Xgeva (Denosumab) for the Prevention of Metastatic Bone Cancer, United States of America

Xgeva (Denosumab) is a preventive medicine developed by Amgen to check the spread of cancer to the bones. Amgen announced in May 2011 that it has received a positive response from the Committee for Medical Products for Human Use (CHMP) to market the drug in the member states of the EU. The drug is under review for its application in the prevention of skeletal related events (SREs) and the spread of cancer to the bones. If approved, it will receive marketing authorisation for all the countries in the EU.

Xgeva has been proven to be superior to Zometa in preventing the SREs in patients with solid tumours such as lung cancer, breast cancer and prostate cancer.

The drug was approved by the European Medicine Agency (EMA) and the FDA in 2010 for the treatment of osteoporosis in post-menopausal women. The FDA has approved the drug for its application in preventing the spread of cancer to the bones too.

The drug has also received approval in Canada for minimising the risk of developing SREs in patients with bone metastasis from breast cancer, prostate cancer, non-small cell lung cancer and other solid tumours.

GSK will market the drug in the countries where Amgen does not have a presence.

Bone metastasis

When a person develops cancer, there is a high risk that it spreads to the other parts of the body. This process is called metastasis. It occurs in more than 1.5 million people suffering from cancer. Several types of cancers, including lung, breast, prostrate, kidney, thyroid and the multiple myeloma's, can lead to bone metastasis.

Drug mechanism

The bone tissue damage is caused by cells called osteoclasts which remove the matrix. These bone cells (osteoclasts) are activated by a protein called RANK Ligand (RANKL).

A monoclonal antibody, Xgeva binds to RANKL and hinders it from activating the osteoclasts. The inhibition decreases the differentiation, activity and survival of the osteoclastic bone cells. The drug thus reduces tissue damage and avoids bone erosion and breakage.

Overdose of the drug can, however, lead to severe reduction of calcium in blood and Osteonecrosis of the jaw (ONJ), a disease which occurs due to reduced flow of blood.

Clinical trails

A three phased clinical trail was conducted to discover the effectiveness of Xgeva.

Phase 1 clinical trials were conducted in 2008 in Japan to study the safety, pharmacodynamics and pharmacokinetics of denosumab in women suffering from breast cancer.

Phase 2 clinical trials were conducted in 2009 to evaluate the drug's effectiveness in the prevention of relapsed multiple myeloma.

Phase 3 trials were conducted to evaluate the prevention of SREs in patients suffering from breast and prostrate cancer.

The Phase 3 trial included a randomised, double-blind study to compare the delaying time of first-on study SREs of Xgeva and Zometa in advanced cancer patients. The study also compared the effectiveness of Xgeva and Zometa in the prevention of SREs in patients suffering from advanced breast cancer and prostate cancer.

The first comparative study enrolled approximately 1,776 cancer patients with solid tumours and bone metastasis. The patients were administered either 120mg of Denosumab or 4mg of Zometa every four weeks. Denosumab, with median time of 19 months, was superior to Zometa with 14.4 months of median time to first on-study SRE.

For the second study, around 2,046 breast cancer patients were enrolled. Two groups of patients were formed and administered either 120mg of Denosumab or 4mg of Zometa in a 15 minute infusion. The doses were given once in four weeks. The results of the study showed that Xgeva was more effective than Zometa in delaying the time of SREs in patients suffering from advanced breast cancer.

For the third study, around 1,900 men with advanced prostate cancer were enrolled. The results showed that Xgeva was superior to Zometa in delaying the time and therefore, the primary endpoint was met.