PA-1

Pathophysiology of Metastatic Bone Disease and the

Role of Bisphosphonates

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PA-2

Disease prevalence, Disease prevalence, Bone mets. Bone mets. MedianMedianU.S. (in thousands)U.S. (in thousands) incidence (%)incidence (%) survival (mo) survival (mo)

MyelomaMyeloma 75 - 100 75 - 100 70 - 9570 - 95 2424RenalRenal 198 198 20 - 2520 - 25 1212MelanomaMelanoma 467 467 14 - 4514 - 45 66BladderBladder 582 582 4040 6 - 96 - 9ThyroidThyroid 207 207 6060 4848LungLung 386 386 30 - 4030 - 40 77BreastBreast 1,993 1,993 65 - 7565 - 75 2424ProstateProstate 984 984 65 - 7565 - 75 3636

Clinical Importance and Prognosis of Bone Metastases

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NCI, 1997; International Myeloma Foundation, 2001.

PA-3

Skeletal Complications in Metastatic Bone Disease Are Significant

% of patients affected in PLACEBO arms of:

Pamidronate trials ZOMETA® trials

Disease Breast Myeloma Prostate OthersObservation time 12 months 9 months 15 months 9 months

Radiation to bone 33 22 29 32

Fractures 41 30 22 21

Hypercalcaemiaof malignancy 9 6 1 3

Surgery to bone 8 5 3 4

Spinal cordcompression 2 3 7 4

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PA-4

Role of the osteoclast in bone pathology

Growthfactors

Osteoclast activity

Osteolysis Direct bone destruction

Bone

Bone secondariesPrimary

Local factorsSystemic factors

Tumour cells

Bony complications

Pathophysiology of Bone Metastases

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Activatedosteoclast

PA-5

Cancer and Bone Cell Interactions

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Osteolytic bone disease Osteoblastic bone disease

Osteoclast

Osteoblast

UnknownGFs

TGF-

PA-6

Bone RemodellingCancer Effects

C

Coupled andbalanced

Bone

Uncoupled butbalanced

Bone

Coupled butimbalanced

Bone

Uncoupled andimbalanced

Bone

PA-7

Lytic Blastic MixedX-ray pattern

Bo

ne

-sp

ec

ific

alk

alin

e p

ho

sp

hat

as

e (

ng

/mL

)

N-t

elo

pe

pti

de

(BC

E/M

Cr)

Bone Markers in Osteolytic and Bone Markers in Osteolytic and Osteosclerotic Metastatic Bone DiseaseOsteosclerotic Metastatic Bone Disease

0

10

30

20

40

50

60

Lytic Blastic MixedX-ray pattern

0

100

300

200

400

500

C

Lipton A. Semin Oncol. 2001;28:54-59.

PA-8

Increasedbone

resorption

Hypercalcaemia

Fracture

Bone pain

Consequences of Increased Bone Resorption

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Bone

PA-9

Treatment of Bone Metastases

Traditional treatmentsTraditional treatments Radiotherapy/radionuclides

Endocrine treatment

Chemotherapy

Orthopaedic intervention

Analgesics

Complementary approachComplementary approach

Osteoclast inhibition

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PA-10

Bisphosphonate Pharmacology

Proposed mode of actionProposed mode of action

Aminobisphosphonates Bisphosphonates

Bisphosphonates

Precursorcells

Matureosteoclasts

Accession

Tumourcells

Prostaglandinsand other

factors

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PA-11

§Not placebo-controlled.

Prevention of Skeletal-Related Events Phase III Pamidronate Studies

Breast cancer Conte, 1996 (N = 295) - chemotherapy§

– Increased time to progression - 249 versus 168 days (P = .02) Hultborn, 1996 (N = 401) - chemotherapy§

– Increased time to progression - 14 versus 9 months (P < .01)

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Theriault, 1999 (N = 374) - endocrine– Reduced proportion of SREs - 47% versus 57% (P = .057)

Hortobagyi, 1996 (N = 382) - chemotherapy – Reduced proportion of SREs - 43% versus 56% (P = .008)

Myeloma Berenson, 1996 (N = 377) - first and second-line therapy

– Reduced proportion of SREs - 24% versus 41% (P < .001)

PA-12

Proportion of Patients Having SREsPooled Breast Cancer Clinical Trials (N = 756)

45

20

35

56

3341

0

20

40

60

80

100

All SREs(–HCM)

Radiationto bone

Fractures

Pe

rce

nt

of

pa

tie

nts

51

29

40

64

4352

0

20

40

60

80

100

All SREs(–HCM)

Radiationto bone

Fractures

Pe

rce

nt

of

pa

tie

nts

Pam 90 mg Placebo

12 months 24 months

P = .002 P < .001 P = .078 P < .001 P < .001 P = .002

Lipton A, et al. Cancer. 2000;88:1082-1090. Novartis. Data on file.

