On November 18 2010, the FDA approved Amgen's Xgeva or denosumab to be used in the prevetion of cancer-related bone injury. (Note: The FDA indicates multiple myeloma as solid tumor but in fact multiple myeloma is a cancer of plasma cell residing in the bone marrow. So it's not really a solid tumor)
Denosumab is a monoclonal antibody that works to inhibit RANKL or nuclear factor kB ligand. In general, RANKL binds to RANK receptor to increase differentiation and maturation of osteoclastic precursor cells into mature osteoclast. Osteoclast works to increase bone resorption (in other word, increase the destruction of bone cells in order to release mineral contents within the bone cells). Under normal physiological situations, osteoclastic activity is important in bone development. When the activity is out of control, bone resorption can occur and make the bone more prone to fracture.
Denosumab inhibits RANKL and as a result denosumab will prevent RANKL from binding to its receptor. This results in less differentiation and maturation of osteoclast. Hence, less bone resorption will occur.
Currently denosumab is marketed under the brand name Prolia by Amgen. Prolia is approved for the treatment of postmenopausal women with osteoporosis at high risk for fracture. Prolia was approved in June 2010.
Other Medications that have been approved for the same indication as XGEVA:
- Zometa (zoledronic acid) of Novartis. Zometa works differently from denosumab even though the exact mechanism is unclear
- Aredia or pamidronate sodium of Novartis. Same as Zometa, the exact mechanism of Aredia is still unclear.
- Other marketing applications for XGEVA have been submitted for review in the EU, Australia, Canada and Switzerland.
- Daiichi-Sankyo Company is its licensing partner in Japan. A marketing application was submitted in August 2010.
- Upon approval, Amgen plans to launch XGEVA by the end of November.
- Most common serious side effects:
- low level of calcium in the blood (hypocalcemia)
- osteonecrosis of the jaw that could cause pain, swelling, numbness or infections
- Other side effects:fatigue/asthenia, low level of phosphate in the blood (hypophosphatemia) and nausea
- XGEVA is available in a single-use vial which contains 120 mg of denosumab in 1.7 ml of solution.
- XGEVA needs to be stored in refrigerator at 2oC to 8oC in the original box. Do not freeze.
- Amgen has XGEVA First Step (TM) Coupon Program that could help patients having access to XGEVA.
- If eligible, first XGEVA injection will be of no charge and subsequent injections will be charged to a maximum of $25.
- Patients can access it @ Amgen Assist
- The FDA approved XGEVA based on the results of three international, randomized, double-blind, active-controlled, noninferiority trials which compared XGEVA against zoledronic acid.
- In all three trials: patients were randomly assigned into either the XGEVA group or zoledronic acid group.
- Patients in the XGEVA group were instructed to perform subcutaneous injection of 120 mg XGEVA every 4 weeks
- Patients in the zoledronic acid group were given intravenous solution of 4 mg zoledronic acid every 4 weeks.
- Trial 1 evaluated XGEVA and zolendronic acid in patients with advanced breast cancer and bone metastasis
- The result showed XGEVA was significantly increased median time to Skeletal-related events (SRE) compared to zolendronic acid.
- It was noninferior to zoledronic acid
- Trial 2 evaluated XGEVA and zolendronic acid in patients with solid tumors other than breast and castrate-resistant prostate cancer with bone metastasis and multiple myeloma.
- It was noninferior to zoledronic acid.
- Median time to SRE was similar to both groups.
- Trial 3 evaluated XGEVA and zolendronic acid in patients with castrate-resistant and bone metastasis.
- The result showed XGEVA was significantly increased median time to Skeletal-related events (SRE) compared to zolendronic acid (20.7 mons vs 17.1 mons)
- It was noninferior to zoledronic acid