REGULATORY HISTORY of ZOMETA and AREDIA JAW OSTEONECROSIS (ONJ)

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REGULATORY HISTORY of ZOMETA and AREDIA JAW
OSTEONECROSIS (ONJ)

• Oncologic Drug Advisory Committee
• March 4, 2005
• Nancy S. Scher, M.D.

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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
• Pagets Disease of bone

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Aredia Approval Dates

• 1991 Hypercalcemia of malignancy
• 1995 Osteolytic lesions of multiple myeloma
• 1996 Osteolytic bone metastases of breast cancer

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Skeletal Related Events (SRE) A Composite
Endpoint

• Pathologic fractures
• Radiation therapy to bone
• Surgery to bone
• Spinal cord compression

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Aredia Randomized Trials1 Multiple Myeloma

• Multiple myeloma indication based on single
  double-blind, randomized, placebo-controlled
  trial, n392, Aredia 90 mg monthly IV x 9 months
• Proportion with SRE A24, P41 (plt0.001)
• Time to first SRE AgtP (p0.001)

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Aredia Randomized Trials2 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 (n372) or chemotherapy
  (n382)
• Aredia superior to placebo for SRE endpoints

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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

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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.

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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

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Zometa Randomized Trials1

• 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

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Zometa Randomized Trials2
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Zometa Randomized Trials3 Time to First SRE
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Number of ONJ Spontaneous Reports to FDA by Year

• 2001
• 0 (1 femoral head)
• 2002
• 9 cases
• 2003
• 60 cases
• 2004 (May)
• 69 cases

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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

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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

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ONJ Labeling ChangesZometa 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)

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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

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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

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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