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PA-13

Proportion of Patients Having SREsMultiple Myeloma (N = 377)

2414 17

41

2230

0

20

40

60

80

100

All SREs(–HCM)

Radiationto bone

Fractures

Per

cen

t o

f p

atie

nts

38

2531

51

34 37

0

20

40

60

80

100

All SREs(–HCM)

Radiationto bone

FracturesP

erce

nt

of

pat

ien

ts

Pam 90 mg Placebo

9 months 21 months

P < .001 P = .049 P = .004 P = .015 P = .060 P = .255

Berenson JR, et al. N Engl J Med. 1996;334:488-493.Berenson JR, et al. J Clin Oncol. 1998;16:593-602.

39

PA-14

Total Number of SREs Recorded During Randomised Clinical Trials of Pamidronate

Breast Breast MyelomaProtocol 19 Protocol 18 Protocol 12

24 mo 24 mo 21 mo

Pam Pam PamSRE 90 mg Placebo 90 mg Placebo 90 mg Placebo

All SRE (+HCM)All SRE (+HCM) 387387 630630 475475 648648 307307 376376

Pathologic fracturePathologic fracture 251251 349349 331331 403403 170170 189189

Vertebral fractureVertebral fracture 103103 148148 115115 143143 9696 123123

Nonvertebral fractureNonvertebral fracture 148148 201201 216216 260260 7474 6666

Radiation to boneRadiation to bone 105105 207207 114114 192192 9797 129129

Surgery to boneSurgery to bone 1414 2828 1515 2424 1515 2525

Spinal cord compressionSpinal cord compression 44 77 77 88 22 88

HypercalcaemiaHypercalcaemia 1313 3939 88 2121 2323 2525

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PA-15

Effects of Pamidronate on Pain and Analgesic Consumption

Breast cancerBreast cancerChemotherapyChemotherapy

24 mo24 mo

Breast cancerBreast cancerEndocrine

24 mo

MultipleMultiplemyelomamyeloma

9 mo9 mo

1.52 1.55

0.590.74

0.0

0.5

1.0

1.5

2.0

2.5

3.0

Pain scoreRTOG

AnalgesicscoreRTOG

P = .028 P = .009

1.38

2.28

0.24

0.9

0.0

0.5

1.0

1.5

2.0

2.5

3.0

Pain scoreRTOG

AnalgesicscoreRTOG

P = .011 P = < .001

0.180.55

-0.46-0.09

-1.0

-0.5

0.0

0.5

1.0

1.5

2.0

2.5

3.0

Pain scoreRTOG

AnalgesicscoreRTOG

P = .089 P = .050

Pamidronate Placebo

Pain and analgesic scores at the last measurement mean change from baseline

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PA-16

Prostate Cancer and Other Tumours

Increased bone resorption with osteosclerotic metastases

Useful pain relief from acute high-dose bisphosphonate treatment

No previous randomised trial evidence for bisphosphonate effects on SREs

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PA-17

(–HCM) at 6 months—Protocols 032 and INT05Total N = 378

0

0.1

0.2

0.3

0.4

Total

24% 24%

P = 1.0

Pro

po

rtio

n w

ith

SR

E (

–HC

M)

SRE SMR

Mea

n S

MR

(–H

CM

)

0

0.2

0.4

0.6

0.8

Total

Pam 90 mgPlacebo

P = .942

17

0.30 0.29

Pamidronate in Prostate CancerNo Effect on Proportion of Patients With SRE and Mean SMR

Lipton A, et al. Cancer Invest. 2001;20:45-47.

