Prof. Robert Coleman, MD, FRCP Cancer Research Centre Pathophysiology C 4/19/2017 1:42 AM Pathophysiology of Metastatic Bone Disease and the Role of Bisphosphonates Prof. Robert Coleman, MD, FRCP Cancer Research Centre Weston Park Hospital Sheffield, England

Clinical Importance and Prognosis of Bone Metastases Disease prevalence, Bone mets. Median U.S. (in thousands) incidence (%) survival (mo) Myeloma 75 - 100 70 - 95 24 Renal 198 20 - 25 12 Melanoma 467 14 - 45 6 Bladder 582 40 6 - 9 Thyroid 207 60 48 Lung 386 30 - 40 7 Breast 1,993 65 - 75 24 Prostate 984 65 - 75 36 NCI, 1997; International Myeloma Foundation, 2001.

Skeletal Complications in Metastatic Bone Disease Are Significant % of patients affected in PLACEBO arms of: Pamidronate trials ZOMETA® trials Disease Breast Myeloma Prostate Others Observation time 12 months 9 months 15 months 9 months Radiation to bone 33 22 29 32 Fractures 41 30 22 21 Hypercalcaemia of malignancy 9 6 1 3 Surgery to bone 8 5 3 4 Spinal cord compression 2 3 7 4

Pathophysiology of Bone Metastases C Pathophysiology of Bone Metastases Role of the osteoclast in bone pathology Tumour cells Primary Bone secondaries Systemic factors Local factors Osteoclast activity Osteolysis Growth factors Direct bone destruction Activated osteoclast Bone Bony complications

Cancer and Bone Cell Interactions Osteolytic bone disease Osteoblastic bone disease TGF- Unknown GFs Osteoblast Osteoclast

Bone Remodelling Cancer Effects Coupled and balanced Bone Coupled but imbalanced Bone Uncoupled but balanced Bone Uncoupled and imbalanced Bone

Bone Markers in Osteolytic and Osteosclerotic Metastatic Bone Disease 60 500 50 400 40 300 Bone-specific alkaline phosphatase (ng/mL) 30 N-telopeptide (BCE/M Cr) 200 20 100 10 Lytic Blastic Mixed Lytic Blastic Mixed X-ray pattern X-ray pattern Lipton A. Semin Oncol. 2001;28:54-59.

Consequences of Increased Bone Resorption Hypercalcaemia Increased bone resorption Fracture Bone pain Bone

Treatment of Bone Metastases C Treatment of Bone Metastases Traditional treatments Radiotherapy/radionuclides Endocrine treatment Chemotherapy Orthopaedic intervention Analgesics Complementary approach Osteoclast inhibition

Bisphosphonate Pharmacology Proposed mode of action Aminobisphosphonates Bisphosphonates Mature osteoclasts Precursor cells Prostaglandins and other factors Accession Tumour cells Bisphosphonates

Prevention of Skeletal-Related Events Phase III Pamidronate Studies C 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) 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) §Not placebo-controlled.

39 Proportion of Patients Having SREs Pooled Breast Cancer Clinical Trials (N = 756) 12 months 24 months P = .002 P < .001 P = .078 P < .001 P < .001 P = .002 Pam 90 mg Placebo Lipton A, et al. Cancer. 2000;88:1082-1090. Novartis. Data on file.

Proportion of Patients Having SREs Multiple Myeloma (N = 377) 39 Proportion of Patients Having SREs Multiple Myeloma (N = 377) 9 months 21 months P < .001 P = .049 P = .004 P = .015 P = .060 P = .255 Pam 90 mg Placebo Berenson JR, et al. N Engl J Med. 1996;334:488-493. Berenson JR, et al. J Clin Oncol. 1998;16:593-602.

C Total Number of SREs Recorded During Randomised Clinical Trials of Pamidronate Breast Breast Myeloma Protocol 19 Protocol 18 Protocol 12 24 mo 24 mo 21 mo Pam Pam Pam SRE 90 mg Placebo 90 mg Placebo 90 mg Placebo All SRE (+HCM) 387 630 475 648 307 376 Pathologic fracture 251 349 331 403 170 189 Vertebral fracture 103 148 115 143 96 123 Nonvertebral fracture 148 201 216 260 74 66 Radiation to bone 105 207 114 192 97 129 Surgery to bone 14 28 15 24 15 25 Spinal cord compression 4 7 7 8 2 8 Hypercalcaemia 13 39 8 21 23 25

Effects of Pamidronate on Pain and Analgesic Consumption Pain and analgesic scores at the last measurement mean change from baseline Breast cancer Chemotherapy 24 mo Breast cancer Endocrine 24 mo Multiple myeloma 9 mo P = .028 P = .009 P = .011 P = < .001 P = .089 P = .050 Pamidronate Placebo

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

Proportion with SRE (–HCM) 17 Pamidronate in Prostate Cancer No Effect on Proportion of Patients With SRE and Mean SMR (–HCM) at 6 months—Protocols 032 and INT05 Total N = 378 SRE SMR P = 1.0 24% 24% Mean SMR (–HCM) P = .942 Proportion with SRE (–HCM) 0.30 0.29 Lipton A, et al. Cancer Invest. 2001;20:45-47.

Adverse Events Profile of Pamidronate Acute phase response Fever, myalgia, arthralgia Anaemia Mineral disorders Renal effects Dose and infusion time related

Zoledronic Acid Zoledronic acid is a new, highly potent bisphosphonate Pathophysiology 4/19/2017 1:42 AM 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.

ZOMETA® Key Preclinical Properties In vitro Potently inhibits osteoclast formation and bone resorption regardless of pathogenetic stimulus In 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

ZOMETA® Key Clinical Pharmacology Properties 39 ZOMETA® Key Clinical Pharmacology Properties Similar to other bisphosphonates in vitro Low protein binding; no uptake by red blood cells No interaction with CYP450 metabolising enzymes Similar to other bisphosphonates in 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) §Berenson J, et al. J Clin Pharmacol. 1997;37:285.

ZOMETA® Key Clinical Pharmacology Properties 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 Normal Mild Moderate/Severe 900 800 700 600 AUC0-24h, ng/mL•h 500 400 300 200 100 1 2 3 Treatment cycle

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

Median % change from baseline Urinary N-telopeptide/Creatinine Ratio After the First and Subsequent (q4 wk) Doses of ZOMETA® (Study 007) ZOMETA 0.4 mg ZOMETA 2 mg ZOMETA 4 mg Pam 90 mg -20 Median % change from baseline -40 -60 -80 Baseline Wk 1 Wk 4 Wk 12 Wk 24 Wk 40 ZOMETA dose 1 2 3 4 5 6 7 8 9

Efficacy in Hypercalcaemia of Malignancy Pathophysiology C 4/19/2017 1:42 AM Efficacy in Hypercalcaemia of Malignancy 88% P = .002* 83.3% P = .010* 87% P = .015* 82.6% P = .005* 56% P = .021* 70% 64% Complete responders (%) 45% 33% Please add text for each treatment day Pooled Protocols 036 and 037—complete response rate: normalisation of corrected serum calcium  10.8 mg/dL ( 2.7 mmol/L) *Denotes statistical significance versus pamidronate. Major P, et al. J Clin Oncol. 2001;19:558-567.

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