Stakeholder Opinions Myelodysplastic Syndromes First approvals spur some interest in a niche market

CHAPTER 1 EXECUTIVE SUMMARY 3
Scope of analysis 3
Datamonitor insight into the MDS market 3
Related reports 5
Upcoming reports 5
CHAPTER 2 OVERVIEW OF MYELODYSPLASTIC SYNDROMES 7
Introduction 7
Myelodysplastic syndromes (MDS) are a heterogeneous group of hematological malignancies 7
Risk factors in the development of MDS 8
Hallmark of MDS - A hypercellular bone marrow with dysplastic changes in combination with peripheral cytopenias 9
Hypercellularity 10
Dysplasia 11
Peripheral cytopenias 12
Mortality often results from the complications of peripheral blood cytopenias 12
MDS is often a diagnosis of exclusion 12
The molecular pathogenesis of MDS 13
Chromosomal abnormalities are common but little is known about the molecular basis of the disease 13
MDS arises as a multistep process 14
Accelerated apoptosis underlies the cytopenias in early MDS 16
Excessive proliferation accompanies disease progression 16
The classification of MDS 16
French American British (FAB) System 17
The FAB classification system is based on morphological criteria 17
Limitations of the FAB system 18
World Health Organization (WHO) System 18
The WHO classification system incorporates new diagnostic information 18
Classification of chronic myelomonocytic leukemia (CMML) 21
Limitations of the WHO classification system 22
International Prognostic Scoring System (IPSS) 22
The IPSS classification system is the current standard for evaluating prognosis in MDS patients 22
Limitations of the IPSS system 24
Epidemiology 25
The epidemiology of MDS is poorly monitored 25
MDS is predominantly a disease of the elderly 26
A recent study shows that the majority of patients fall into the IPSS Low and Intermediate-1 risk groups 27
The incidence of MDS is expected to rise 27
There will be more than 57,000 new cases of MDS across the seven major markets in 2016 29
CHAPTER 3 CURRENT TREATMENT OPTIONS FOR MDS 32
Overview of MDS management 32
The aim of treatment differs in lower- and higher-risk patients 33
The choice of therapy is not solely dependent on a patient's IPSS risk group 34
Summary of current trends in MDS management 34
The management of IPSS lower-risk MDS patients 37
Supportive care approaches 38
Red blood cell (RBC) transfusion and iron chelation therapy 39
Erythropoietin (EPO) 42
Granulocyte-colony stimulating factor (G-CSF) 46
Platelet transfusions 48
Non-chemotherapy low-intensity agents 49
Thalomid (thalidomide; Celgene/Pharmion) 50
Revlimid (lenalidomide; Celgene) 52
Antithymocyte globulin and cyclosporin A 58
Anti-TNF therapy 61
Vitamin D analogs 63
Low-intensity chemotherapy 63
Vidaza and Dacogen 63
The management of IPSS higher-risk patients 64
Low-intensity chemotherapy - the hypomethylating agents 65
Vidaza (azacitidine; Pharmion) 65
Dacogen (decitabine; MGI Pharma) 71
Comparisons between Vidaza and Dacogen 76
Hematopoietic stem cell transplantation 77
HSCT is the only potentially curative option for MDS patients but its use in older patients is problematic 77
The morbidity and mortality risks associated with HSCT often prohibits its use in lower-risk patients 78
Different transplantation options exist for the treatment of MDS 78
High-intensity chemotherapy 81
High-intensity chemotherapy is an alternative option for higher-risk patients 81
The use of high-intensity chemotherapy may be difficult to justify 82
The management of CMML 82
Supportive care and low-intensity therapy 82
High-intensity therapy 83
CHAPTER 4 UNMET NEEDS IN MDS 84
Summary of unmet needs 84
A better understanding of the molecular pathogenesis 84
Increased R&D efforts 85
Low-intensity therapies with improved efficacy and better toxicity profiles 87