PA-18

Adverse Events Profile of Pamidronate

Acute phase response

– Fever, myalgia, arthralgia

Anaemia

Mineral disorders

Renal effects

– Dose and infusion time related

PA-19

Zoledronic Acid

Zoledronic acid is a new, highly potent bisphosphonate

Heterocyclic nitrogen-containing bisphosphonate composed of

– A core bisphosphonate moiety

– An imidazole-ring side chain containing 2 critically positioned nitrogen atoms

Green JR, et al. J Bone Miner Res. 1994;9:745-751.Green JR, et al. Pharmacol Toxicol. 1997;80:225-230.

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PA-20

ZOMETA® Key Preclinical Properties

In vitroIn vitro Potently inhibits osteoclast formation and bone

resorption regardless of pathogenetic stimulus

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In vivoIn vivo Potently inhibits bone resorption in a variety of

models of benign and malignant bone disease irrespective of tumour types

Preserves bone architecture and strength Novel anti-angiogenic and anti-pain effects Reduces the number and size of bone metastases

in models of tumour-induced osteolysis

PA-21

ZOMETA®

Key Clinical Pharmacology Properties

Similar to other bisphosphonates Similar to other bisphosphonates in vitroin vitro

Low protein binding; no uptake by red blood cells

No interaction with CYP450 metabolising enzymes

Similar to other bisphosphonates Similar to other bisphosphonates in vivoin vivo

Rapid postinfusion decline of plasma concentrations of drug; plasma drug concentrations are dose proportional

Majority of drug is taken up by bone; remainder is rapidly eliminated into urine unchanged (ca. 40% of dose 0-24h)

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§Berenson J, et al. J Clin Pharmacol. 1997;37:285.

PA-22

Mild to moderate renal impairment (CLcr 30 - 80 mL/min) is associated with a small increase in AUC0-24h and Cmax, but has no effect on urinary excretion

The increase in AUC0-24h and Cmax is not affected by cumulative dose

Dose adjustments in renal impairment (CLcr 30 - 80 mL/min) are not needed

Treatment cycle

1 2 3

AU

C0-

24h, n

g/m

L•h

100

200

300

400

500

600

700

800

900

Normal Mild Moderate/Severe

ZOMETA®

Key Clinical Pharmacology Properties

PA-23

Phase II Study (007) Results Support ZOMETA® 4-mg Infusion Every 3 to 4 Wk

ZOMETA® given every 4 wk produced sustained effects on serum and urinary markers of bone resorption

The 4-mg dose was most effective in suppressing markers of bone resorption

Skeletal events and pathologic fractures occurred slightly less frequently in patients treated with 4 mg than 2 mg ZOMETA

ZOMETA 0.4 mg was clearly ineffective compared with 2 mg and 4 mg

Time to first skeletal event in breast cancer patients was almost 2 mo longer in the 4-mg versus 2-mg dose group

PA-24Urinary N-telopeptide/Creatinine Ratio After the First and Subsequent (q4 wk) Doses of ZOMETA® (Study 007)

-80

-60

-40

-20

0

Baseline Wk 1 Wk 4 Wk 12 Wk 24 Wk 40

ZOMETA dose 1 2 3 4 5 6 7 8 9

Med

ian

% c

han

ge

fro

m

bas

elin

e

ZOMETA 0.4 mg ZOMETA 2 mg

ZOMETA 4 mg Pam 90 mg

PA-25

Pooled Protocols 036 and 037—complete response rate: normalisation of corrected serum calcium 10.8 mg/dL ( 2.7 mmol/L)

Co

mp

lete

res

po

nd

ers

(%)

*Denotes statistical significance versus pamidronate. Major P, et al. J Clin Oncol. 2001;19:558-567.

Efficacy in Hypercalcaemia of Malignancy

0

20

40

60

80

100

Day 0 Day 4 Day 7 Day 10

ZOMETA® 4 mg (n = 86)

ZOMETA 8 mg (n = 90)

Pamidronate 90 mg (n = 99)

83.3%P = .010*

56%P = .021*

88%P = .002*

87%P = .015*82.6%

P = .005*

45%

33%

64%70%

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PA-26

Conclusions

Metastatic bone disease is an important healthcare problem

Pathophysiology is similar across all tumour types

Osteoclast activation accompanies all bone metastases

Currently available bisphosphonates have a limitedrange of activity

ZOMETA® is a potent inhibitor of osteoclast activity and provides a bone-specific treatment

C