Metastasis-Free Survival for More Than Four Months

Up to 90 Percent of Men with Advanced Prostate Cancer Will Develop Bone Metastases ^{ii iii iv}

Cambridge, UK (June 2011) – Amgen has announced primary results of a pivotal Phase 3 trial (‘147) demonstrating that denosumab significantly increased bone metastasis-free survival for more than four months in men with castrate-resistant metastaticprostate cancer that has not yet spread to bone. ⁱFull results of the ‘147 study we represented for the first time today in a late-breaking plenary session at the American Urological Association (AUA) 2011 Annual Meeting in Washington, D.C.

The data showed that denosumab significantly improved median bone metastasis freesurvival by 4.2 months, a risk reduction of 15 percent, compared with placebo (29.5versus 25.2 months, respectively; hazard ratio [HR] 0.85; 95 percent CI: 0.73, 0.98;P=0.028)ⁱ. Denosumab also significantly delayed the time to first bone metastases by 3.7 months compared with placebo (HR 0.84; 95 percent CI: 0.71, 0.98; P=0.032; risk reduction of 16 percent). Denosumab also reduced the risk of bone metastases that were symptomatic by 33 percent (HR 0.67; 95 percent CI: 0.49, 0.92; P=0.01). Overall survival was similar between groups (HR 1.01; 95 percent CI: 0.85, 1.20; P=0.91), and the hazard ratio for progression-free survival was 0.89 (95 percent CI: 0.78, 1.02,P=0.093).

"This is an exciting study showing that denosumab could improve survival of castrateresistantprostate cancer patients and prevent the cancer spreading to the bones”, said Freddie Hamdy MD, Nuffield Professor of Surgery at the University of Oxford. “Bonemetastases can cause significant complications for the patients including severe bone pain, fracture and spinal cord compression and are associated with a higher risk of mortality. Denosumab would be a useful addition to therapeutics strategies in managing prostate cancer induced bone disease, and appears to be the first bone-targeted agent which could reduce the risk of developing bone metastases in these patients.”

In the ‘147 trial, adverse events and serious adverse events were relatively similar between the denosumab and placebo arms. ⁱ. Hypocalcaemia and osteonecrosis of the jaw (ONJ) were reported with increased frequencies in the denosumab treated patients. The yearly rate of ONJ in the denosumab arm was similar to prior denosumab trial results. Back pain was the most common adverse event reported in the denosumab arm of the trial.

Study Designⁱ

Study ‘147 was a randomised, placebo-controlled, multi-centre phase 3 study comparing the treatment effect of denosumab to placebo in prolonging bone metastasis free survival - a measure of the time that patients live without progressing to bonemetastases - in 1,432 men with hormone-refractory (castrate-resistant) prostate cancerwith rapidly-rising prostate-specific antigen (PSA) levels who had no bone metastasesat baseline. The primary endpoint of the trial was time to first occurrence of bone metastases or death from any cause with secondary end points including time to first occurrence of bone metastases (excluding death) and overall survival.

About denosumab

Denosumab is the first and only RANK Ligand inhibitor approved by the U.S. Food and Drug Administration (FDA) indicated for the prevention of skeletal-related events (SREs)in patients with bone metastases from solid tumours. Denosumab is not indicated for the prevention of SREs in patients with multiple myeloma. ^v. Denosumab is the first novel bone metastases treatment for advanced cancer patients in nearly a decade.Delivered as an every four week 120 mg subcutaneous injection, denosumab providesa unique option for urologists and oncologists to prevent skeletal-related events inpatients with advanced cancer.

Denosumab is a fully human monoclonal antibody that binds to RANK Ligand, a proteinessential for the formation, function and survival of osteoclasts (the cells that breakdown bone). ^vi. Denosumab prevents RANK Ligand from activating its receptor, RANK,on the surface of osteoclasts, thereby decreasing bone destruction.

Denosumab has been studied in over 7,000 patients with cancer.^{i vii viii ix} In clinical trials,denosumab demonstrated a clinically meaningful improvement compared to the previous standard of care in preventing bone complications. Denosumab is also being investigated for the potential use to delay the onset of bone metastasis in adjuvant breast cancer.

Denosumab Skeletal-Related Events Regulatory Status

Amgen has submitted marketing applications for denosumab in the European Union, Australia, and Switzerland for the prevention of SREs in patients with bone metastasesfrom solid tumours. In Japan, Amgen is working with its licensing partner, Daiichi-Sankyo Company, Limited and a marketing application was submitted.

Denosumab is also marketed as Prolia® ▼ in other indications.^vi

Denosumab Important Safety Informationv

Denosumab can cause severe hypocalcaemia. Correct pre-existing hypocalcaemia priorto denosumab treatment. Monitor calcium levels and administer calcium, magnesium, and vitamin D as necessary. Advise patients to contact a healthcare professional for symptoms of hypocalcaemia.

ONJ can occur in patients receiving denosumab. Patients who are suspected of havingor who develop ONJ while on denosumab should receive care by a dentist or an oralsurgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition.

The most common adverse reactions in patients receiving denosumab were fatigue/asthenia, hypophosphatemia, and nausea. The most common serious adverse reaction in patients receiving denosumab was dyspnea. The most common adverse reactions resulting in discontinuation of denosumab were osteonecrosis and hypocalcaemia.

Bone Metastases and Skeletal-Related Events: 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 90 percent of patients with metastatic disease.^{ii iii iv x}

Approximately 50-70 percent of cancer patients with bone metastases will experience debilitating SREs. ^{xi xii xiii} . Events considered to be SREs include fractures, spinal cord compression and severe bone pain that may require surgery or radiation.^xivSuch events can profoundly disrupt a patient’s life and can cause disability and pain. ^{xv xvi xvii}

Denosumab and Amgen's Research in Bone Biology

The denosumab 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-related bone diseases.