REGULATORY HISTORY of ZOMETA and AREDIA JAW OSTEONECROSIS (ONJ) Oncologic Drug Advisory Committee March 4, 2005 Nancy S. Scher, M.D.

Aredia: Approved Indications Treatment of patients with osteolytic bone metastases of breast cancer and osteolytic lesions of multiple myeloma in conjunction with standard antineoplastic therapy Hypercalcemia of malignancy Paget’s Disease of bone

Aredia: Approval Dates 1991 Hypercalcemia of malignancy 1995 Osteolytic lesions of multiple myeloma 1996 Osteolytic bone metastases of breast cancer

Skeletal Related Events (SRE): A Composite Endpoint Pathologic fractures Radiation therapy to bone Surgery to bone Spinal cord compression

Aredia: Randomized Trials 1 Multiple Myeloma Multiple myeloma indication based on single double-blind, randomized, placebo-controlled trial, n=392, Aredia 90 mg monthly IV x 9 months Proportion with SRE: A=24%, P=41% (p<0.001) Time to first SRE: A>P (p=0.001)

Aredia: Randomized Trials 2 Breast Cancer Two double-blind, randomized, placebo- controlled trials in breast cancer Aredia 90 mg IV q3-4 weeks x 24 months Patients with ≥1 osteolytic lesion and receiving concomitant hormonal (n=372) or chemotherapy (n=382) Aredia superior to placebo for SRE endpoints

Zometa: Approved Indications Treatment of patients with multiple myeloma and patients with documented bone metastases from solid tumors, in conjunction with standard antineoplastic therapy. Prostate cancer should have progressed after treatment with at least one hormonal therapy. Hypercalcemia of malignancy

Zometa: Approval Dates August 2001 –Hypercalcemia of malignancy February 2002 –Patients with multiple myeloma and bone metastases from solid tumors, in conjunction with standard antineoplastic therapy.

Expanded Bone Metastasis Indications for Zometa Multiple myeloma and bone metastases of solid tumors, not limited to breast cancer Lesion type not limited to osteolytic Optimal duration of therapy not defined

Zometa: Randomized Trials 1 Oncology indication based on 3 randomized studies Multiple myeloma or metastatic breast cancer; Zometa 4 mg vs. Aredia 90 mg q3-4 weeks Metastatic prostate cancer; placebo control Metastatic solid tumors other than breast or prostate cancer; placebo control Primary endpoints: - Time to first SRE - Proportion of patients with SRE

Zometa: Randomized Trials 2 Patient PopulationNumber of Patients Median Duration Therapy Control MM/Breast Cancer months Aredia 90 mg Prostate Cancer months Placebo Other Solid Tumors months Placebo

Zometa: Randomized Trials 3 Time to First SRE StudyStudy Arm (No. Patients) Median (days) Hazard Ratio (95% CI) P-value Prostate Cancer Zometa 4 mg (n = 214) Placebo (n=208) NR (0.49, 0.91)0.011 Solid Tumors Zometa 4 mg (n = 257) Placebo (n=250) (0.55, 0.96)0.023 MM/Breast Cancer Zometa 4 mg (n=561) Aredia 90 mg (n=565) (0.77, 1.09)0.32

Number of ONJ Spontaneous Reports to FDA by Year 2001 –0 (1 femoral head) 2002 –9 cases 2003 –60 cases 2004 (May) –69 cases

Literature Reports of ONJ Associated with Bisphosphonates Rosenberg and Ruggiero 8/03 AAOMS: 26 cases Marx 8/03 letter: 36 cases Wang 9/03: 3 cases Migliorati 11/03 letter JCO: 5 cases Ruggiero 5/04: 63 cases Estilo 6/04 ASCO: 13/124 chart review ASH 12/04: Multiple authors

Profile of Patients with ONJ Diagnosis of malignancy No head and neck radiotherapy Treatment regimen included IV bisphosphonates High proportion had recent invasive dental procedure

ONJ Labeling Changes Zometa and Aredia Zometa Adverse Events section updated to include ONJ in September 2003 (Aredia October 2003) Zometa Precautions section updated August 2004 (Aredia August 2004)

Zometa Label: Adverse Events ONJ reported in patients treated with bisphosphonates Majority associated with a dental procedure Multiple risk factors for ONJ (e.g. cancer, chemotherapy, radiotherapy, corticosteroids) Although causality cannot be determined, prudent to avoid dental surgery, as recovery may be prolonged

Zometa Label: PRECAUTIONS ONJ reported in cancer patients receiving treatment regimens including bisphosphonates Many patients were also receiving chemotherapy and corticosteroids Majority of cases associated with dental procedures Many patients had signs of local infection including osteomyelitis Baseline dental exam if risk factors (e.g. cancer, chemotherapy, corticosteroids, poor oral hygiene) While on treatment, avoid invasive dental procedures No data if discontinuing therapy reduces risk of ONJ

Summary Zometa and Aredia are effective drugs for the bone metastasis indication An unusual adverse event has been identified in some patients treated with IV bisphosphonates The true incidence of ONJ is unknown