Earlier today, Bayer HealthCareannounced that it had submitted a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) seeking approval for the antineoplastic radium Ra 223 dichloride (radium-223), an investigational compound for the treatment of castration-resistant prostate cancer (CRPC) patients with bone metastases.

Radium Ra 223 dichloride (radium-223), formerly referred to as radium-223 chloride, is an investigational alpha particle emitting pharmaceutical in development for CRPC patients with bone metastases. It isan isotope of radium and chemically identical to natural radium-226 that is common, in small amounts, to most rocks and soils in the earth.

Research has shown that based on theshort physical half-life of radium-223 and its short-lived cascade of four alpha-emitting daughter products, the isotopeis useful intreating bone cancer metastases in the skeleton that result from advanced prostate cancer. Furthermore, a study by Henriksen et al. has shown that radium-223 may be more effective in a cancer treatment setting than other bone-pain-palliation agents because the alpha particles are highly efficient in cell-killing. In contrast to beta-emitting radionuclides, the alpha particles from radium-223 and daughters do not completely traverse marrow space, leading to a comparative reduction in marrow toxicity.[1] Radium-223 may also have exciting new applications in radioimmunotherapy of cancer.

Radiological evidence
Prostate cancer is the most common cancer among men in the United States (other than skin cancer).[2] Approximately 16% of prostate cancer cases are considered regional or distant, which means that the cancer has spread beyond the prostate to nearby or distant areas of the body (metastasis).[3] A majority of men with CRPC have radiological evidence of bone metastases.[4] Bone metastases secondary to prostate cancer typically target the lumbar spine, vertebrae and pelvis.[5] In fact, bone metastases are the main cause of morbidity and death in patients with CRPC.[6]

Key role in treatment
“If approved, radium-223 has the potential to play a key role in the treatment of men with CRPC that has metastasized to the bone,” said Pamela A. Cyrus, MD, Vice President and Head of U.S. Medical Affairs, Bayer HealthCare Pharmaceuticals. “The development of a compound like radium-223 is an example of Bayer’s commitment to investing in approaches to treat hard-to-treat cancers.”

Radium-223 was granted fast track designation by the FDA. The fast track process is designed to facilitate the development and expedited review of drugs to treat serious diseases and fill an unmet medical need. Fast track designation must be requested by the drug company and can be initiated at any time during the drug development process.

Clinical trial
The submission was based on data from theALSYMPCA (ALpharadin in SYMptomatic Prostate CAncer) trial, a Phase III, randomized, double-blind, placebo-controlled international study of radium-223 with BSC vs. placebo with BSC in symptomatic CRPC patients with bone metastases. The trial enrolled 921 patients in more than 100 centers in 19 countries. The study treatment consisted of up to six intravenous administrations of radium-223 or placebo each separated by an interval of four weeks.

The primary endpoint of the study was overall survival. Secondary endpoints included time to occurrence of skeletal-related events (SRE), time to total alkaline phosphatase (ALP) and prostate-specific antigen (PSA) progression, total ALP response and normalization, safety, and quality of life.

In September 2009, Bayer signed an agreement with Algeta ASA(Oslo, Norway) for the development and commercialization of radium-223. Under the terms of the agreement, Bayer will develop, apply for health authority approvals worldwide, and commercialize radium-223 globally. Algeta will co-promote radium-223 with Bayer in the US.

Radium-223 is an investigational agent and is not approved by the FDA, the European Medicines Agency (EMA), or other health authorities.

References
[1] Henriksen G., Fisher D.R., Roeske J.C., Bruland ?.S., and Larsen R.H. Targeting of Osseous Sites with Alpha Emitting 223Ra: Comparison with the Beta Emitter 89Sr in Mice. J. Nucl. Med. 44: 252-259; 2003.
2] American Cancer Society. Prostate Cancer: Detailed Guide. Last accessed October 26, 2012.
3] National Cancer Institute, Surveillance Epidemiology and End Results (SEER). SEER Stat Facts: Prostate; Survival & Stage, 2002-2008.
[4] Sartor, O. Radiopharmaceutical and chemotherapy combinations in metastatic castrate-resistant prostate cancer: a new beginning. JCO. 2009;15:2417-2418.
[5] Bone and Cancer Foundation. Questions & Answers about Prostate Cancer Bone Metastasesand Treatment-Related Osteoporosis. Last accessed May 17, 2012.
6] Lange PH, Vasella RL. Mechanisms, hypotheses and questions regarding prostate cancer metastatic to bone. Cancer & Metastasis Reviews.1999;17:331-336.

Clinical trials
NCT00699751– A Phase III Study of Radium-223 Dichloride in Patients With Symptomatic Hormone Refractory Prostate Cancer With Skeletal Metastases (ALSYMPCA)

Photo: Bone tumors can develop whenprostate cancer spread to the skeleton (imaged as dark spots). Radium-223 helps treat these tumors and relieve the intense pain that they cause. Courtesy: Pacific Northwest National Laboratory

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