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Osteonecrosis of the Jaw (ONJ) and Bisphosphonates. Oncologic Drugs Advisory Committee March 4, 2005 Novartis Pharmaceuticals. Novartis Presentation. ONJ Reported in Bisphosphonate-Treated Patients — An Overview D. Young, MD Novartis Pharmaceuticals Corp

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osteonecrosis of the jaw onj and bisphosphonates

Osteonecrosis of the Jaw (ONJ)and Bisphosphonates

Oncologic Drugs Advisory CommitteeMarch 4, 2005

Novartis Pharmaceuticals

novartis presentation
Novartis Presentation
  • ONJ Reported in Bisphosphonate-Treated Patients — An Overview

D. Young, MD Novartis Pharmaceuticals Corp

  • Clinical Benefit of Bisphosphonates in Cancer Patients With Metastatic Bone Disease

J. Berenson, MD Institute for Myeloma & Bone Cancer Research

external advisors
External Advisors*

* The views expressed by these individuals are their own and not necessarily those of Novartis Oncology.

summary of presentation 1
Summary of Presentation (1)
  • Zometa® and Aredia® are important medications that reduce complications of bone metastases in patients with solid tumors and multiple myeloma
  • Novartis has actively examined issue of ONJ since first spontaneous reports received in Dec 2002
    • ONJ remains poorly understood
    • Frequency estimates variable; however, ONJ appears to be an infrequent occurrence
    • Insufficient evidence to support difference between Zometa and Aredia
summary of presentation 2
Summary of Presentation (2)
  • Novartis is committed to
    • Ensuring patient safety
    • Enhancing understanding of ONJ through additional clinical investigation
    • Continuing dissemination of evolving information and guidance to health-care providers and patients
  • Balance of benefit-risk for Zometa® and Aredia® remains favorable
metastatic bone disease is an important clinical problem in cancer patients
Metastatic Bone Disease is an Important Clinical Problem in Cancer Patients

Incidence of

bone metastases,

% 2

Annual estimate

new cases - US,x10001

Median survival,

months2-4

Myeloma

16

70 - 95

50 - 67

Renal

36

20 - 25

8 - 21

14 - 45

Melanoma

60

5 - 31

63

Bladder

9 - 20

40

Thyroid

26

49

60

17 - 33

Lung

173

30 - 40

Breast

65 - 75

18 - 24

213

Prostate

232

65 - 75

16 - 24

1. Jemal A, et al. CA Cancer J Clin. (2005)

2. Coleman RE. Cancer Treat Rev. (2001)

3. DeVita VT, et al. Cancer Principles & Practice of Oncology.  Lippincott Williams & Wilkins. NY (2005) 

4. Shoup M, et al. J Am Coll Surg. (2003)

zometa and aredia in metastatic bone disease
Effective in the prevention of complications of bone metastases in breast cancer and multiple myeloma

Zometa is effective in prostate cancer, whereas Aredia is not. Unlike Aredia, Zometa was tested and showed efficacy in other tumor types such as lung, renal, colorectal, and bladder cancer

Benefit-risk profile is well established, with known, manageable renal adverse events

Recommended in ASCO guidelines for the management of multiple myeloma and metastatic breast cancer patients with bone lesions*, †

Zometa® and Aredia® in Metastatic Bone Disease

* Hillner, et al. J Clin Oncol. 2003;21:4042-4057.

† Berenson, et al. J Clin Oncol. 2002;20:3719-3736.

osteonecrosis on background
Etiology and pathogenesis not well understood

Impaired blood supply leading to ischemia proposed as pathologic process preceding ON*

Most commonly seen in hip†

Multiple risk factors suspected, including cancer and cancer treatments

Bisphosphonates used to treat ON with some success‡

(NS10-02) Zometa Core presentation ONJ (CO).ppt

Osteonecrosis (ON): Background

* Glueck et al (1997). In: Urbaniak JR and Jones JP, eds. Osteonecrosis, AAOS, 105-116

† Assouline-Dayan et al (2002). Semin Arthritis Rheum; 32:94-124.

