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Stakeholder Opinions: Cancer Cachexia - Higher profile needed to unlock market potential of neglected syndrome

ABOUT DATAMONITOR HEALTHCARE 2
About the Oncology pharmaceutical analysis team 2

CHAPTER 1 EXECUTIVE SUMMARY 4
Scope of analysis 4
Datamonitor insight into the cancer cachexia market 4
Contributing experts 5
Related reports 6
Upcoming reports 6

CHAPTER 2 CANCER CACHEXIA OVERVIEW 8
Key findings 8
Introduction to cancer cachexia 9
Characteristics of cancer cachexia 9
Cancer cachexia is a syndrome characterized by progressive weight loss 9
Defining cancer cachexia 10
Cancer cachexia lacks a universal definition... 10
...although recent progress has been made towards a definition 11
Progression of cancer cachexia 13
Cancer cachexia covers a broad spectrum of severity 13
Impact of cancer cachexia 14
Survival is lower in cancer patients with cachexia 14
Patients with cancer cachexia show a poorer response to chemotherapy 15
Cancer cachexia adversely affects quality of life 15
Pathophysiology of cancer cachexia 15
Cancer cachexia results from a combination of reduced food intake and altered metabolism driven by host-tumor interactions 15
Reduced food intake 17
Altered metabolism 18
Additional factors contributing to the cachexia syndrome 19
Epidemiology of cancer cachexia 20
Introduction 20
Forecast cancer incidence in the seven major markets 20
Forecast cancer mortality in the seven major markets 21
Cancer cachexia forecasts 23
Weight loss is most common in patients with gastrointestinal tumors and lung cancers 23
Over 1.3 million incurable cancer patients may be potential candidates for palliative treatment for cachexia in the seven major markets in 2009 28

CHAPTER 3 CURRENT TREATMENT OPTIONS AND CONTROVERSIES 30
Key findings 30
Palliative care in oncology 31
Cachexia is one of several symptoms experienced by cancer patients that require palliative care 31
A number of different types of clinician are involved in cancer cachexia management 32
Current treatment options 33
Drugs used to treat cancer cachexia 33
There is a lack of comprehensive guidelines for the treatment of cancer cachexia 34
Progestational agents are widely used for cancer cachexia therapy 37
Megestrol acetate is one of the most extensively studied agents for cancer cachexia treatment 37
Progestational agents improve appetite but have several limitations 38
Corticosteroids were the first therapy option for cancer cachexia 39
Short-term corticosteroid use improves end-stage cancer patients' well being 39
Nutritional support often helps to increase food intake but does not reverse loss of lean body mass 41
Eicosapentaenoic acid has been extensively investigated but has not shown evidence of clinical efficacy 41
Cannabinoids show lower efficacy in cachexia treatment compared to megestrol acetate 42
Advances in cancer cachexia treatment are likely to require a multimodal approach 43

CHAPTER 4 UNMET NEEDS AND CHALLENGES FACING DRUG DEVELOPERS 48
Key findings 48
Unmet needs 48
In the absence of effective therapies, most cancer cachexia patients do not receive any treatment 48
Pharmaceutical and biotech companies appear reluctant to invest in high-risk cachexia clinical trials 49
Patient recruitment to cancer cachexia clinical trials is problematic 50
Cancer cachexia needs a universally accepted definition 51
Progress in cancer cachexia is hindered by the low profile of the condition 52
The visibility of cancer cachexia is low in the medical oncology community 52
The syndrome needs a higher profile in the oncology community in order to move treatment forward and establish a market 53
Improvement is needed in approaches to palliative care for cancer patients 54
Earlier integration of palliative care into management of cancer patients and better coordination between oncologists and nutritionists is needed 54
Low rate of hospice admissions and tendency to administer chemotherapy late in the course of cancer patients' lives has hindered palliative care 55

CHAPTER 5 DRUG DEVELOPMENT 56
Key findings 56
Overview of the cancer cachexia clinical pipeline 57
Pipeline drugs 58
Angiotensin II-targeting agents 58
Vitor (imidapril hydrochloride; Ark Therapeutics) 58
Hormone-based therapies/hormone mimetics 62
Ghrelin, a circulating appetite-stimulating hormone, shows potential in cancer cachexia therapy 62
Anamorelin (RC-1291; Sapphire Therapeutics/Ono) 63
Growth hormone releasing peptide-2 is also able to directly affect appetite and is in development for cancer cachexia 66
Ostarine (MK-2866; GTx/Merck & Co) 66
Anti-inflammatory drugs 69
Thalomid (thalidomide; Celgene) 69
AVR118 (Advanced Viral Research Corp) 73
VT-122 (Vicus Therapeutics) 76
Drugs targeting neurotransmitter receptors 76
Mirtazapine 76
Olanzapine 77
Cancer cachexia clinical trial design 78
Patient selection 78
Variations in entry criteria across clinical trials reflect the lack of consensus over a definition of the syndrome 78
The choice of tumor type is critical to cancer cachexia clinical trial design 79
Endpoints 80
Change in body weight does not give robust evidence of anti-cachexia activity 80
Lean body mass is a more suitable surrogate of anti-cachexia activity than body weight and is currently the most appropriate primary endpoint 81
Survival is rarely used as an endpoint in cachexia trials 82
Quality of life (QOL) is an important endpoint in cancer cachexia clinical trials 82
Measuring physical function potentially provides objective and quantitative evidence of QOL improvement 83
Cancer cachexia awaits a validated biomarker 84
Pharmacoeconomic endpoints could be considered in clinical trial design 85
BIBLIOGRAPHY 86
Bibliography 86
Datamonitor reports 95

