Phase 2 Interim Data Show Denosumab Decreased Bone Turnover in Advanced Cancer Patients with Bone Metastases

Amgen (NASDAQ:AMGN), the world's largest biotechnology company,announced interim data from two Phase 2 clinical studies of denosumab,an investigational fully human monoclonal antibody that inhibits RANKLigand. As reported at the 42nd Annual Meeting of the American Societyof Clinical Oncology (ASCO), denosumab treatment resulted in a rapidsuppression of bone turnover among advanced cancer patients with bonemetastases; these results were also sustained at all time pointsmeasured in the study.

Bone metastases are one of the most frequent causes of pain inpeople with cancer and may lead to skeletal-related events (SREs) suchas fractures, the need for bone surgery or radiation, and othercomplications. When tumor cells invade bone, they secrete growthfactors that stimulate RANK Ligand production, promoting increasedbone resorption. RANK Ligand is an essential mediator of theformation, function and survival of osteoclasts, the cells responsiblefor resorbing or breaking down bone.

"By targeting RANK Ligand, denosumab works differently frombisphosphonates because it inhibits osteoclasts at all stages ofdevelopment and activity. As the only investigational RANK Ligandinhibitor in late-stage development, denosumab represents a potentialnew way to treat bone disease," said Allan Lipton, M.D., professor ofMedicine/Oncology at Penn State University, Milton S. Hershey Collegeof Medicine in Hershey, Pa., and an investigator in both studies. "Ourdata show denosumab was clinically active as it reduced levels of abone turnover biomarker in both IV bisphosphonate-naive and -treatedpatients."

Interim results from the ongoing Phase 2 study of 255 IVbisphosphonate-naive breast cancer patients with established bonemetastases, evaluating different doses of denosumab administeredmonthly or every three months, were presented in an oral session thismorning. Urinary N-telopeptide levels, a biomarker for bone turnover,are increased by metastatic bone disease. Researchers reported that atstudy week 13, there was a median decrease in urinary N-telopeptidefor each denosumab treatment cohort ranging from 63 percent to 82percent. Based on the dose responses, the Phase 3 trial will evaluate120 mg dosed monthly. (Abstract #512)

In this study, the most frequent adverse events reported fordenosumab-treated patients were nausea, vomiting, asthenia (weakness),and diarrhea. No binding or neutralizing antibodies were detected. Themost frequent adverse events reported for the IVbisphosphonate-treated patients were pyrexia (infection-inducedfever), arthralgia (joint pain), asthenia, and bone pain.

In an interim analysis of a separate Phase 2 study of 49 prostate,breast, and multiple myeloma patients on established IV bisphosphonatetherapy, twice as many patients achieved normalization of boneturnover when they were switched from IV bisphosphonate therapy todenosumab. Specifically, at week 13, 76 percent of denosumab patients,and 38 percent of patients who remained on the IV bisphosphonate,achieved normal levels of bone turnover. This reduction in boneturnover was also achieved more rapidly (ten days versus 112 days)among the denosumab arm than in the IV bisphosphonate arm. The mediantime to uNTx less than 50 nM BCE / nM Cr was ten days (95 percent CI:9, 11) for the combined denosumab-treated group and 112 days (95percent CI: 16, -) for the IV bisphosphonate-treated group. (Abstract#8562)

In this study, the most frequent adverse events reported fordenosumab-treated patients were nausea, peripheral edema, anemia, andbone pain. For patients receiving IV bisphosphonates the mostfrequently reported adverse events were bone pain, constipation,anemia, back pain, chills, and fatigue. In both trials, both sets ofpatients were also on standard cancer treatments such as chemotherapyand hormone therapy.

