Denosumab Trial met Primary and all Secondary Endpoints

AmgenAmgen (Nasdaq: AMGN) has announced that a pivotal, Phase 3, head-to-head trial evaluating denosumab versus Zometa(R) (zoledronic acid) in the treatment of bone metastases in 1,901 men with advanced prostate cancer met its primary and secondary endpoints. Denosumab demonstrated superiority over Zometa for both delaying the time to the first on-study skeletal related event (SRE) (fracture, radiation to bone, surgery to bone or spinal cord compression) (hazard ratio 0.82, 95 percent CI: 0.71, 0.95), and reducing the rate of multiple SREs (hazard ratio 0.82, 95 percent CI: 0.71, 0.94). Both results were statistically significant.

Overall rates of adverse events and serious adverse events, including infections, were generally similar between the two arms. Osteonecrosis of the jaw was infrequent (22 patients receiving denosumab as compared with 12 patients receiving Zometa) and there was no statistically significant difference between treatment arms. As with previous studies in advanced cancer patients, hypocalcemia was more frequent in the denosumab arm. Both overall survival and the time to cancer progression were balanced between treatment arms.

"These Phase 3 results demonstrate the ability of denosumab to delay bony complications in patients suffering from metastatic prostate cancer," said Roger M. Perlmutter, M.D., Ph.D., executive vice president of Research and Development at Amgen. "Denosumab has shown remarkable consistency in reducing the serious complications of bone metastases. Today's results greatly enhance our understanding of the efficacy of denosumab in multiple different tumor types."

This study is the final of three pivotal trials in a total of over 5,700 advanced cancer patients investigating the potential of denosumab to treat bone metastases. Results from the previous two trials were presented in September 2009. These three studies will form the basis of the clinical evidence package for denosumab in advanced cancer, which will be submitted to regulatory authorities later this year.

Full efficacy and safety data for the prostate cancer study will be submitted to the American Society for Clinical Oncology, for possible presentation at their meeting in early June. Additionally, results are expected in the second half of the year from a study investigating whether denosumab may prolong bone metastasis-free survival in prostate cancer patients.

Study Design
This study was an international, Phase 3, randomized, double-blind study comparing denosumab with Zometa in the treatment of bone metastases in patients with advanced prostate cancer. Patients enrolled in the study were randomized in a one-to-one ratio to receive either 120 mg of denosumab subcutaneously every four weeks (Q4W) or Zometa administered intravenously as at least a 15 minute infusion at a dose of 4 mg every four weeks as per the labeled instructions. The study consisted of 1,901 patients, mean age of 71, who have bone metastases from hormone-refractory prostate cancer.

In clinical trials testing new medications for bone metastases, treatment success has been measured by whether the bone complications, or SREs, caused by the bone metastases are reduced or delayed. The primary and secondary endpoints of the denosumab bone metastases studies use a composite endpoint of four SREs - fracture, radiation to bone, surgery to bone, and spinal cord compression - to measure the effectiveness of denosumab versus Zometa.

The primary endpoint was to evaluate if denosumab is non-inferior to Zometa with respect to the first on-study SRE in patients with advanced prostate cancer and bone metastases. Secondary endpoints were to evaluate if denosumab was superior to Zometa with respect to the first on-study SRE, as well as first-and-subsequent on-study SREs, and to assess the safety and tolerability of denosumab compared with Zometa.

About Denosumab and Amgen's Research in Bone Biology
Denosumab is the first fully human monoclonal antibody in late stage clinical development that specifically targets RANK Ligand, the essential regulator of osteoclasts (the cells that break down bone). With more than 19,000 patients in trials across indications worldwide, the denosumab development program is the largest ever initiated by Amgen. This broad and deep 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 induced bone disease. Over 11,000 patients have been enrolled in the denosumab oncology clinical trials testing the drug for bone loss and destruction associated with cancer treatment-induced bone loss in breast and prostate cancers, for the prevention of skeletal related events due to the spread of cancer to the bone in multiple myeloma and multiple solid tumors, and for its potential to delay bone metastases in prostate cancer.

Bone Metastases: Impact and Prevalence
Bone metastases, cancer cells that separate from tumors and migrate to bone tissue where they settle and grow, occur in more than 1.5 million people worldwide.(1) With improvements in cancer care, including earlier diagnosis and new treatment options, leading to increases in survival rates(2), the number of patients developing metastatic disease secondary to a primary cancer is increasing. Bone metastases are a significant problem for patients with certain types of advanced cancer, with incidence rates of nearly 100 percent in myeloma patients and as high as 75 percent in breast and prostate cancer patients.

With bone metastases the growing cancer cells weaken and destroy the bone around the tumor. The damage the tumor has caused to the bone can result in a number of serious complications, collectively called SREs. All are serious complications for advanced cancer patients.

The economic burden of U.S. patients with bone metastases is significant and is estimated to be $12.6 billion annually.(3) Patients with bone metastases who experience an SRE incur significantly higher medical costs compared with those who do not experience an SRE.(4)

Bone Metastases in Prostate Cancer
Nearly 50 percent of castrate-resistant patients with prostate cancer who are not treated for bone metastases experience an SRE, suffering intractable pain and functional impairment.(5,6) SREs pose significant incremental healthcare costs for patients and for the system. Patients with cancer pain are among the most difficult to treat and require much time and effort from physicians and their healthcare team.(7)

About Amgen
Amgen discovers, develops 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 and 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, 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. To learn more about our pioneering science and our vital medicines, visit www.amgen.com.

(1) Capanna R, Coia LR, Coleman R. et al. eds. Textbook of Bone Metastases. Hoboken, NJ: Edition: John Wiley and Sons; 2005:105.
(2) Mundy GR. Metastasis to bone: causes, consequences and therapeutic opportunities. Nat Rev Cancer. 2002 Aug;2(8):584-93.
(3) Schulman K and Kohles J. Cancer. 2007;109:2334-2342.
(4) GVD/Barber ISPOR 2008 Poster; Schulman 2007; Delea et al. 2006.
(5) Saad F, et al. Long-term efficacy of zoledronic acid for prevention of skeletal complications in patients with metastatic hormone-refractory prostate cancer. J Nat Cancer Inst. 2004; 96(11):879-882.
(6) Coleman RE. Metastatic bone disease: Clinical features, pathophysiology and treatment strategies. Cancer Treat Rev. 2001: 27:165-176.
(7) Podnos YD, Borneman TR, Koczywas M, Uman G, Ferrell BR. Symptom concerns and resource utilization in patients with lung cancer. J Pall Med 2007;10(4):899-903.

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