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Bondronat achieves better outcomes in metastatic bone disease Ingo Diel CGG-Klinik GmbH Mannheim, Germany.

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Presentation on theme: "Bondronat achieves better outcomes in metastatic bone disease Ingo Diel CGG-Klinik GmbH Mannheim, Germany."— Presentation transcript:

1 Bondronat achieves better outcomes in metastatic bone disease Ingo Diel CGG-Klinik GmbH Mannheim, Germany

2 Keypad question 1 What bisphosphonate do you mainly use for treating metastatic bone disease? 1.Clodronate 2.Pamidronate 3.Zoledronic acid 4.Bondronat

3 Keypad question 2 Do you consider intravenous or oral bisphosphonates to be more effective against skeletal complications from metastatic bone disease? 1.Intravenous more effective 2.Oral more effective 3.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 *p=0.0033; **p=0.0001Tripathy D, et al. Bone 2004;34(Suppl. 1):S91 Intravenous Bondronat 6mg Risk reduction versus placebo (%) Oral Bondronat 50mg 01020304050 Placebo-controlled, 96-week trials in breast cancer patients

7 Markers of bone turnover correlate with outcome Rate of bone resorption = rate of bone complications 1 Reducing markers of bone resorption with bisphosphonates reduces incidence of skeletal-related events (SREs) 1–3 1 Brown JE, et al. Br J Cancer 2003;89:2031–7 2 Brown JE, et al. J Natl Cancer Inst 2005;97:59–69 3 Lipton A, et al. J Clin Oncol 2005;23(Suppl. 16S):11S(abstract 532) High Low HighLow Bone resorption Bone complications

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

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 metastatic bone pain with Bondronat Phase III studies

11 Long-term bone pain relief (up to 2 years) with intravenous Bondronat Diel I, et al. Eur J Cancer 2004;40:1704–12 Time (weeks) p<0.001 0.3 0.2 0.1 0 –0.1 –0.2 –0.3 –0.4 –0.5 Mean change in pain score from baseline 01224364860728496 Placebo (n=158) Bondronat 6mg (n=154) Phase III study (MF 4265) 25% reduction KEY SLIDE 2

12 Long-term bone pain relief (up to 2 years) with oral Bondronat Body JJ, et al. Pain 2004;111:306–12 p=0.001 Phase III studies (MF 4414/4434) Time (weeks) 0.3 0.2 0.1 0 –0.1 –0.2 –0.3 –0.4 –0.5 Mean change in pain score from baseline 01224364860728496 Placebo (n=277) Bondronat 50mg (n=287) KEY SLIDE 3 24% reduction

13 Rapid relief of metastatic bone pain 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 Mild pain 876543210876543210 Mean VAS pain score 014284256708498112126140 Day 3 p<0.001 Time (days) Severe pain VAS = 10-point visual analog scale

16 80 70 60 50 40 30 20 10 0 Karnofsky Index 876543210876543210 014284256708498112126140 Day 3 p<0.001 Cares for oneself >50% of patients bedridden Time (days) Bondronat reduced metastatic bone pain from urologic cancer VAS = 10-point visual analog scale Mean VAS pain score Heidenreich A, et al. Eur J Cancer 2003;1(Suppl. 5):S270(abstract 897) KEY SLIDE 4

17 Ongoing metastatic bone pain 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 Study design Day 12322–28168 Zoledronic acid 4mg q3–4 w Bondronat 6mg q3–4 w Oral daily Bondronat 50mg + placebo infusion q3–4 w Zoledronic acid 4mg q3–4 w + oral daily placebo Bon-I-Pain (n=450) Bondronat 6mg x 3 Zoledronic acid 4mg x 1 + placebo x 2 Bon-O-Pain (n=450) Bondronat 6mg x 3 Zoledronic acid 4mg x 1 + placebo x 2

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 effective as zoledronic acid, but what about their safety profiles?

22 Treatment-related AEs Oral Bondronat is well tolerated versus zoledronic acid Body JJ, et al. Breast Cancer Res Treat 2005;94 (Suppl. 1):S260(abstract 6035) Multicenter, open-label, 12-week trial in breast cancer patients Serious AEs Any AE 100 75 50 25 0 Patients (%) 65 76 6 8 22 51 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 Possibly or probably related to treatment Patients (%) 50 40 30 20 10 0 Pyrexia and flu-like symptoms not a concern with intravenous Bondronat Multicenter, open-label, 12-week, bone marker trial in breast cancer or multiple myeloma patients Bergström B, et al. Davos 2006 i.v. Bondronat 6mg (n=39) i.v. zoledronic acid 4mg (n=38) 13% 26%

25 What about renal safety?

26 Keypad question 3 How do renal safety profiles differ between bisphosphonates? 1.Large difference 2.Moderate difference 3.Minimal/insignificant difference 4.No difference 5.Undecided

27 Renal toxicity is not a class effect Bondronat Zoledronic acid Protein binding87%56% Renal half-life24 days150–200 days Cumulative No Yes renal toxicity Renal safetyYesNo comparable 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 increase in 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

29 100 80 60 40 20 0 01224364860728496 Study duration (weeks) Patients without renal function deterioration (%) Bondronat 6mg Placebo Body JJ, et al. Eur J Cancer Care. In press 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% 94% 88% KEY SLIDE 5

30 Further evidence for intravenous Bondronat renal safety Extension of phase III trial 1 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 studies 2,3 No renal safety concerns as with standard dosing in various cancer types 1 Pecherstorfer M, et al. Ann Oncol 2004;15(Suppl. 3):iii49 2 Mancini I, Body JJ, et al. J Clin Oncol 2004;22:3587–92 3 Heidenreich 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 AUC to 6mg dose) Bondronat (ibandronate). European SmPC. Roche, October 2003

34 Implications of Bondronat renal 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 29 p=0.0183 Andersen-Gill (cross-trial comparison) Risk reduction versus placebo (%) Intravenous 6mg Oral 50mg Bondronat 1 Risk reduction versus placebo (%) Intravenous 4mg Zoledronic acid 2 1 Body JJ, et al. J Clin Oncol 2003;22(Suppl.):46(abstract 184) 2 Kohno N, et al. J Clin Oncol 2005;23:3314–21 38 p<0.0001 41 p<0.0001 50 40 30 20 10 0 50 40 30 20 10 0

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

40 What about GI side effects with oral Bondronat?

41 Side effects with oral Bondronat are manageable Patients (%) 100 80 60 40 20 0 HypocalcemiaDyspepsiaNauseaEsophagitisAbdominal 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) Phase III studies (MF 4414/4434)

42 Further evidence for oral Bondronat safety Patients were offered oral Bondronat for a further 2 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 Patients (%) 50 40 30 20 10 0 Bondronat 50mg (n=137) Zoledronic acid 4mg (n=137) *Possibly or probably related to treatment during Days 1–3 Body JJ, et al. Breast Cancer Res Treat 2005;94 (Suppl. 1):S260(abstract 6035)


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