About the Phase 2 Study of Bisphosphonate-Naive Patients

The Phase 2 randomized, active-controlled study of denosumab wasdesigned to evaluate dosing options and its effect in decreasing boneturnover in breast cancer patients with bone metastases who had notpreviously received intravenous bisphosphonate therapy. The studyenrolled 255 patients with bone metastases who were receivingconcurrent chemotherapy or hormonal therapy. Patients were randomizedto one of five double-blind denosumab-treated groups (30 mg, 120 mg,or 180 mg monthly; 60 mg or 180 mg every three months) or anopen-label bisphosphonate arm. The primary endpoint was the percentagechange from baseline to week 13 in the level of urinary N-telopeptide.Also evaluated were the percentage of patients with greater than orequal to a 65 percent decrease in urinary N-telopeptide from baseline,time to a 65 percent reduction in urinary N-telopeptide, incidence ofSREs, and safety.

About the Phase 2 Study of Patients on Established IVBisphosphonate Therapy

The Phase 2 randomized, open-label study of denosumab was designedto evaluate its effect in decreasing bone turnover in advanced cancerpatients with bone metastases who had previously received intravenousbisphosphonate therapy. Patients were randomized to one of twodenosumab-treated groups (180 mg monthly or 180 mg every three months)or a bisphosphonate arm. An interim analysis was performed on 49patients completing week 13. The primary endpoint was the percentageof patients with a urinary N-telopeptide less than 50 nM BCE/mMcreatinine at week 13. Also evaluated was the time to a urinaryN-telopeptide level less than 50 nM BCE/mM creatinine, and safety. Atthe time of the analysis, 49 patients were enrolled in the study at amean age range of 62.5 years and the median duration of prior IVbisphosphonate therapy was 5.1 months. Tumors included prostate(n=24), breast (n=20), and other/multiple myeloma (n=5).

About Bone Metastases

Bone metastases are deposits of cancer cells that separate fromtumors, enter the bloodstream or the lymph system, and migrate to bonetissue where they settle and grow. These bone metastases often occurin bones near the center of the body including the spine, ribs,pelvis, hips and shoulders.

More than 10 million people worldwide suffer from bone metastases.Approximately 452,000 people in the United States have cancer withmetastases to the bone.

About Denosumab

Denosumab is an investigational RANK Ligand inhibitor beingstudied for its potential to prevent and treat bone destruction.Denosumab is currently being studied to determine its potential todelay bone metastases as well as inhibit and treat bone destructionacross many stages of cancer. It is also being studied in a range ofother bone loss conditions including treatment-induced bone loss,multiple myeloma, osteoporosis, and rheumatoid arthritis.

Denosumab: Clinical Studies in Cancer

A comprehensive clinical program evaluating denosumab is ongoingincluding: a Phase 3 trial investigating the frequency of SREs inadvanced breast cancer patients; a Phase 3 study in the prevention ofbone metastases in prostate cancer; two Phase 3 studies intreatment-induced bone loss (one in breast cancer patients and anotherin prostate cancer patients); two Phase 2 studies in advanced cancerpatients (one in patients naive to bisphosphonates and one in patientson established IV bisphosphonate therapy); and a Phase 2 study for thetreatment of patients with multiple myeloma.

Denosumab: Additional Clinical Studies

Denosumab is also being studied in a range of bone loss conditionsoutside the oncology setting including osteoporosis and bone erosionsin rheumatoid arthritis. Other ongoing studies include two Phase 3studies (one in prevention and one in treatment) in postmenopausalosteoporosis and a Phase 2 study in the treatment of bone erosions inrheumatoid arthritis.

For more information about ongoing denosumab clinical trials,please visit www.amgentrials.com or www.clinicaltrials.gov.

About Amgen

Amgen discovers, develops and delivers innovative humantherapeutics. A biotechnology pioneer since 1980, Amgen was one of thefirst companies to realize the new science's promise by bringing safeand effective medicines from lab, to manufacturing plant, to patient.Amgen therapeutics have changed the practice of medicine, helpingmillions 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, Amgenremains committed to advancing science to dramatically improvepeople's lives. To learn more about our pioneering science and ourvital medicines, visit www.amgen.com.

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