Denosumab (Xgeva®), the World’s First RANKL Inhibitor, Granted Conditional Approval in China for Giant Cell Tumor of Bone

On May 22, the National Medical Products Administration (NMPA) granted conditional approval for the marketing of Denosumab, indicated for the treatment of adults and skeletally mature adolescents with giant cell tumor of bone that is unresectable or where surgical resection may result in severe functional impairment. Denosumab, a first-in-class anti-RANKL monoclonal antibody developed by Amgen, received its initial global approval in the European Union on May 26, 2010, and was included in the first batch of the List of Overseas New Drugs in Urgent Clinical Need. The approval of Denosumab in China will introduce an innovative therapeutic option for the treatment of giant cell tumor of bone.

This product’s import registration application in China was supported by overseas clinical data, thereby qualifying for a waiver of local clinical trials. The primary supportive clinical data submitted by the applicant were all obtained outside China. Accordingly, on May 21, the National Medical Products Administration (NMPA), after consolidating input from its various technical departments, granted conditional marketing approval for this product. Simultaneously, the NMPA required the applicant to continue conducting clinical studies in China post-approval and to develop and strictly implement a risk management plan.

Multiple companies in China are developing denosumab biosimilars. Among them, the denosumab biosimilar (LY06006) developed by Luye Pharma and Boan Biotech has entered Phase III clinical trials for the indication of postmenopausal osteoporosis. Products from other companies (including, but not limited to, Keymed Biosciences, Qilu Pharmaceutical, Hualan Biological Engineering, and Henlius) are in Phase I clinical trials or preclinical stages.

This article focuses on the key clinical trial data of denosumab!

I. Denosumab: The World’s First RANKL Monoclonal Antibody

On May 26, 2010, denosumab was first approved in the European Union. To date, it has been approved for multiple clinical indications under the brand names Prolia and Xgeva. The indications approved in the United States are listed in the table below.

Refer to the prescribing information for denosumab.

Denosumab and Giant Cell Tumor of Bone

Giant Cell Tumor of BoneGiant cell tumor of bone (GCTB) is an extremely rare and rapidly progressive primary bone tumor characterized by abundant expression of receptor activator of nuclear factor kappa-B ligand (RANKL). It typically presents as eccentric osteolytic lesions in the metaphysis and epiphysis of long bones, or in the spine and sacrum. The lesions are highly vascularized and aggressively osteolytic, with ill-defined margins and a wide transition zone. According to current hypotheses, the neoplastic component of GCTB consists of RANKL-expressing mononuclear stromal cells, which recruit osteoclast-like giant cells, thereby driving the tumor’s aggressive osteolytic activity.

Denosumab is a novel RANKL inhibitor developed by Amgen, Inc. It is a fully human monoclonal IgG2 antibody that exhibits high affinity and specificity for both soluble and transmembrane forms of human RANKL. In patients with giant cell tumor of bone, denosumab inhibits RANKL secreted by the tumor stromal components, significantly reducing or eliminating osteoclast-like tumor-associated giant cells. Consequently, bone lysis is reduced, tumor progression is slowed, and the proliferative stroma is replaced by dense, non-proliferative, differentiated woven new bone, thereby improving clinical outcomes.

Clinical Data on Denosumab for Giant Cell Tumor of Bone:

Denosumab for giant cell tumor of bone mainly includes two pivotal clinical trials, Study 20040215 (NCT00396279) and

Study 20062004 (NCT00680992). NCT00396279 enrolled 37 patients, and NCT00680992 enrolled 270 patients. Clinical data demonstrated an overall response rate (ORR) of 25%, indicating that denosumab provides clinical benefit to patients with giant cell tumor of bone.

Denosumab China Clinical Trial Registration Information

The following section primarily presents data from two other key clinical trials on denosumab:

The following data are not from the Chinese population and are all extracted from drug prescription information.

1. Skeletal-Related Events in Patients with Bone Metastases from Solid Tumors

Study 20050136 (NCT00321464) Enrolls Patients with Advanced Breast Cancer and Bone Metastasis Events

Study 20050244 (NCT00330759) enrolled patients with solid tumors (excluding breast and prostate cancer), bone metastasis events, and multiple myeloma.

Study 20050103 (NCT00321620) enrolled patients with castration-resistant prostate cancer and bone metastases.

Data from three clinical trials demonstrate that denosumab, compared with zoledronic acid, prolongs the time to first skeletal-related event (SRE), providing significant clinical benefit to patients with bone metastases from solid tumors.

2. Postmenopausal Women with Osteoporosis at Increased Risk of Fracture

Excerpted from Denosumab for Prevention of Fractures in Postmenopausal Women with Osteoporosis

Data from NCT00089791 indicate that the incidence of vertebral fractures was 2.3% with denosumab versus 7.2% with placebo. Denosumab, compared with placebo, reduced the risk of vertebral fractures by 68% (HR 0.32), hip fractures by 40% (HR 0.60), and non-vertebral fractures by 20% (HR 0.80).

II. Development of Denosumab Biosimilars in China

Since its market launch, denosumab has seen year-on-year sales growth. In 2018, the global sales of Prolia and Xgeva reached USD 4.077 billion. Multiple domestic companies have positioned themselves in the development of denosumab biosimilars, among which Luye Pharma’s LY06006 is the most advanced. As a biosimilar of Prolia, it initiated Phase III clinical trials in China on April 8, 2019, taking the lead.

Furthermore, other denosumab biosimilars in China are still in the early stages of clinical development, and their subsequent progress warrants long-term attention!