Amgen announced detailed results from a phase 3 trial evaluating denosumab administered subcutaneously versus Zometa (zoledronic acid) administered as an intravenous infusion in the treatment of bone metastases in 1,776 advanced cancer patients with solid tumours (not including breast and prostate cancer) or multiple myeloma. These results were presented at the 2009 ECCO 15 - ESMO 34 European Multidisciplinary Congress in Berlin, Germany (Abstract Number: 20LBA).

For the primary endpoint of this study, the median time to first on-study skeletal related event (SRE) (fracture, radiation to bone, surgery to bone, or spinal cord compression) was 20.6 months for those patients receiving denosumab and 16.3 months for those patients receiving Zometa (hazard ratio 0.84, 95 percent CI: 0.71-0.98), which is statistically significant for non-inferiority (p=0.0007). Although numerically greater, the delay in the time to first SRE associated with denosumab was not statistically superior compared to Zometa based upon the statistical testing strategy (adjusted p=0.06) (secondary endpoint). The time to first-and-subsequent SRE was also numerically greater but not statistically superior compared to Zometa (hazard ratio 0.90, 95 per cent CI: 0.77-1.04, p=0.14) (secondary endpoint).

"It is encouraging to see denosumab's efficacy in this broad cancer population. There is no need for renal monitoring or dose adjustments due to renal impairment," said David Henry, M.D., clinical professor of Medicine, Pennsylvania Hospital, Philadelphia, PA, United States of America. "Furthermore, the positive results of this study, combined with the convenience of a monthly subcutaneous injection and without the flu-like symptoms associated with Zometa administration, make this an exciting potential treatment option for advanced cancer patients."

Bone metastases, the spread of tumours to the bone, are a serious concern for many advanced cancer patients. When cancer spreads to the bone, the growing cancer cells weaken and destroy the bone around the tumour. This damage can result in a number of serious bone complications, collectively called skeletal related events.

Denosumab also delayed the median time to first on-study SRE or hypocalcaemia of malignancy (HCM) compared to Zometa (hazard ratio 0.83, 95 percent CI: 0.71, 0.97; p=0.02). The median time to first on-study SRE or HCM was 19.0 months for denosumab and 14.4 months for Zometa.

Bone destruction is a major cause of pain in approximately 70 per cent of patients with metastatic disease. In an exploratory analysis, patients on the denosumab arm reported worsening of pain later than those on the Zometa arm (57 days versus 36 days, respectively).

Adverse events rates (96 per cent denosumab, 96 per cent Zometa) and serious adverse events (63 per cent denosumab, 66 per cent Zometa) were similar between groups and were consistent with what has previously been reported for these two agents. Rates of osteonecrosis of the jaw (ONJ) were balanced and infrequent in both treatment groups (10 patients receiving denosumab as compared with 11 patients receiving Zometa). Infectious adverse events were balanced between the two treatment arms, as was overall survival (hazard ratio 0.95, 95 per cent CI: 0.83-1.08; p=0.43) and the time to cancer progression (hazard ratio 1.00, 95 per cent CI: 0.89, 1.12; p=1.0).

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 tumour 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 tumours, and for its potential to delay bone metastases in prostate cancer.

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