‡ Agarwala S et al. Rheumatology (Oxford). 2002.

osteonecrosis of the jaw onj

(NS3-19) July15,2004FDAONImeetingslides.doc

Osteonecrosis of the Jaw (ONJ)
  • Involves portion of jaw bone (maxilla or mandible)
    • No consensus on diagnostic criteria for ONJ
  • Incidence unknown
  • Pathogenesis not understood
    • Similar risk factors to ON suggested
  • Risk factors specificto jaw bones may play a role
    • Exposure to external environment through teeth
    • Risk of trauma from repeated dental procedures
onj in cancer patients

(NS10-04) Zometa Core presentation ONJ (CO).ppt - Slide 4

ONJ in Cancer Patients
  • Awareness was limited, now growing
  • ONJ incidence in cancer patients unknown
  • Few literature reports before 20031-3
    • Most often reported - osteoradionecrosis (ORN) following head and neck radiation
      • Reported incidence of 8.2%4
  • Novartis received first spontaneous report of ONJ in IV BP-treated cancer patient in Dec 2002

1. Winer et al.J Am Dent Assoc. (1972)2. Schwartz. Head Neck Surg. (1982)3. Sung et al. Spec Care Dent. (2002)

4. Reuther et al. Oral Max Surgery. (2003)

review of available data on onj
Review of Available Data on ONJ
  • Clinical trials
  • Spontaneous reports to Novartis
  • Literature
  • MD Anderson Cancer Center study
limitations in existing datasets available datasets
Limitations in Existing DatasetsAvailable Datasets
  • Controlled clinical trials
    • Most meaningful, quality assured, source verified, reliable
    • Lack of awareness of ONJ, follow-up to be updated
  • Spontaneous reports (Novartis database)
    • Incomplete case data
    • Diagnostic, selection, and reporting biases
  • Literature
    • Reports: anecdotal, completeness of data unknown
    • Web survey: uncontrolled, anonymous, selection bias, QA, and source verification
  • MDACC
    • Planned retrospective review
    • Ongoing, 25% completed
review of available data on onj13
Clinical trials

Spontaneous reports to Novartis

Literature

MD Anderson Cancer Center study

Review of Available Data on ONJ
novartis current case definition
Any case or report suggestive of the following to maxillofacial area was considered “ONJ”

Osteonecrosis

Osteomyelitis

Exposed bone

Bone necrosis

Sequestrum

Impaired healing post-dental procedure

Novartis Current “Case Definition”
pivotal trials study design and follow up 1

25

Pivotal Trials: Study Design and Follow-up (1)

*Dose of Zometa® is variable, Aredia® dose 90 mg.

N/A = Not available; Z = Zometa; A = Aredia.

pivotal trials onj cases

(NS4-13) Zometa Briefing Document January 2005.doc Table 4-4

Pivotal Trials: ONJ Cases*

* Trials included in search: Zometa trial: 007, 010, 011, 039, 704, 036, 037 and 1501Aredia: P12, P18, P19

†Includes 1 patient who received Zometa 0.4 mg ×10

onj cases in pivotal trials 1
ONJ Cases in Pivotal Trials (1)

MM = Multiple myeloma; H&N = Head and neck cancer; PC = Prostate cancer.

OM = Osteomyelitis, ON = Osteonecrosis, ASN = aseptic necrosis

onj cases in pivotal trials 2
ONJ Cases in Pivotal Trials (2)

MM = Multiple myeloma; H&N = Head and neck cancer; PC = Prostate cancer.

