AmgenAmgen (Nasdaq: AMGN) announced the publication of results from a Phase 3 head-to-head trial that compared XGEVA(TM) (denosumab) to Zometa(R) (zoledronic acid) in preventing bone complications called skeletal-related events (SREs) in 1,901 men with prostate cancer and bone metastases. The study, published in The Lancet, met its primary and secondary endpoints and demonstrated XGEVA's superiority compared to Zometa in preventing SREs.

XGEVA was approved by the U.S. Food and Drug Administration (FDA) on Nov. 18, 2010 for the prevention of SREs in patients with bone metastases from solid tumors, including prostate cancer. XGEVA is not indicated for the prevention of SREs in patients with multiple myeloma. XGEVA, the first and only FDA-approved RANK Ligand inhibitor, is the first new treatment for advanced cancer patients with bone metastases in nearly a decade.

"Bone metastases represent a significant risk for advanced prostate cancer patients due to the potential for serious bone complications such as fracture and spinal cord compression," said Karim Fizazi, M.D., Ph.D., head of the department of Medical Oncology, Institut Gustave-Roussy, Villejuif, France. "The results of this study show that XGEVA prevents these serious bone complications more effectively than Zometa without the requirement of intravenous infusion and without the need for dose adjustment for renal function. XGEVA represents an important new treatment option for advanced prostate cancer patients with bone metastases."

Bone metastases, the spread of cancer to the bones, are a serious concern for patients with advanced cancer and present a considerable burden to the healthcare system. Weakened bones due to metastases can lead to fractures and compression of the spinal cord and necessitate procedures including major surgery and radiation, designed to prevent or manage these bone complications. The primary goal of treatment for bone metastases is to prevent the occurrence of debilitating and costly bone complications, which can disrupt a patient's life and cause disability, pain and hospitalization.

XGEVA is a fully human monoclonal antibody that binds to RANK Ligand, a protein essential for the formation, function and survival of osteoclasts (the cells that break down bone). XGEVA prevents RANK Ligand from activating its receptor, RANK on the surface of osteoclasts, thereby decreasing bone destruction.

This study is one of three pivotal Phase 3 head-to-head trials comparing XGEVA to Zometa. In total, these studies, which formed the basis of the FDA's approval, enrolled over 5,700 patients with advanced cancer.

Study Results
An SRE consists of any of the following: fracture, radiation to bone, surgery to bone or spinal cord compression. All can be serious complications for advanced cancer patients. In this study, XGEVA was superior to Zometa in significantly delaying the time to first on-study SRE (hazard ratio 0.82, 95 percent CI: 0.71, 0.95; P = 0.008) with a median time to first on-study SRE of 20.7 months versus 17.1 months for Zometa. XGEVA was also superior to Zometa in significantly delaying the development of multiple SREs (time to first and subsequent on-study SRE) (hazard ratio 0.82, 95 percent CI: 0.71, 0.94; P = 0.008).

Overall rates of adverse events (AEs) and serious adverse events were generally similar between the two arms. Osteonecrosis of the jaw (ONJ) was infrequent, 22 patients receiving XGEVA (2 percent), as compared with 12 patients receiving Zometa (1 percent); the incidence of ONJ was not significantly different between treatment arms (P = 0.09). As with previous studies in advanced cancer patients, hypocalcemia was more frequent in the XGEVA arm. Overall survival and progression-free survival were similar between treatment arms. The most common AEs for XGEVA were anemia, back pain, and nausea, and the most common AEs for Zometa were anemia, back pain, and decreased appetite.

Study Design
Study "103" is an international, Phase 3, randomized, double-blind study comparing XGEVA with Zometa in the treatment of bone metastases in patients with advanced prostate cancer to prevent SREs. Patients enrolled in the study were randomized in a one-to-one ratio to receive either 120 mg of XGEVA subcutaneously every four weeks (Q4W) or Zometa administered intravenously at a dose of 4 mg in a 15 minute infusion every four weeks adjusted for renal function as per the Zometa label instructions. The study consisted of 1,901 patients with a median age of 71, who had bone metastases from castration resistant prostate cancer. The primary endpoint was time to first on-study SRE.

XGEVA Important Safety Information
XGEVA can cause severe hypocalcemia. Correct pre-existing hypocalcemia prior to XGEVA treatment. Monitor calcium levels and administer calcium, magnesium, and vitamin D as necessary. Advise patients to contact a healthcare professional for symptoms of hypocalcemia.

ONJ can occur in patients receiving XGEVA. Patients who are suspected of having or who develop ONJ while on XGEVA should receive care by a dentist or an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition.

The most common adverse reactions in patients receiving XGEVA were fatigue/asthenia, hypophosphatemia, and nausea. The most common serious adverse reaction in patients receiving XGEVA was dyspnea. The most common adverse reactions resulting in discontinuation of XGEVA were osteonecrosis and hypocalcemia.

Denosumab is also marketed as Prolia(R) in other indications.

XGEVA Skeletal-Related Events Regulatory Status
XGEVA was approved by the FDA for the prevention of SREs in patients with bone metastases from solid tumors on Nov. 18, 2010. XGEVA is not indicated to prevent SREs in patients with multiple myeloma.

Administered as a single 120 mg subcutaneous injection every four weeks, XGEVA provides a new option for urologists and oncologists to prevent serious bone complications in men with prostate cancer.

Amgen has also submitted marketing applications for XGEVA in the European Union, Australia, Canada and Switzerland. In Japan, Amgen is working with its licensing partner, Daiichi-Sankyo Company, Limited and a marketing application was submitted.

Bone Metastases and Skeletal Related Events: Prevalence and Impact
Bone metastases occur in more than 1.5 million patients with cancer worldwide and are most commonly associated with cancers of the prostate, lung, and breast, with incidence rates as high as 75 percent of patients with metastatic disease.(1)

Approximately 50-70 percent of cancer patients with bone metastases will experience debilitating SREs.(2-4) Events considered to be SREs include fractures, spinal cord compression, and severe bone pain that may require surgery or radiation.(5) Such events can profoundly disrupt a patient's life and can cause disability and pain.(6-8)

Denosumab and Amgen's Research in Bone Biology
The denosumab development program demonstrates Amgen's commitment to researching and delivering pioneering medicines to patients with unmet medical needs. Amgen is studying denosumab in numerous tumor types across the spectrum of cancer-related bone diseases. Over 11,000 patients have been enrolled in the denosumab oncology clinical trials. In addition to this newly approved indication, XGEVA is also being investigated for its potential to delay bone metastases in prostate and breast cancer.

About Amgen
Amgen discovers, develops, manufactures, and delivers innovative human therapeutics. A biotechnology pioneer since 1980, Amgen was one of the first companies to realize the new science's promise by bringing safe, effective medicines from lab to manufacturing plant to patient. Amgen therapeutics have changed the practice of medicine, helping millions of people around the world in the fight against cancer, kidney disease, rheumatoid arthritis, bone disease, and other serious illnesses. With a deep and broad pipeline of potential new medicines, Amgen remains committed to advancing science to dramatically improve people's lives.

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