Amgen's Denosumab Injection Nears Third Indication Approval in China for Prevention of Skeletal-Related Events in Multiple Myeloma and Solid Tumor Bone Metastases

Recently, the third marketing application for Amgen’s denosumab injection in China (with the relevant acceptance number JXSS19000009) has entered the administrative approval stage, indicating that the drug is expected to receive approval for a third indication in the country. It is reported that the indication pending approval is: prevention of skeletal-related events in patients with bone metastases from multiple myeloma and solid tumors.

Denosumab is a human immunoglobulin G2 (IgG2) monoclonal antibody with high specificity and affinity for RANKL. By binding to RANKL, this drug prevents the activation of the RANK signaling pathway in osteoclasts, thereby disrupting the "vicious cycle" of bone metastasis in cancer, ultimately inhibiting tumor growth and reducing bone destruction.

This originator drug, developed by Amgen, is currently approved for multiple indications worldwide. The drug’s strength and brand name vary by indication: Prolia® is available at a strength of 60 mg/mL, while Xgeva® is available at 70 mg/mL. Under the brand name Prolia®, the drug is approved for the treatment of postmenopausal osteoporosis. Under the brand name Xgeva® (known as RANMARK® in Japan), it is approved for the prevention of skeletal-related events (SREs) in patients with bone metastases from solid tumors and multiple myeloma, the treatment of giant cell tumor of bone (GCTB) in adults and skeletally mature adolescents, and the treatment of hypercalcemia of malignancy (HCM) refractory to bisphosphonate therapy.

According to Amgen’s financial reports, sales of Prolia®/Xgeva® have maintained a steady growth trend in recent years, with total denosumab sales reaching $4.607 billion in 2019. However, due to the impact of the COVID-19 pandemic this year, denosumab sales were affected to some extent, amounting to $3.411 billion in the first three quarters of 2020.

In China, denosumab was included in the First Batch of List of Urgently Needed Overseas New Drugs for Clinical Use, released by the Center for Drug Evaluation (CDE) in November 2018. Drugs included in this list may submit relevant materials in accordance with the Review and Approval Procedures for Urgently Needed Overseas New Drugs for Clinical Use, directly file marketing applications, and benefit from a specialized expedited review channel established by the CDE. Less than a year later, in May 2019, the National Medical Products Administration (NMPA) approved the drug for the treatment of giant cell tumor of bone that is unresectable or where surgical resection may result in severe functional impairment, including adult and adolescent patients with skeletal maturity (defined as having at least one mature long bone and body weight ≥45 kg). The brand name is Xgeva.

In June 2020, denosumab was approved by the NMPA for the treatment of osteoporosis in postmenopausal women at high risk of fracture, under the brand name Prolia, becoming the first and currently the only anti-RANKL monoclonal antibody used for the treatment of osteoporosis in China.

Bone metastasis is one of the common complications of advanced malignant tumors, especially in advanced breast cancer, prostate cancer, and lung cancer. On average, one out of every three patients will develop bone metastasis. Once patients with advanced tumor bone metastasis experience skeletal-related events such as pathological fractures, spinal cord compression, or hypercalcemia, it can have a significant negative impact on their quality of life and survival. Currently, the main drugs used in China for the prevention and treatment of bone metastasis-related events are bisphosphonates, such as zoledronic acid, ibandronic acid, and pamidronate.

Denosumab has been approved abroad for the prevention of skeletal-related events in patients with bone metastases from advanced tumors. Compared with bisphosphonates, denosumab offers the following advantages in preventing skeletal-related events: (1) It is not only targeted but also has direct antitumor effects; (2) Its clinical efficacy is superior to that of bisphosphonates, and it remains effective in patients who have failed bisphosphonate therapy; (3) It has a favorable safety profile, with a lower incidence of nephrotoxic side effects; (4) It is more convenient to administer, as denosumab is given via subcutaneous injection, whereas bisphosphonates require intravenous infusion. We look forward to the early approval of denosumab’s indication for the prevention of skeletal-related events.

In November 2019, BeiGene and Amgen entered into a global strategic oncology collaboration. Under the terms of this agreement, BeiGene is responsible for the commercialization and development in China of three approved or filed oncology drugs from Amgen: Xgeva (denosumab), Kyprolis (carfilzomib), and Blincyto (blinatumomab). Additionally, the two companies will collaborate on the development of 20 investigational oncology assets in Amgen’s pipeline, with BeiGene leading their development and commercialization in China. Currently, denosumab has been launched in the Chinese market this July.

Furthermore, it is worth noting that with the upcoming adjustment of the National Reimbursement Drug List (NRDL) in 2020, Denosumab Injection was included in the “List of Declared Drugs That Passed the Formal Review for the 2020 Adjustment of the National Reimbursement Drug List.” The NRDL adjustment process has entered the declaration and review phase. We look forward to the early inclusion of Denosumab in the national medical insurance coverage to benefit more patients.

Although denosumab was approved for marketing in China relatively late, multiple domestic companies have already entered the biosimilar market. According to the Insight database, four companies—Qilu Pharmaceutical, Boan Biotechnology, Maiwei Biotechnology, and Keyence Therapeutics—are in Phase III clinical trials; five companies are in Phase I clinical trials; and two companies have received approval to conduct clinical trials.

Furthermore, to further clarify technical principles and help improve the R&D efficiency of enterprises, the CDE released in April this year the drafted "Guidelines for Clinical Trials of Biosimilar Denosumab Injection (for Malignant Tumor Indications) (Draft for Comments)."