Stakeholder Opinions: Bone Metastases - Impending patent expiries may help make or break newer agents

Stakeholder Opinions: Bone Metastases - Impending patent expiries may help make or break newer agents

Introduction

Bone metastases are a complication of some advanced cancers including cancers of the breast, lung, prostate, kidney and thyroid. The incidence of bone metastases across these tumor types in the seven major markets is forecasted to total 225,174 in 2008. While treatment with bisphosphonates reduces the risk of skeletal complications, they do not improve survival in the majority of patients.

Scope

ABOUT DATAMONITOR HEALTHCARE 2
About the Oncology pharmaceutical analysis team 2
CHAPTER 1 EXECUTIVE SUMMARY 3
Scope of analysis 3
Datamonitor insight into bone metastases 3
Related reports 4
Upcoming reports 4
CHAPTER 2 OVERVIEW OF BONE METASTASES 6
Bone metastases are a frequent complication of advanced cancers 6
Cancer cells commonly metastasize to the bone 6
The principles of cancer metastases 6
The 'seed and soil' hypothesis 8
Is bone a fertile 'soil' for metastatic growth? 9
The bone remodeling process 9
Bone resorption by osteoclasts 10
Bone formation by osteoblasts 13
Bone metastases cause dysregulation of the normal bone remodeling process 14
Osteolytic metastases 14
Cancer cells induce the formation of growth factors and cytokines involved in osteoclast activation 14
Parathyroid hormone-related peptide mediates osteolysis 15
The vicious cycle of osteolytic metastasis 15
Osteoblastic metastases 16
Endothelin-1 may be an important regulator of bone formation 16
Possible mediators of osteoblastic metastases 17
Anatomy and complications of bone metastases 18
Bone pain 19
Hypercalcemia 19
Pathological fractures 20
Spinal cord compression 20
Diagnosis of bone metastases 20
The value of biochemical markers of bone metabolism 21
Epidemiology 22
Incidence of advanced cancers 23
Estimated incidence of bone metastases 26
Multiple myeloma incidence 28
Survival of patients with bone metastases 29
CHAPTER 3 CURRENT TREATMENT OPTIONS FOR BONE METASTASES 31
Introduction to bone metastases treatment 31
Bisphosphonates 32
Bisphosphonates reduce the risk of skeletal-related events 34
Pamidronate 35
Clinical trial data 35
Bondronat (ibandronate) 36
Clinical trial data 36
Ongoing clinical development 38
Clodronate 38
Clinical trial data 39
Ongoing clinical development of clodronate 39
Zometa (zoledronate) 40
Clinical trial data 40
Ongoing clinical development 42
The choice and duration of bisphosphonate therapy 44
The choice of administration is matched to patient needs 44
Zometa has significant advantages over other bisphosphonates 45
The duration of bisphosphonate therapy is based on clinical judgment 45
Adverse effects of bisphosphonates 46
Osteonecrosis of the jaw 47
Future directions for bisphosphonate therapy 48
Bisphosphonates reduce elevated levels of bone markers 48
Can bisphosphonates prevent bone metastases? 49
Reducing tumor burden by inhibiting bone metastases 50
Radiotherapy helps reduce bone pain 51
Radiopharmaceuticals 51
Surgery is often wrongly deemed "too risky" 53
CHAPTER 4 UNMET NEEDS IN BONE METASTASES 54
There is a need to predict which patients will develop bone metastases 54
Patients may be on bisphosphonates for too long 55
New therapies required to improve current poor patient survival 56
Drugs needed to specifically target osteoblastic metastases 56
Summary of unmet needs 57
CHAPTER 5 PIPELINE ANALYSIS 59
The bone metastases pipeline overview 59
Phase III drug profiles 59
Denosumab (Amgen/Daiichi Sankyo) 59
Key historical events 61
Clinical trial data for denosumab 62
Clinical development of denosumab 64
Datamonitor comments 65
Phase II drug profiles 67
Alpharadin (AT1-BC-1; Algeta) 67
Key historical events 67
Clinical trial data for Alpharadin 68
Clinical development of Alpharadin 70
Datamonitor comments 70
MER-101 (Merrion) 71
Clinical development of MER-101 71
