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Bondronat achieves better outcomes in metastatic bone disease

Bondronat achieves better outcomes in metastatic bone disease. Ingo Diel CGG-Klinik GmbH Mannheim, Germany. Keypad question 1. What bisphosphonate do you mainly use for treating metastatic bone disease? Clodronate Pamidronate Zoledronic acid Bondronat. Keypad question 2.

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Bondronat achieves better outcomes in metastatic bone disease

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  1. Bondronat achieves better outcomesin metastatic bone disease Ingo Diel CGG-Klinik GmbHMannheim, Germany

  2. Keypad question 1 • What bisphosphonate do you mainly use for treating metastatic bone disease? • Clodronate • Pamidronate • Zoledronic acid • Bondronat

  3. Keypad question 2 • Do you consider intravenous or oral bisphosphonates to be more effective against skeletal complications from metastatic bone disease? • Intravenous more effective • Oral more effective • Both the same

  4. What do patients need from their bisphosphonate? • Prevention of skeletal complications –a standard of care • Rapid and sustained relief from metastatic bone pain • Favorable safety profile

  5. What do patients need from their bisphosphonate? • Prevention of skeletal complications –a standard of care • Rapid and sustained relief from metastatic bone pain • Favorable safety profile

  6. Bondronat prevents bone events Placebo-controlled, 96-week trials in breast cancer patients IntravenousBondronat6mg OralBondronat50mg 0 10 20 30 40 50 Risk reduction versus placebo (%) *p=0.0033; **p=0.0001 Tripathy D, et al. Bone 2004;34(Suppl. 1):S91

  7. Markers of bone turnover correlatewith outcome • Rate of bone resorption = rate of bone complications1 • Reducing markers of bone resorption with bisphosphonates reduces incidence of skeletal-related events (SREs)1–3 High Bone resorption Low Low High Bone complications 1Brown JE, et al. Br J Cancer 2003;89:2031–7 2Brown JE, et al. J Natl Cancer Inst 2005;97:59–693Lipton A, et al. J Clin Oncol 2005;23(Suppl. 16S):11S(abstract 532)

  8. KEY SLIDE 1 Multicenter, open-label, 12-week trial in breast cancer patients Bondronat 50mg (n=128) Zoledronic acid 4mg (n=126) Oral Bondronat is as effective as intravenous zoledronic acid 0.8 0.6 0.4 0.2 0 76% 73% S-CTX (ng/mL) Baseline Week 12 Baseline Week 12 Body JJ, et al. J Clin Oncol 2005;23(Suppl. 16S):12S(abstract 534)

  9. What do patients need from their bisphosphonate? • Prevention of skeletal complications –a standard of care • Rapid and sustained relief from metastatic bone pain • Favorable safety profile

  10. Long-term relief of metastaticbone pain with Bondronat Phase III studies

  11. KEY SLIDE 2 Long-term bone pain relief (up to2 years) with intravenousBondronat Phase III study (MF 4265) 0.3 0.2 0.1 0 –0.1 –0.2 –0.3 –0.4 –0.5 Placebo (n=158) Bondronat 6mg (n=154) Mean change in pain scorefrom baseline p<0.001 25%reduction 0 12 24 36 48 60 72 84 96 Time (weeks) Diel I, et al. Eur J Cancer 2004;40:1704–12

  12. KEY SLIDE 3 Long-term bone pain relief (up to2 years) with oralBondronat Phase III studies (MF 4414/4434) 0.3 0.2 0.1 0 –0.1 –0.2 –0.3 –0.4 –0.5 Placebo (n=277) Bondronat 50mg (n=287) 24%reduction Mean change in pain scorefrom baseline p=0.001 0 12 24 36 48 60 72 84 96 Time (weeks) Body JJ, et al. Pain 2004;111:306–12

  13. Rapid relief of metastatic bonepain with Bondronat Phase II studies with loading-dose Bondronat

  14. Loading-dose Bondronat relieves severe metastatic bone pain Study design • Open, prospective and non-randomized • Intravenous Bondronat (6mg for 3 consecutive days) followed by 6mg every 3–4 weeks for 20 weeks • Patients: 53 (metastatic prostate, renal or bladder cancer) Results • 83% of patients had pain relief (≥3-point VAS reduction) starting on Day 2 • 25% of patients became pain-free Heidenreich A, et al. Eur J Cancer 2003;1(Suppl. 5):S270(abstract 897)