APPENDIX 96
List of tables 96
List of figures 96
About Datamonitor 97
About Datamonitor Healthcare 97
About the Oncology analysis team 98
Disclaimer 99

List of Tables
Table 1: Crude incidence rates per 100,000 persons for all types of cancer (excluding non-melanoma skin cancer) in the seven major markets, 2002 20
Table 2: Forecast total incidence of all types of cancer (excluding non-melanoma skin cancer ) in the seven major markets, 2009-2018 21
Table 3: Crude mortality rates for all types of cancer (excluding non-melanoma skin cancer) in the seven major markets, 2002 21
Table 4: Forecast total mortality from all types of cancer (excluding non-melanoma skin cancer ) in the seven major markets, 2009-2018 22
Table 5: Percentage of cancer patients with weight loss across different tumor types 23
Table 6: Number of patients diagnosed with cancer experiencing weight loss by tumor type in the seven major markets, 2009 24
Table 7: Forecast number of patients diagnosed with cancer who will experience weight loss during the course of their disease in the seven major markets, 2009-2018 26
Table 8: Forecast number of cancer patients experiencing weight loss in the last 1-2 weeks of life in the seven major markets, 2009-2018 28
Table 9: Current treatment options for cancer cachexia, 2009 34
Table 10: Pipeline drugs in clinical development for cancer cachexia, 2009 57
Table 11: Vitor: key historical events, 1993-2008 59
Table 12: Anamorelin: key historical events, 2001-07 64
Table 13: Ostarine: key historical events, 2006-08 67
Table 14: Thalomid: key historical events, 1996-2008 70
Table 15: AVR118: key historical events, 2003-08 74
Table 16: Ongoing trials in cancer cachexia, 2009 74
Table 17: VT-122: key historical events, 2007-08 76

List of Figures
Figure 1: Characteristics associated with cancer cachexia 10
Figure 2: Spectrum of cancer cachexia severity and approximate associated survival 14
Figure 3: Schematic overview of cancer cachexia pathophysiology 17
Figure 4: Number of patients diagnosed with cancer experiencing weight loss by tumor type in the seven major markets, 2009 25
Figure 5: Forecast number of patients diagnosed with cancer who will experience weight loss during the course of their disease in the seven major markets, 2009-2018 27
Figure 6: Forecast number of cancer patients experiencing weight loss in the last 1-2 weeks of life in the seven major markets, 2009-2018 29
Figure 7: Cancer patient treatment flow chart 32
Figure 8: National Comprehensive Cancer Network (NCCN) guidelines for cancer cachexia patients with long life expectancy 35
Figure 9: National Comprehensive Cancer Network (NCCN) guidelines for cancer cachexia patients with short life expectancy 36
Figure 10: Placebo-controlled study of megestrol acetate in cancer cachexia patients 38
Figure 11: Phase III study of megestrol acetate versus dexamethasone and fluoxymesterone 40
Figure 12: Phase III of eicosapentaenoic acid (EPA) in gastrointestinal or lung cancer patients with cachexia 42
Figure 13: Phase III trial of dronabinol versus megestrol acetate in advanced cancer patients 43
Figure 14: Phase III study of eicosapentaenoic acid (EPA) with or without megestrol acetate in cancer cachexia 44
Figure 15: Study of megestrol acetate and ibuprofen combination in gastrointestinal cancer patients with cachexia 45
Figure 16: Phase III trial comparing various treatment options in advanced cancer patients with cachexia 46
Figure 17: Summary of unmet needs in cancer cachexia, 2009 48
Figure 18: Pilot Phase III trial of Vitor in cachectic non-small cell lung cancer patients 60
Figure 19: Phase II/III trial of Vitor in advanced cancer patients with cachexia symptoms 61
Figure 20: Phase II study of anamorelin in cachectic patients with advanced solid tumor cancers 65
Figure 21: Phase II study of Ostarine in cancer cachexia 68
Figure 22: Phase II trial of Thalomid in advanced cancer patients 71
Figure 23: Randomized trial of Thalomid in pancreatic cancer patients with cachexia 72
Figure 24: Results of Phase I/II study of AVR118 in cancer and AIDS cachexia 75
Figure 25: Phase II trial of mirtazapine in advanced cancer patients 77