Denosumab Demonstrated Superiority Over Zometa(R) in Delay of Complications
Due to Bone Metastases in Advanced Prostate Cancer

The Third of Three Pivotal Head-To-Head Trials Submitted To FDA for Treatment of Patients with Bone Metastases

MISSISSAUGA, ON, June 5 /CNW/ - Amgen (NASDAQ: AMGN) today announced detailed results from a Phase 3, head-to-head trial which compared the efficacy and safety of denosumab versus Zometa(R) (zoledronic acid) in 1,901 patients with hormone-refractory prostate cancer and bone metastases. The study met its primary and secondary endpoints and demonstrated denosumab's superiority over Zometa in delaying or preventing skeletal related events (SREs). These statistically significant results will be presented in an oral session on June 6, 2010 at the American Society of Clinical Oncology (ASCO) 2010 Annual Meeting in Chicago (Late Breaking Abstract Number No.LBA4507).

In patients with skeletal metastases, the growing cancer cells weaken and destroy the bone around the tumor. This can result in a number of serious complications, collectively called SREs, comprising fracture, radiation to bone, surgery to bone or spinal cord compression. All can be serious complications for advanced cancer patients.

In this study, denosumab 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. Denosumab 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 = 0.004).

"Bone metastases are debilitating complications of prostate cancer, affecting up to 75 percent of advanced prostate cancer patients," said Karim Fizazi, M.D., Ph.D., Head of the Department of Medical Oncology, Institut Gustave-Roussy, Villejuif, France. "Denosumab showed superior efficacy in preventing skeletal complications, and was generally well tolerated. These results in conjunction with the convenient subcutaneous dosing and without the need for renal monitoring, show that denosumab has the potential to be a meaningful advance over current treatments."

Overall rates of adverse events (AEs) and serious adverse events, including infections, were generally similar between the two arms. Osteonecrosis of the jaw (ONJ) was infrequent (22 patients receiving denosumab (2.3 percent) as compared with 12 patients receiving Zometa (1.3 percent)); the incidence of ONJ was not significantly different between treatment arms. As with previous studies in advanced cancer patients, hypocalcemia was more frequent in the denosumab arm. Both overall survival (hazard ratio 1.03; 95 percent CI: 0.91, 1.17; P=0.65) and the time to cancer progression (hazard ratio 1.06; 95 percent CI: 0.95, 1.18; P=0.30) were balanced between treatment arms. The most common AEs for denosumab were anemia, back pain, and nausea, and the most common AEs for Zometa were anemia, back pain, and decreased appetite.

This study is the final of three pivotal trials involving over 5,700 advanced cancer patients that explored the potential of denosumab to treat bone metastases. These three studies form the basis of the clinical evidence package for denosumab in advanced cancer, and were submitted to regulatory authorities in the United States (U.S.) and in the European Union (EU).

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 had 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 used 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.

Bone Metastases: 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.(i)

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

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). 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-related bone diseases. Over 11,000 patients have been enrolled in the denosumab oncology clinical trials, testing the drug for the reduction of SREs in patients with breast and prostate cancer, as well as other solid tumors and multiple myeloma, for the amelioration of treatment-induced bone loss in patients with non-metastatic breast or prostate cancers, and for its potential to delay bone metastases in prostate cancer.

About Amgen Canada

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 broad and deep 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.ca.

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    REFERENCES
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    (i)   Coleman RE. Skeletal complications of malignancy.Cancer Suppl.1997:
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    (ii)  Schulman K and Kohles J. Cancer. 2007;109:2334-2342.
    (iii) GVD/Barber ISPOR 2008 Poster; Schulman 2007; Delea et al. 2006.
    

For further information: Sabrina Paiva, Amgen Canada Inc., Tel: [phone], E-mail: [email protected]; Naziah Lasi-Tejani, Hill & Knowlton Canada, Tel: [phone], E-mail: [email protected]