OM = Osteomyelitis, ON = Osteonecrosis, ASN = aseptic necrosis

onj cases other trials
ONJ Cases: Other Trials
  • Completed trials: no ONJ cases as of Jan 2005*
    • 23 trials in Zometa® program (N = 3428)
        • Zometa 3217
        • Aredia 125
        • Placebo 86
    • 26 trials in Aredia® program (N = 1401)
        • Aredia 1214
        • Placebo 187
  • Ongoing trials: 4 ONJ cases reported
    • > 10,000 patients enrolled

*Except for 1 case of osteomyelitis of the jaw (OMJ) that existed prior to study entry.

onj cases in ongoing zometa trials

(NS4-13) Zometa Briefing Document January 2005.doc Table 4-4

ONJ Cases in Ongoing Zometa® Trials*

† This study is not sponsored by Novartis.

* All studies use Zometa 4 mg.

** Patient had pre-existing osteomyelitis of the jaw at study entry.

review of available data on onj23
Clinical trials

Spontaneous reports to Novartis

Literature

MD Anderson Cancer Center study

Review of Available Data on ONJ
spontaneous reports of onj zometa or aredia

(NS4-8) Zometa Briefing Document January 2005.doc Table 4-2

Spontaneous Reports Of ONJ*Zometa® or Aredia®†
  • As of 22 Feb 2005, total reports = 875

* Includes reportable cases from the literature.

† The number of reported cases from generic pamidronate is unknown.

‡ 91% of patients diagnosed with ONJ and 28% diagnosed with osteomyelitis.

spontaneous reports of onj reported risk factors

(NS9-12) Zometa Mar 4, 05 ODAC Meeting Briefing Appx 3.doc

Spontaneous Reports Of ONJReported Risk Factors

† In 188 (31%) reports the patients had received both corticosteroids and chemotherapy.

‡ Broad criteria used, including all conditions and medications with potential impact on bone metabolism. Includes 3 patients with herpes virus infection of the maxillofacial area.

spontaneous reports of onj reported dental events

(NS9-11) Zometa Mar 4, 05 ODAC Meeting Briefing Appx 3.doc

Spontaneous Reports Of ONJReported Dental Events
  • At least 50% of cases (n = 303) reported dental events preceding the diagnosis of ONJ
spontaneous reports of onj reported outcomes
Spontaneous Reports Of ONJReported Outcomes

‡ 224/610 reports assessable for outcome analysis. § Also includes recovered with sequelae.

spontaneous reports time to onset of onj
Spontaneous Reports: Time to Onset of ONJ
  • Direct comparison of time to onset between Zometa® & Aredia® is not feasible
    • No common definition of ONJ
    • Aredia available since 1991, Zometa since 2001
    • Utilization of Aredia has declined significantly since 2001 (including generic introduction)
    • Recent awareness could have accelerated diagnosis of ONJ
    • Concurrent therapy has changed significantly over time with contribution unknown
review of available data on onj29
Clinical trials

Spontaneous reports to Novartis

Literature

MD Anderson Cancer Center study

Review of Available Data on ONJ
literature report of onj ruggiero et al 2004
Literature Report of ONJ:Ruggiero et al. 2004*
  • 63 cases between Feb 01- Nov 03
    • MM (28), BC (20), prostate (3), other (5), no cancer (7)
    • Pamidronate (57%), zoledronic acid (31%), oral BP (12%)
    • 71% female
    • Mandible (63%), maxilla (37%)
    • Typical presentation: pain, non-healing extraction socket, exposed bone
    • Other treatments: chemotherapy
    • Previous dental procedure: 86%
    • Majority required surgical removal of involved bone

* Ruggiero SL, et al. J Oral Maxillofac Surg; 2004; 62 (5):527 - 534.

literature report of onj durie et al 2004
Web-based patient survey

Key issues

Data reliability/quality

Anonymous responders

Unable to assure data quality

Potential bias & analyses considerations

Patients with an event, more motivated to respond

Patients with more recent event, may be more likely to respond

Kaplan-Meier & logistic regression must be interpreted with caution

Not adjusted for time as confounding factor

Impact of approval / launch / usage time

Aredia® approved since 1991 & Zometa® since 2001

Literature Report of ONJ: Durie et al. 2004*

* Durie et al. Blood 2004;104:Abstract 756.

