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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? 1. Clodronate 2. Pamidronate 3. Zoledronic acid 4. Bondronat 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 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 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 Bondronat prevents bone events Placebo-controlled, 96-week trials in breast cancer patients Intravenous Bondronat 6mg 40* Oral Bondronat 50mg 38** 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 Markers of bone turnover correlate with outcome Reducing markers of bone resorption with bisphosphonates reduces incidence of skeletal-related events (SREs)1–3 Bone resorption Rate of bone resorption = rate of bone complications1 High Low Low High Bone complications Brown JE, et al. Br J Cancer 2003;89:2031–7 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) 1 2 KEY SLIDE 1 Oral Bondronat is as effective as intravenous zoledronic acid Multicenter, open-label, 12-week trial in breast cancer patients Bondronat 50mg (n=128) Zoledronic acid 4mg (n=126) S-CTX (ng/mL) 0.8 76% 73% 0.6 0.4 0.2 0 Baseline Week 12 Baseline Week 12 Body JJ, et al. J Clin Oncol 2005;23(Suppl. 16S):12S(abstract 534) 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 Long-term relief of metastatic bone pain with Bondronat Phase III studies KEY SLIDE 2 Long-term bone pain relief (up to 2 years) with intravenous Bondronat Mean change in pain score from baseline Phase III study (MF 4265) 0.3 Placebo (n=158) Bondronat 6mg (n=154) 0.2 0.1 0 –0.1 p<0.001 25% reduction –0.2 –0.3 –0.4 –0.5 0 12 24 36 48 60 Time (weeks) 72 84 96 Diel I, et al. Eur J Cancer 2004;40:1704–12 KEY SLIDE 3 Long-term bone pain relief (up to 2 years) with oral Bondronat Phase III studies (MF 4414/4434) Mean change in pain score from baseline 0.3 Placebo (n=277) Bondronat 50mg (n=287) 0.2 0.1 0 24% reduction –0.1 –0.2 p=0.001 –0.3 –0.4 –0.5 0 12 24 36 48 60 Time (weeks) 72 84 96 Body JJ, et al. Pain 2004;111:306–12 Rapid relief of metastatic bone pain with Bondronat Phase II studies with loading-dose Bondronat 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) Bondronat reduced metastatic bone pain from urologic cancer Mean VAS pain score 8 Severe pain 7 6 5 4 3 2 Mild pain Day 3 1 p<0.001 0 0 14 VAS = 10-point visual analog scale 28 42 56 70 84 Time (days) 98 112 126 140 Heidenreich A, et al. Eur J Cancer 2003;1(Suppl. 5):S270(abstract 897) KEY SLIDE 4 8 80 7 70 Cares for oneself 6 60 50 5 >50% of patients bedridden 4 40 3 30 2 20 Day 3 1 p<0.001 10 0 0 14 VAS = 10-point visual analog scale 28 42 56 70 84 Time (days) 98 112 126 Karnofsky Index Mean VAS pain score Bondronat reduced metastatic bone pain from urologic cancer 0 140 Heidenreich A, et al. Eur J Cancer 2003;1(Suppl. 5):S270(abstract 897) Ongoing metastatic bone pain trials with Bondronat 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 Study design Day 1 2 3 Bon-I-Pain (n=450) Bon-O-Pain (n=450) 22–28 168 Bondronat 6mg x 3 Bondronat 6mg q3–4 w Zoledronic acid 4mg x 1 + placebo x 2 Zoledronic acid 4mg q3–4 w Bondronat 6mg x 3 Oral daily Bondronat 50mg + placebo infusion q3–4 w Zoledronic acid 4mg x 1 + placebo x 2 Zoledronic acid 4mg q3–4 w + oral daily placebo 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 Oral Bondronat is at least as effective as zoledronic acid, but what about their safety profiles? Oral Bondronat is well tolerated versus zoledronic acid Multicenter, open-label, 12-week trial in breast cancer patients Patients (%) 100 75 76 Oral Bondronat (n=137) Intravenous zoledronic acid (n=137) 65 51 50 22 25 6 8 0 Any AE AE = adverse event Serious AEs Treatment-related AEs Body JJ, et al. Breast Cancer Res Treat 2005;94 (Suppl. 1):S260(abstract 6035) 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 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 50 Patients (%) 40 30 26% 20 13% 10 0 i.v. Bondronat 6mg (n=39) Possibly or probably related to treatment i.v. zoledronic acid 4mg (n=38) Bergström B, et al. Davos 2006 What about renal safety? 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 Renal toxicity is not a class effect Bondronat Zoledronic acid Protein binding 87% 56% Renal half-life 24 days 150–200 days Cumulative renal toxicity No Yes Renal safety comparable to placebo Yes No 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 KEY SLIDE 5 Renal safety of intravenous Bondronat comparable with placebo Patients without renal function deterioration (%) Deterioration with Bondronat 6mg consistent with placebo (p=0.22, ns) – at 1 year: 2% vs 4%; at 2 years: 6% vs 12% 100 94% 88% 80 60 40 Bondronat 6mg Placebo 20 0 0 12 24 36 48 60 72 Study duration (weeks) 84 96 Body JJ, et al. Eur J Cancer Care. In press 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 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 What are the benefits of Bondronat’s renal safety for routine clinical practice? Intravenous Bondronat is simple Creatinine clearance (mL/min) Initiation dose of zoledronic acid (mg) >60 4.0 50–60 3.5 40–49 3.3 30–39 3.0 Bondronat (mg) 6.0 Zometa (zoledronic acid). European SmPC. Novartis, April 2005 Bondronat (ibandronate). European SmPC. Roche, October 2003 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 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 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 Questions Back-up slides Oral Bondronat and intravenous zoledronic acid: SRE efficacy Andersen-Gill (cross-trial comparison) Bondronat1 Zoledronic acid2 40 30 50 38 p<0.0001 29 p=0.0183 20 10 0 Intravenous 6mg Oral 50mg Risk reduction versus placebo (%) Risk reduction versus placebo (%) 50 41 p<0.0001 40 30 20 10 0 Intravenous 4mg 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 1 Bondronat maintains quality of life Intravenous Placebo (n=143) Bondronat 6mg (n=137) Oral Placebo (n=277) Bondronat 50mg (n=287) Change from baseline (global assessment, EORTC QLQ-C30) 0 Better –10 –20 –30 p=0.032 –40 –50 p=0.005 Worse Diel I, et al. Eur J Cancer 2004;40:1704–12 Body JJ, et al. Pain 2004;111:306–12 What about GI side effects with oral Bondronat? Side effects with oral Bondronat are manageable Phase III studies (MF 4414/4434) 100 Patients (%) 80 Placebo (n=277) Bondronat 50mg (n=286)* 60 40 20 5.1 9.4 4.7 7.0 1.4 3.5 0.7 2.1 0.7 2.1 0 Hypocalcemia Dyspepsia *Two serious AEs: nausea (n=1), duodenal ulcer (n=1) Diarrhea rate lower than placebo Nausea AE Esophagitis Abdominal pain 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) 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 Pyrexia and flu-like symptoms* not a concern with Bondronat 50 Patients (%) 40 27 30 20 10 1 0 Bondronat 50mg (n=137) *Possibly or probably related to treatment during Days 1–3 Zoledronic acid 4mg (n=137) Body JJ, et al. Breast Cancer Res Treat 2005;94 (Suppl. 1):S260(abstract 6035)