Denosumab Demonstrates Superiority Over Zometa(R)

AmgenAmgen (Nasdaq: AMGN) today announced detailed results from a Phase 3, head-to-head trial evaluating denosumab versus Zometa(R) (zoledronic acid) in the treatment of bone metastases in 2,046 patients with advanced breast cancer that met its primary and secondary endpoints and demonstrated superior efficacy compared to Zometa. These results were presented today during the Presidential Session at the 2009 ECCO 15 - ESMO 34 European Multidisciplinary Congress in Berlin, Germany (Abstract Number 2LBA).

Denosumab administered subcutaneously demonstrated superiority for both delaying the time to the first on-study skeletal related events (SREs) (fracture, radiation to bone, surgery to bone, or spinal cord compression) (hazard ratio 0.82, 95 percent CI: 0.71, 0.95), and delaying the time to first-and-subsequent SREs (hazard ratio 0.77, 95 percent CI:0.66, 0.89). Both results were statistically significant in this 34 month study. The median time to first on-study SRE was not reached for denosumab and therefore could not be estimated. The median time to first on-study SRE was 26.5 months for Zometa, the current standard of care.

"Up to 80 percent of patients with advanced breast cancer will develop bone metastases that are often associated with severe and painful bone complications, which are a serious concern for both patients and physicians," said Alison Stopeck, M.D., associate professor of Medicine, Arizona Cancer Center, University of Arizona Health Sciences Center, Tucson, AZ, United States of America. "Denosumab was superior to Zometa in preventing skeletal related events and delayed worsening of bone pain. In addition, denosumab also presented some potential tolerability advantages for many patients, including a lower incidence of renal toxicity and acute phase reactions, combined with the convenience of a monthly subcutaneous injection. Denosumab would be a welcome new treatment option for advanced breast cancer patients."

Denosumab also delayed the median time to first on-study SRE or hypercalcemia of malignancy (HCM) compared to Zometa (hazard ratio 0.82, 95 percent CI: 0.70, 0.95; p=0.007). The median time to first on-study SRE or HCM was not reached for denosumab and therefore could not be estimated. The median time to first on-study SRE or HCM was 25.2 months for Zometa.

Bone pain can dominate the daily lives of patients with metastatic disease involving bone and is often characterized as severe or intolerable.(1) In a pre-specified exploratory analysis, patients on the denosumab arm reported worsening of pain later than those on the Zometa arm (88 days versus 64 days, respectively; hazard ratio 0.87, 95 percent CI: 0.79, 0.97; p=0.009).

Overall, the incidence of adverse events (96 percent denosumab, 97 percent Zometa) and serious adverse events (44 percent denosumab, 46 percent Zometa) was consistent with what has previously been reported for these two agents. Adverse events potentially associated with renal toxicity occurred in 4.9 percent of patients treated with denosumab compared to 8.5 percent in patients treated with Zometa. Osteonecrosis of the jaw (ONJ) was seen infrequently in both treatment groups (20 patients receiving denosumab (2.0 percent) as compared with 14 patients (1.4 percent) receiving Zometa). There was no statistically significant difference in the rate of ONJ between the two treatment arms. Overall survival (hazard ratio 0.95, 95 percent CI: 0.81, 1.11; p=0.50) and time to cancer progression (hazard ratio 0.99, 95 percent CI: 0.89, 1.11; p=0.90) was balanced between treatment arms.

Detailed data from another Phase 3, head-to-head trial evaluating denosumab versus Zometa was presented yesterday (Abstract #20LBA). In this study of 1,776 advanced cancer patients with solid tumors (not including breast and prostate cancer) or multiple myeloma, denosumab met its primary endpoint and demonstrated non-inferiority compared to Zometa in the treatment of bone metastases.

Webcast Information
An analyst/investor event will also be held from the Congress on September 24th, at 6:30 a.m. Eastern Time to discuss data presented at ECCO-ESMO. A webcast of the event can be found on Amgen's Web site at www.amgen.com, under Investors. The audio webcast will be archived and available for replay for at least 72 hours.

Study Design
This was an international, Phase 3, randomized, double-blind study comparing denosumab with Zometa in the treatment of bone metastases in patients with advanced breast 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 at a dose of 4 mg in a 15 minute infusion every four weeks as per the label instructions.

In clinical trials testing new medications for bone metastases, treatment success has been measured by whether the bone complications, or SREs, caused by the tumor are reduced or delayed. The primary and secondary endpoints of the denosumab bone metastases studies use a composite endpoint of four SREs - fracture, the need for radiation to bone, the need for bone surgery, 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 breast 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 the 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 the reduction of SREs in breast cancer patients, for the amelioration of treatment-induced bone loss in patients with breast or prostate cancers, for the prevention of SREs due to the spread of cancer to the bone in patients with multiple myeloma or those suffering from a variety of 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.(2) With improvements in cancer care, including earlier diagnosis and new treatment options, leading to increases in survival rates(3), 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. These include fracture of a bone, the need for radiation to bone, the need for bone surgery, or spinal cord compression. All are serious complications for advanced cancer patients.

The economic burden of United States (U.S.) patients with bone metastases is significant and was estimated to be $12.6 billion last year.(4) Patients with bone metastases who experience an SRE incur significantly higher medical costs compared with those who do not experience an SRE.(5)

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) Diel IJ. Effectiveness of bisphosphonates on bone pain and quality of life in breast cancer patients with metastatic bone disease: A review. Support Care Cancer. 2007: 15:1243-1249.
(2) Coleman, R. Potential use of bisphosphonates in the prevention of metastases in early-stage breast cancer. Clin Breast Cancer. 2007; 7(Suppl 1):S29-35. 2Coleman RE. Metastatic bone disease: clinical features, pathophysiology and treatment strategies. Cancer Treat Rev. 2001;27:165-76.
(3) Capanna R, Coia LR, Coleman R. et al. eds. Textbook of Bone Metastases. Hoboken, NJ: Edition: John Wiley and Sons; 2005:105.
(4) Mundy GR. Metastasis to bone: causes, consequences and therapeutic opportunities. Nat Rev Cancer. 2002 Aug;2(8):584-93.
(5) Schulman K and Kohles J. Cancer. 2007;109:2334-2342
(6) GVD/Barber ISPOR 2008 Poster; Schulman 2007; Delea et al. 2006

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