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Osteonecrosis of the Jaw (ONJ) and Bisphosphonates

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

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  1. Osteonecrosis of the Jaw (ONJ)and Bisphosphonates Oncologic Drugs Advisory CommitteeMarch 4, 2005 Novartis Pharmaceuticals

  2. 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

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

  4. 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

  5. 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

  6. 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)

  7. 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.

  8. 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.

  9. (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

  10. (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)

  11. Review of Available Data on ONJ • Clinical trials • Spontaneous reports to Novartis • Literature • MD Anderson Cancer Center study

  12. 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

  13. Clinical trials Spontaneous reports to Novartis Literature MD Anderson Cancer Center study Review of Available Data on ONJ

  14. Screening for Potential ONJ CasesNovartis Databases

  15. 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”

  16. 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.

  17. 25 Pivotal Trials: Study Design and Follow-up (2) Z = Zometa®; A = Aredia®.

  18. (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

  19. 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

  20. 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

  21. 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.

  22. (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.

  23. Clinical trials Spontaneous reports to Novartis Literature MD Anderson Cancer Center study Review of Available Data on ONJ

  24. (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.

  25. (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.

  26. (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

  27. Spontaneous Reports Of ONJReported Outcomes ‡ 224/610 reports assessable for outcome analysis. § Also includes recovered with sequelae.

  28. 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

  29. Clinical trials Spontaneous reports to Novartis Literature MD Anderson Cancer Center study Review of Available Data on ONJ

  30. (NS4-7) Zometa Briefing Document January 2005.doc Table 4-1 Literature Reports of ONJ

  31. 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.

  32. 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.

  33. Clinical trials Spontaneous reports to Novartis Literature MD Anderson Cancer Center study Review of Available Data on ONJ

  34. (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.

  35. (NS4-16) Zometa Briefing Document January 2005.doc Table 4-7 MD Anderson Cancer Center StudyInterim Data: ONJ Cases by Tumor Type * Thyroid cancer

  36. (NS4-18) Zometa Briefing Document January 2005.doc Table 4-8 MD Anderson Cancer Center Interim Data: 18 Cases * 4 months on Aredia. 57 months on Aredia followed by Zometa.

  37. ONJ in Cancer Patients Treated With BPsFrequency Estimates

  38. (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

  39. Novartis Initiatives

  40. (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

  41. 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

  42. 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

  43. (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

  44. 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

  45. 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

  46. 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)

  47. 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

  48. (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)

  49. (NS22-3) Leo’s SWOG slides.ppt slide 3 SWOG 0307: Osteonecrosis of the Jaw Surveillance Plan

  50. 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

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