review of available data on onj33
Clinical trials

Spontaneous reports to Novartis

Literature

MD Anderson Cancer Center study

Review of Available Data on ONJ
md anderson cancer center study objectives and methods

(NS10-11) Zometa Core presentation ONJ (CO).ppt

MD Anderson Cancer Center Study Objectives and Methods
  • Principal Investigator: Ana Hoff, MD
  • Objectives†
    • Identify ONJ cases in cancer patients treated with IV BPs to estimate frequency
    • Identify risk factors associated with ONJ
  • Methods
    • Retrospective chart review in past 10 yr
      • All IV BP users (N = 4032)
      • Identify patients with ONJ and ON of other sites
  • 963 charts reviewed by Jan 12, 2005
  • Issue: Non random chart review
    • Charts sorted by pharmacy records based on number of BP infusions (highest to lowest)
    • 7 charts reviewed out of sequence because ONJ was suspected

† Amendment to expand the review to non-bisphosphonate users being considered.

onj in cancer patients treated with bps open questions

(NS3-19) July15,2004FDAONImeetingslides.doc

ONJ in Cancer Patients Treated With BPs: Open Questions
  • Natural history
  • Clear case definition
    • Diagnostic criteria
    • Staging system
    • Severity measures
  • Time to onset
  • Risk factors
  • Prevention measures
  • Treatment algorithm
  • Causality
novartis initiatives completed activities

(NS21-5)

12/02 First ONJ report to Novartis

9/03 – 11/03 Zometa® PI update/ Aredia® PI update

3/04Updated PIswith additionalONJ info

8/04 Zometa and Aredia labels revised

2002

2003

2004

2005

4/04initiate MDACC study

2Q-3Q Oncologist & dental surgeon visited to collect data

9/04 Distribution of“Dear Doctor”letter

4/04ICchanges made

6/04 Distribution of the “white paper” at ASCO

2/05 ASCOburst(FDA)

3/04 Ad. board #2(generate guidelines; “white paper”)

1/03 Initiate f/u &data collection on cases

5/04 Patient initiative/Generation of education materials

12/03 Ad. board #1 (understand ONJ)

Novartis Initiatives—Completed Activities
recommended management of onj advisory panel march 24 2004 1
Recommended Management of ONJAdvisory Panel – March 24, 2004 (1)
  • Diagnosis
    • Typical symptoms: pain, soft-tissue swelling and infection, loose teeth, and exposed bone
    • Imaging (eg, panoramic and tomographic), biopsy, and cultures may be helpful
  • Treatment
    • Nonsurgical approach preferred: minimal debridement, cover exposed bone, protective stint
    • Antibiotics, antifungal and antiviral agents, oral rinses
    • Close follow-up, and cessation of BP therapy may be considered. Risk of SRE needs to be considered when stopping BP therapy
recommended management of onj advisory panel march 24 2004 2
Recommended Management of ONJAdvisory Panel – March 24, 2004 (2)
  • Prevention
    • Avoid elective jaw procedures
    • Routine dental exams including panoramic radiograph
    • Tooth extraction prior to BP therapy if possible
    • Preventive dentistry prior to chemotherapy
    • Patient education regarding importance of good hygiene
    • Oncologist to perform visual inspection of oral cavity prior to BP therapy and at each follow-up visit
    • Cessation of BP therapy may be considered if oral surgery required, risk of SRE needs to be considered when stopping BP therapy
patient outreach with advocacy groups

(NS22-17) Patient Advocacy ONJ.ppt slide 1

Patient Outreach With Advocacy Groups
  • Meeting held May 2004
    • 9 patient advocacy groups attended representing multiple tumor types (breast, myeloma, prostate, lung, and kidney)
  • Additional follow-up with 14 groups (Dec 2004/early 2005)
  • Planned activity: post ODAC briefing teleconference with patient advocacy groups
patient brochure
Definition, signs, and symptoms of ONJ

Routine dental hygiene for patients with cancer

Dental care recommendations to patients with cancer

Urge patients to communicate with physicians and dentists regarding adverse events

(NS21-1) “Taking Care of Yourself While Living With Cancer: Dental Health and Osteonecrosis of the Jaw” Novartis Patient Information Brochure. 2004.