  15. Bondronat reduced metastatic bone pain from urologic cancer 8 7 6 5 4 3 2 1 0 Severe pain Mean VAS pain score Mild pain Day 3p<0.001 0 14 28 42 56 70 84 98 112 126 140 Time (days) VAS = 10-point visualanalog scale Heidenreich A, et al. Eur J Cancer 2003;1(Suppl. 5):S270(abstract 897)

  16. KEY SLIDE 4 80 70 60 50 40 30 20 10 0 Cares for oneself >50% of patients bedridden Karnofsky Index Bondronat reduced metastatic bone pain from urologic cancer 8 7 6 5 4 3 2 1 0 Mean VAS pain score Day 3p<0.001 0 14 28 42 56 70 84 98 112 126 140 Time (days) VAS = 10-point visualanalog scale Heidenreich A, et al. Eur J Cancer 2003;1(Suppl. 5):S270(abstract 897)

  17. Ongoing metastatic bonepain trials with Bondronat

  18. Metastatic bone pain program • Phase III trials to evaluate rapid relief of bone pain with loading-dose Bondronat • Trials recruiting patients with malignant bone disease and moderate-to-severe bone pain(VAS score ≥4) • Primary endpoint is decrease in bone pain • percentage of responders

  19. Bondronat 6mg x 3 Bondronat 6mg q3–4 w Bon-I-Pain (n=450) Zoledronic acid 4mg x 1 + placebo x 2 Zoledronic acid 4mg q3–4 w Oral daily Bondronat 50mg + placebo infusion q3–4 w Bondronat 6mg x 3 Bon-O-Pain (n=450) Zoledronic acid 4mg x 1 + placebo x 2 Zoledronic acid 4mg q3–4 w +oral daily placebo Study design Day 1 2 3 22–28 168

  20. What do patients need from their bisphosphonate? • Prevention of skeletal complications –a standard of care • Rapid and sustained relief from metastatic bone pain • Favorable safety profile

  21. Oral Bondronat is at least as effectiveas zoledronic acid, but what abouttheir safety profiles?

  22. 100 75 50 25 0 Patients (%) Any AE Serious AEs Treatment-related AEs Oral Bondronat is well tolerated versus zoledronic acid Multicenter, open-label, 12-week trial in breast cancer patients 76 65 51 22 8 6 Body JJ, et al. Breast Cancer Res Treat 2005;94(Suppl. 1):S260(abstract 6035) AE = adverse event

  23. Acute-phase reactions due to aminobisphosphonates • Acute-phase reactions • IL-mediated pyrexia with bone and/or joint pain and leucocytosis • Flu-like symptoms • begin 10 hours after infusion, last 1–2 days • occurs typically after first infusion

  24. Pyrexia and flu-like symptomsnot a concern with intravenous Bondronat Multicenter, open-label, 12-week, bone marker trial in breast cancer or multiple myeloma patients 50 40 30 20 10 0 26% Patients (%) 13% i.v. Bondronat 6mg(n=39) i.v. zoledronic acid 4mg(n=38) Possibly or probably relatedto treatment Bergström B, et al. Davos 2006

  25. What about renal safety?

  26. Keypad question 3 • How do renal safety profiles differ between bisphosphonates? • Large difference • Moderate difference • Minimal/insignificant difference • No difference • Undecided

  27. Renal toxicity is not a class effect Bondronat Zoledronic acid Protein binding 87% 56% Renal half-life 24 days 150–200 days Cumulative No Yes renal toxicity Renal safety Yes Nocomparable to placebo

  28. Intravenous Bondronat renal safety:96-week phase III trial and follow-up Study design • Bondronat 6mg infused over 3–4 weeks (n=152) compared with placebo (n=157) • Pre-specified recording of renal AEs • Post-hoc Kaplan-Meier analysis of time to increasein serum creatinine • 0.5mg/dL if baseline <1.4mg/dL • 1.0mg/dL if baseline >1.4mg/dL, or • twice the baseline value Body JJ, et al. Ann Oncol 2003;14:1399–405 Body JJ, et al. Eur J Cancer Care. In press

  29. KEY SLIDE 5 Bondronat 6mg Placebo Renal safety of intravenous Bondronat comparable with placebo • Deterioration with Bondronat 6mg consistent with placebo (p=0.22, ns) • at 1 year: 2% vs 4%; at 2 years: 6% vs 12% 100 80 60 40 20 0 94% 88% Patients without renalfunction deterioration (%) 0 12 24 36 48 60 72 84 96 Study duration (weeks) Body JJ, et al. Eur J Cancer Care. In press