Datamonitor comments 72
Odanacatib (Merck) 73
Key Historical events 73
Clinical development of odanacatib 73
Datamonitor comments 74
CHAPTER 6 KEY OPINION LEADERS INTERVIEWED 76
Key opinion leaders interviewed 76
APPENDIX 77
Bibliography 77
Journals 77
Websites 85
Other 87
Abbreviations 90
List of tables 91
List of figures 92
About Datamonitor 93
About Datamonitor Healthcare 93
About the Oncology analysis team 94
Disclaimer 95
List of Tables
Table 1: Regulation of bone resorption 11
Table 2: Regulation of bone formation 13
Table 3: Biochemical markers of bone metabolism 22
Table 4: Total incidence of five cancer types across the seven major pharmaceutical markets, 2002-18 24
Table 5: Incidence of advanced cancers in the seven major pharmaceutical markets, 2002-18 25
Table 6: Incidence of advanced cancers in the seven major pharmaceutical markets in 2008 26
Table 7: Estimated incidence of bone metastases in five cancer types across the seven major pharmaceutical markets, 2002-18 27
Table 8: Estimated incidence of bone metastases in five cancer types across the seven major pharmaceutical markets in 2008 28
Table 9: Incidence of multiple myeloma in the seven major pharmaceutical markets, 2002-18 29
Table 10: Bisphosphonates approved for bone metastases in oncology, 2008 33
Table 11: Approval information for Bondronat in Oncology 36
Table 12: Ongoing Phase III development of Bondronat, 2008 38
Table 13: Ongoing Phase III development of clodronate 40
Table 14: Zometa reduces the risk of skeletal-related events across different tumor types 42
Table 15: Ongoing Phase III clinical development for Zometa, 2008 43
Table 16: Bisphosphonates: IV/oral regimens and potencies relative to Didronel* 45
Table 17: Study outcomes for Zometa in the prevention of bone metastases 49
Table 18: Phase III trial for the combination of radiopharmaceuticals with Zometa 52
Table 19: Pipeline drugs for bone metastases, 2008 59
Table 20: Denosumab: key historical events 62
Table 21: Denosumab: ongoing clinical trials in bone metastases 64
Table 22: Alpharadin: key historical events 68
Table 23: Alpharadin: ongoing clinical development in bone metastases 70
Table 24: Odanacatib: key historical events 73
Table 25: Odanacatib: ongoing clinical development in bone metastases 74
Table 26: Abbreviations used in Stakeholder Opinions: Bone Metastases, 2008 90
List of Figures
Figure 1: The principles of cancer metastases 7
Figure 2: Common sites of metastases for different primary cancers 8
Figure 3: The bone remodeling process 9
Figure 4: Osteoclast activation via RANKL/RANK binding on osteoclast precursors 10
Figure 5: The effect of osteoprotegerin on osteoclast activation 12
Figure 6: The vicious cycle of osteolytic metastasis 16
Figure 7: Factors involved in osteoblastic bone metastases 17
Figure 8: Skeletal regions most affected by bone metastases 18
Figure 9: Detecting bone metastases 21
Figure 10: Percentage incidence of bone metastases by advanced primary cancer type 23
Figure 11: Percentage incidence of advanced cancers 24
Figure 12: Generating the incidence of bone metastases* 27
Figure 13: Median and 5-year survival rates for bone metastases patients 30
Figure 14: A brief overview of bone metastases treatment 32
Figure 15: Pamidronate: results from two Phase III trials in breast cancer patients with bone metastases 35
Figure 16: Bondronat: Phase III trial results in breast cancer bone metastases patients 37
Figure 17: Clodronate trial results in breast cancer bone metastases patients 39
Figure 18: Zometa: Phase III results in breast and multiple myeloma patients 41
Figure 19: Adverse effects associated with bisphosphonate therapy 46
Figure 20: Unmet needs in bone metastases 57
Figure 21: Denosumab: mechanism of action 61
Figure 22: Denosumab: Phase II results in bisphosphonate-naïve breast cancer patients 63
Figure 23: Alpharadin: Phase II results in hormone-refractory prostate cancer patients with bone metastases 69