Bondronat achieves better outcomesin metastatic bone disease

Ingo DielCGG-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

*p=0.0033; **p=0.0001 Tripathy D, et al. Bone 2004;34(Suppl. 1):S91

40*

38**

IntravenousBondronat

6mg

Risk reduction versus placebo (%)

OralBondronat

50mg

0 10 20 30 40 50

Placebo-controlled, 96-week trials in breast cancer patients

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

1Brown JE, et al. Br J Cancer 2003;89:2031–7 2Brown JE, et al. J Natl Cancer Inst 2005;97:59–69

3Lipton A, et al. J Clin Oncol 2005;23(Suppl. 16S):11S(abstract 532)

High

LowHighLow

Bo

ne

reso

rpti

on

Bone complications

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-C

TX

(n

g/m

L)

0.8

0.6

0.4

0.2

0Baseline Week 12 Baseline Week 12

76%73%

Bondronat 50mg (n=128)

Zoledronic acid 4mg (n=126)

KEY SLIDE 1

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 metastaticbone pain with Bondronat

Phase III studies

Long-term bone pain relief (up to2 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

Mea

n c

han

ge

in p

ain

sco

refr

om

bas

elin

e

0 12 24 36 48 60 72 84 96

Placebo (n=158)

Bondronat 6mg (n=154)

Phase III study (MF 4265)

25%reduction

KEY SLIDE 2

Long-term bone pain relief (up to2 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

Mea

n c

han

ge

in p

ain

sco

refr

om

bas

elin

e

0 12 24 36 48 60 72 84 96

Placebo (n=277)

Bondronat 50mg (n=287)

KEY SLIDE 3

24%reduction

Rapid relief of metastatic bonepain 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)

Heidenreich A, et al. Eur J Cancer 2003;1(Suppl. 5):S270(abstract 897)

Bondronat reduced metastatic bone pain from urologic cancer

Mild pain

8

7

6

5

4

3

2

1

0

Mea

n V

AS

pai

n s

core

0 14 28 42 56 70 84 98 112 126 140

Day 3p<0.001

Time (days)

Severe pain

VAS = 10-point visualanalog scale

80

70

60

50

40

30

20

10

0

Karn

ofsky In

dex

8

7

6

5

4

3

2

1

00 14 28 42 56 70 84 98 112 126 140

Day 3p<0.001

Cares for oneself

>50% of patients bedridden

Time (days)

Bondronat reduced metastatic bone pain from urologic cancer

VAS = 10-point visualanalog scale

Mea

n V

AS

pai

n s

core

Heidenreich A, et al. Eur J Cancer 2003;1(Suppl. 5):S270(abstract 897)

KEY SLIDE 4

Ongoing metastatic bonepain 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 22–28 168

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

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 effectiveas zoledronic acid, but what about

their safety profiles?

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 AEsAny AE

Oral Bondronat (n=137) Intravenous zoledronic acid (n=137)

100

75

50

25

0

Pat

ien

ts (

%) 65

76

6 8

22

51

AE = adverse event

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

Possibly or probably relatedto treatment

Pat

ien

ts (

%)

50

40

30

20

10

0

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

Bergström B, et al. Davos 2006

i.v. Bondronat 6mg(n=39)

i.v. zoledronic acid 4mg(n=38)

13%

26%

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 No Yesrenal toxicity

Renal safety Yes Nocomparable to placebo

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;14:1399–405Body JJ, et al. Eur J Cancer Care. In press

100

80

60

40

20

00 12 24 36 48 60 72 84 96

Study duration (weeks)

Pat

ien

ts w

ith

ou

t re

nal

fun

ctio

n d

eter

iora

tio

n (

%)

Bondronat 6mgPlacebo

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

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):iii492Mancini I, Body JJ, et al. J Clin Oncol 2004;22:3587–92

3Heidenreich 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

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

Creatinine clearance (mL/min)

Initiation dose of zoledronic

acid (mg) Bondronat (mg)

>60 4.0

50–60 3.5

40–49 3.3

30–39 3.0

6.0

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

29p=0.0183

Andersen-Gill (cross-trial comparison)

Ris

k re

du

ctio

n

vers

us

pla

ceb

o (

%)

Intravenous6mg

Oral 50mg

Bondronat1

Ris

k re

du

ctio

nve

rsu

s p

lace

bo

(%

)Intravenous

4mg

Zoledronic acid2

1Body JJ, et al. J Clin Oncol 2003;22(Suppl.):46(abstract 184)2Kohno N, et al. J Clin Oncol 2005;23:3314–21

38p<0.0001

41p<0.0001

50

40

30

20

10

0

50

40

30

20

10

0

Diel I, et al. Eur J Cancer 2004;40:1704–12Body JJ, et al. Pain 2004;111:306–12

Bondronat maintains quality of life

Ch

ang

e fr

om

bas

elin

e(g

lob

al a

sses

smen

t,E

OR

TC

QL

Q-C

30)

Intravenous Oral

p=0.005

p=0.032

Better

Worse

0

–10

–20

–30

–40

–50

Bondronat Bondronat Placebo 6mg Placebo 50mg(n=143) (n=137) (n=277) (n=287)

What about GI side effectswith oral Bondronat?

Side effects with oral Bondronat are manageable

5.1 4.7 1.4 0.7 0.79.4

3.5 2.1 2.17.0

Placebo (n=277) Bondronat 50mg (n=286)*

Pat

ien

ts (

%)

100

80

60

40

20

0Hypocalcemia Dyspepsia Nausea Esophagitis Abdominal

painAE

*Two serious AEs:nausea (n=1), duodenal ulcer (n=1)

Diarrhea rate lower than placeboBody 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)

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

Pyrexia and flu-like symptoms*not a concern with Bondronat

1

27

Pat

ien

ts (

%)

50

40

30

20

10

0Bondronat 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)