文：FDA Approves Amgen's XGEVA? (Denosumab) For The Treatment Of Hypercalcemia Of Malignancy Refractory To Bisphosphonate Therapy
This Approval Provides a New Treatment Option for a Patient Population With High Unmet Medical Need
THOUSAND OAKS, Calif., Dec. 8, 2014 /PRNewswire/ -- Amgen (AMGN) today announced that the U.S. Food and Drug Administration (FDA) has approved a new indication for XGEVA? (denosumab) for the treatment of hypercalcemia of malignancy (HCM) refractory to bisphosphonate therapy. XGEVA was approved and granted Orphan Drug Designation by the FDA, which is reserved for drugs that are intended for the treatment of rare diseases affecting fewer than 200,000 people in the U.S.
HCM is a serious complication in patients with advanced cancer, including those with hematologic malignancies, and indicates poor prognosis.1,2 The condition results from cancer-driven increases in bone resorption, and if untreated, can lead to renal failure, progressive mental impairment, coma and death.1-3
"Our continued study of XGEVA reinforces Amgen's ongoing commitment to address the unmet needs of cancer patients," said Sean E. Harper, M.D., executive vice president of Research and Development at Amgen. "This latest FDA approval for XGEVA provides an important new therapeutic option for patients with a rare condition that cannot be resolved with bisphosphonate therapy."
The approval of XGEVA is based on positive results from an open-label, single-arm study, which enrolled patients with advanced cancer and persistent hypercalcemia after recent bisphosphonate treatment. The primary endpoint was the proportion of patients with a response, defined as albumin-corrected serum calcium (CSC) 11.5 mg/dL (2.9 mmol/L; Common Terminology for Adverse Events [CTCAE] grade 1) within 10 days after the first dose of XGEVA. Secondary endpoints included the proportion of patients who experienced a complete response (defined as CSC 10.8 mg/dL [2.7 mmol/L]) by day 10, time to response and response duration (defined as the number of days from the first occurrence of CSC 11.5 mg/dL). The study achieved its primary endpoint with a response rate at day 10 of 63.6 percent in the 33 patients evaluated. The overall complete response rate was 63.6 percent. The estimated median time to response (CSC 11.5 mg/dL) was nine days, and the median duration of response was 104 days.4,5
The most common adverse reactions in patients receiving XGEVA for hypercalcemia of malignancy were nausea, dyspnea, decreased appetite, headache, peripheral edema, vomiting, anemia, constipation and diarrhea.5
For patients with HCM, XGEVA is administered as a subcutaneous injection (120 mg) every four weeks with additional doses of 120 mg on days eight and 15 of the first month of therapy.5
XGEVA binds to RANK Ligand (RANKL), a protein essential for the formation, function and survival of osteoclasts, the cells responsible for bone resorption, thereby modulating calcium release from bone. XGEVA prevents RANKL from activating its receptor, RANK, on the surface of osteoclasts, thereby decreasing bone destruction and calcium release.5
About Hypercalcemia of Malignancy
Hypercalcemia of malignancy (HCM) is a serious complication in patients with advanced cancer, including those with hematological malignancies.1 In 2012, the estimated prevalence of HCM in cancer patients in the U.S. was 2.7 percent.6 HCM is indicative of poor prognosis and occurs most often in patients with squamous cell cancer (e.g., lung cancer, head and neck cancer), breast cancer, kidney cancer, myeloma and lymphoma.1,2,7 HCM results from cancer-driven increases in bone resorption, and, if untreated, can lead to renal failure, progressive mental impairment, coma and death.1-3
About XGEVA
XGEVA was approved by the FDA for the prevention of skeletal-related events (SREs) in patients with bone metastases from solid tumors in 2010. XGEVA is not indicated for the prevention of SREs in patients with multiple myeloma. In clinical trials, XGEVA demonstrated a clinically meaningful improvement compared to the previous standard of care in preventing SREs. In 2013, XGEVA was approved by the FDA as the first-and-only treatment for 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.