The U.S. Food and Drug Administration (FDA) has invited Amgen to participate in a meeting of the Oncologic Drugs Advisory Committee (ODAC) on Feb. 8, 2012 to discuss the supplemental Biologics License Application (sBLA) for denosumab (XGEVA?) to treat men with castration-resistant prostate cancer (CRPC) at high risk of developing bone metastases.

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 90% of patients with metastatic disease. [1] [2] [3] [4]

Approximately 50-70% of cancer patients with bone metastases will experience debilitating SREs.[5] [6] [7] Events considered to be SREs include fractures, spinal cord compression, and severe bone pain that may require surgery or radiation. [8] Such events can profoundly disrupt a patient’s life and can cause disability and pain.[9][10] [11]

Denosumab 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). The drug prevents RANK Ligand from activating its receptor, RANK, on the surface of osteoclasts, thereby decreasing bone destruction.

Denosumab is the first and only RANK Ligand inhibitor approved by the FDA indicated for the prevention of skeletal-related events (SREs) in patients with bone metastases from solid tumors. The drug was initially approved following a six month priority review by the FDA.

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To date, denosumab has been studied in over 7,000 patients with cancer. In clinical trials, the drug demonstrated a clinically meaningful improvement compared to the previous standard of care in preventing bone complications.

While not not indicated for the prevention of SREs in patients with multiple myeloma, denosumab has been approved for the prevention of SREs in patients with bone metastases from solid tumors. It the first novel bone metastases treatment for advanced cancer patients in nearly a decade. Delivered as an every four week 120 mg subcutaneous injection, it provides a unique option for urologists and oncologists to prevent SREs in patients with bone metastases from solid tumors.

Ongoing research and development program
Denosumab is also being investigated for the potential use to delay the onset of bone metastasis in adjuvant breast cancer.

Development program
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 the prevention of SREs, XGEVA is also being evaluated for its potential to delay bone metastases in adjuvant breast cancer.

FDA committee review meeting
The advisory committee will review results from clinical studies in support of this new indication, including the pivotal ‘147 trial, a randomized, placebo-controlled, multi-center Phase III study that compared denosumab to placebo in prolonging bone metastasis-free survival in men with non-metastatic CRPC who were at high risk for bone metastases based on prostate specific antigen criteria.

A spokesperson for Amgen said that the company plans to discuss the proposed sBLA with the FDA committee to support the use of denosumab in the treatment of men with non-metastatic CRPC, a patient population for whom there are no approved treatments to delay or prevent the spread of cancer to bone.

Second Indication
The sBLA was submitted on June 27, 2011, and a Prescription Drug User Fee Act action date has been scheduled for April 26, 2012. If approved, this will be the second indication for denosumab in the United States (U.S.).

For more information:
[1] Tannock IF, Wit R, Berry WR, Horti J, Pluzanska A, Chi K, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004;351(15):1502-12.
[2] Petrylak DP, Tangen CM, Hussain MH, Lara PN, Jones JA, Taplin ME, et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med. 2004;351(15):1513-1520.
[3] Prostate cancer clinical trial end points: ”RECIST”ing a step backwards. American Association for Cancer Research website. Accessed on February 16, 2011.
[4] Coleman RE. Skeletal complications of malignancy. Cancer. 1997; 80(suppl): 1588-1594.
[5] Lipton A, Theriault RL, Hortobagyi GN. Pamidronate prevents skeletal complications and is effective palliative treatment in women with breast carcinoma and osteolytic bone metastases. Cancer. 2000;88:1082-1090.
[6] Saad F, Lipton A, Cook R, Chen YM, Smith M, Coleman R. Pathologic fractures correlated with reduced survival in patients with malignant bone disease. Cancer. 2007;110:1860-1867.
[7] Rosen LS, Gordon D, Tchekmedyian NS, et al. Nonsmall cell lung carcinoma and other solid tumors. Cancer. 2004;100:2613-2621.
[8] Costa L, Badia X, Chow E, Lipton A, Wardley A. Impact of skeletal complications on patients’ quality of life, mobility, and functional independence. Support Care Cancer. 2008; 16: 879-889.
[9] Norgaard M, Jensen AO, Jacobsen JB, Cetin K, Fryzek JP, Sorensen HT. Skeletal related events, bone metastasis and survival of prostate cancer: a population based cohort study in Denmark (1999 to 2007).J Urol. 2010; 184:162-167.

[10] Johnell O, Kanis JA. An estimate of the worldwide prevalence and disability associated with osteoporotic fractures. Osteoporos In.t 2006;17:1726?1733.
[11] Saad F, Gleason DM, Murray R, et al. A Randomized, Placebo-Controlled Trial of Zoledronic Acid in Patients With Hormone-Refractory MetastaticProstate Carcinoma. Journal Ntl Cancer Inst. 2002;19:1458-1468.

Also read:
Study Finds Denosumab Noninferior to Zoledronic Acid in Delaying or Preventing Skeletal-related Events in Patients with Solid Tumors or Multiple Myeloma
Denosumab Demonstrates Superiority Compared to Zoledronic Acid in the Prevention of Bone Complications for Men With Bone Metastases From Advanced Prostate Cancer
Denosumab Superior to Zoledronic Acid in Reducing Incidence of Skeletal-Related Events in Breast Cancer Patients with Bone Metastases
Denosumab Significantly Improves Bone Metastasis-Free Survival in Men With Prostate Cancer.

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