  30. Further evidence for intravenous Bondronat renal safety Extension of phase III trial1 • Patients offered intravenous Bondronat for a further 2 years (n=62, total drug exposure up to 4 years) • No renal AEs or serum creatinine changes of clinical relevance Loading-dose studies2,3 • No renal safety concerns as with standard dosing in various cancer types 1Pecherstorfer M, et al. Ann Oncol 2004;15(Suppl. 3):iii49 2Mancini I, Body JJ, et al. J Clin Oncol 2004;22:3587–92 3Heidenreich A, et al. Eur J Cancer 2003;1(Suppl. 5):S270

  31. What are the benefits of Bondronat’s renal safety for routine clinical practice?

  32. Intravenous Bondronat is simple Zometa (zoledronic acid). European SmPC. Novartis, April 2005 Bondronat (ibandronate). European SmPC. Roche, October 2003

  33. Unchanged renal labeling for Bondronat • No renal function monitoring mandatory for Bondronat • Can be used in patients with severe renal impairment (<30mL/min creatinine clearance) • intravenous 2mg every 3–4 weeks (similar AUCto 6mg dose) Bondronat (ibandronate). European SmPC. Roche, October 2003

  34. Implications of Bondronatrenal safety for the patient • No added renal safety risks and complications • Fewer hospital visits for renal management or monitoring • Reduces risk of bisphosphonate or chemotherapy discontinuation • Minimizes interaction with concomitant medications that have renal elimination or toxicity • Improves quality of life

  35. Bondronat achieves better outcomes in metastatic bone disease: summary Proven efficacy • Proven efficacy in SREs across tumor types • Unmatched rapid relief of metastatic bone pain • Equivalent bone marker efficacy to zoledronic acid Favorable safety profile • Well tolerated for up to 4 years of treatment • No renal safety concerns, even with loading-dose Loading-dose Bondronat . . . it works! Try it and see for yourself

  36. Questions

  37. Back-up slides

  38. Oral Bondronat and intravenous zoledronic acid: SRE efficacy Andersen-Gill (cross-trial comparison) Bondronat1 Zoledronic acid2 50 40 30 20 10 0 50 40 30 20 10 0 41p<0.0001 38p<0.0001 29p=0.0183 Risk reduction versus placebo (%) Risk reductionversus placebo (%) Intravenous6mg Oral 50mg Intravenous4mg 1Body JJ, et al. J Clin Oncol 2003;22(Suppl.):46(abstract 184) 2Kohno N, et al. J Clin Oncol 2005;23:3314–21

  39. Bondronat maintains quality of life Intravenous Oral Bondronat Bondronat Placebo 6mg Placebo 50mg (n=143) (n=137) (n=277) (n=287) 0 –10 –20 –30 –40 –50 Better Change from baseline(global assessment,EORTC QLQ-C30) p=0.032 Worse p=0.005 Diel I, et al. Eur J Cancer 2004;40:1704–12 Body JJ, et al. Pain 2004;111:306–12

  40. What about GI side effectswith oral Bondronat?

  41. Side effects with oral Bondronat are manageable 100 80 60 40 20 0 Phase III studies (MF 4414/4434) Patients (%) Hypocalcemia Dyspepsia Nausea Esophagitis Abdominal pain AE *Two serious AEs: nausea (n=1), duodenal ulcer (n=1) Diarrhea rate lower than placebo Body JJ, et al. Br J Cancer 2004;90:1133–7 Diel I, et al. Eur J Cancer 2003;1(Suppl. 5):S135(abstract 443)

  42. Further evidence for oralBondronat safety • Patients were offered oral Bondronat for a further2 years (n=115, total drug exposure up to 4 years) • No treatment-related AEs were serious or led to withdrawal • Similar side-effect profile as main study McLachlan SA, et al. Support Care Cancer 2004;12:408

  43. Pyrexia and flu-like symptoms*not a concern with Bondronat 50 40 30 20 10 0 Patients (%) Bondronat 50mg(n=137) Zoledronic acid 4mg(n=137) *Possibly or probably relatedto treatment during Days 1–3 Body JJ, et al. Breast Cancer Res Treat 2005;94(Suppl. 1):S260(abstract 6035)

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