Taking Care of Yourself

While Living With Cancer

Dental Health and

Osteonecrosis of the Jaw

Patient Brochure
clinical investigations actions planned
Clinical Investigations – Actions Planned
  • Develop case definition and severity scale with expert panel
  • Obtain follow up data on patients from pivotal trials for ONJ
  • Develop CRF to capture data regarding ONJ in ongoing studies
  • Implement new studies that include prospective monitoring for ONJ
clinical investigation new studies
Clinical Investigation – New Studies
  • Retrospective chart review for ONJ in MM patients (initiate 2Q 2005)
  • Prospective studies to include ONJ assessment
    • Study 2352: MBC and MM (initiate 4Q 2005)
    • SWOG 0307: Adjuvant BC (under discussion)
  • Prospective registry for ONJ or ONJ natural history study (2H 2005)
phase iii randomized trial with zometa study 2352 design
Phase III Randomized Trial With Zometa®Study 2352 Design

Arm 1, n = 1,405

Zometa 4 mg q 3-4 wk

Breast cancer/myeloma

+ bone metastasis

Zometapretreated:

12 mo

N = 3513

Randomization 2:2:1

Arm 2, n = 1,405

Zometa 4 mg q 3 mo

+ Rescue: Zometa 4 mg q wk after first SRE

Placebo q 4 wk

Arm 3, n = 703

+ Rescue: Zometa 4 mg q wk after first SRE

13-month analysis

for efficacy and safety*

0

* Primary efficacy endpoint: Time to first SRE

swog 0307 study design

(NS22-2) Leo’s SWOG slides.ppt slide 2

SWOG 0307: Study Design
  • Randomized phase III trial; NSABP 34 replacement trial
  • Stage I, II, and III breast cancer on standard adjuvant therapy (n = 6000)

Zometa®* 4 mg IV

q mo x 6 mos, q 3 mos x 2.5 yrs

R

A

N

D

O

M

I ZE

Ibandronate* 50 mg PO daily x 3 yrs

Clodronate* 1600 mg PO daily x 3 yrs

*Daily supplemental calcium (1000 to 1500 mg) and vitamin D (400 to 800 IU)

onj monitoring in clinical trials proposal
ONJ Monitoring in Clinical Trials: Proposal
  • Physical examination of head & neck and oral cavity to
    • Rule out metastatic involvement
    • Detect
      • Breach of the oral mucosa
      • Exposed bone
  • Imaging
    • Panoramic radiograph
  • Assessment frequency based on tumor type and stage of disease (minimum: baseline, q6 months)
  • Develop specific case report forms
    • Dental exam
    • ONJ assessment
conclusions 1
Conclusions (1)
  • Zometa® and Aredia® are important medications that reduce complications of bone metastases in patients with solid tumors and multiple myeloma
  • Novartis has actively examined issue of ONJ since first spontaneous reports received in Dec 2002
    • ONJ remains poorly understood
    • Frequency estimates variable; however, ONJ appears to be an infrequent occurrence
    • Insufficient evidence to support difference between Zometa and Aredia
conclusions 2
Conclusions (2)
  • Novartis is committed to
    • Ensuring patient safety
    • Enhancing understanding of ONJ through additional clinical investigation
    • Continuing dissemination of evolving information and guidance to health-care providers and patients
  • Balance of benefit-risk for Zometa® and Aredia® remains favorable