Low-intensity therapies to improve symptoms of anemia and quality of life 88
More effective management of thrombocytopenia 89
Improved HSCT procedures 89
CHAPTER 5 PIPELINE ANALYSIS 91
Summary 91
Pipeline overview 91
Late-phase product pipeline for MDS 91
Phase II product pipeline for MDS 91
Phase I product pipeline for MDS 93
Late-phase MDS drug profiles 93
Sarasar (Lonafarnib; Schering-Plough) 93
Drug overview 93
Key historical events 94
Clinical trial data 95
Datamonitor comments 97
Phase II MDS drug profiles 98
MGCD0103 (Pharmion/MethylGene) 98
Drug overview 98
Key historical events 98
Clinical trial data 99
Romiplostim (Amgen) 100
Drug overview 100
Key historical events 100
Clinical trial data 100
Ceflatonin (Myelostat; ChemGenex Pharmaceuticals) 103
Drug overview 103
Key historical events 103
Clinical trial data 103
Zarnestra (Tipifarnib; Johnson & Johnson) 104
Drug overview 104
Key historical events 105
Clinical trial data 105
Cloretazine (VNP40101M; Vion Pharmaceuticals) 108
Drug overview 108
Key historical events 108
Clinical trial data 109
Clolar/Evoltra (Clofarabine; Genzyme) 112
Drug overview 112
Key historical events 112
Clinical trial data 113
Telintra (TLK-199; Telik) 116
Drug overview 116
Key historical events 117
Clinical trial data 117
APPENDIX 119
Bibliography 119
Journals 119
Websites 129
Other 130
Key opinion leaders 131
List of tables 132
List of figures 132
Abbreviations 132
About Datamonitor 134
About Datamonitor Healthcare 134
About the Oncology analysis team 135
Disclaimer 136
List of Tables
Table 1: Myelodysplastic syndromes (MDS) 8
Table 2: Common recurring chromosomal abnormalities in MDS 13
Table 3: French American British (FAB) classification of MDS 17
Table 4: World Health Organization (WHO) classification of MDS 19
Table 5: WHO classification of myelodysplastic/myeloproliferative diseases (MDS/MPD) 22
Table 6: Survival and progression to AML for MDS patients within the IPSS risk groups 24
Table 7: IPSS classification of MDS patients 27
Table 8: MDS incidence in the seven major markets, 2002-2016 29
Table 9: Treatment guidelines for MDS 34
Table 10: Iron chelators available in the US and EU markets, 2007 41
Table 11: Branded erythropoietins available in the US and EU markets, 2007 43
Table 12: Erythropoietins: ongoing clinical trials in MDS, 2007 44
Table 13: Branded colony-stimulating factors available in the US and EU, 2007 47
Table 14: Thalomid: key historical events 51
Table 15: Thalomid as a single agent in MDS: clinical trial results 51
Table 16: Revlimid: key historical events 52
Table 17: Revlimid: ongoing clinical trials in MDS, 2007 53
Table 18: Antithymocyte globulin (ATG) available in the US and EU, 2007 58
Table 19: Antithymocyte globulin: ongoing clinical trials in MDS, 2007 59
Table 20: Vidaza: Key historical events 65
Table 21: Vidaza: ongoing clinical trials in MDS, 2007 66
Table 22: Response criteria used in the Phase III study of Vidaza versus supportive care in MDS patients 69
Table 23: Dacogen: key historical events 72
Table 24: Dacogen: ongoing clinical trials in MDS, 2007 73
Table 25: Response criteria used in the Phase III study of Dacogen versus supportive care in MDS patients 75
Table 26: Types of hematopoietic stem cell transplantation (HSCT) 78
Table 27: Comparative results of RIC HSCT studies 80
Table 28: High-intensity chemotherapy regimens in MDS: clinical trial results 81
Table 29: Pipeline drugs in Phase III development for MDS, 2007 91
Table 30: Pipeline drugs in Phase II development for MDS, 2007 92
Table 31: Pipeline drugs in Phase I development for MDS, 2007 93
Table 32: Sarasar: key historical events 94
Table 33: Ongoing clinical trials involving Sarasar in MDS, 2007 95
Table 34: MGCD0103: key historical events 98
Table 35: Ongoing clinical trials for MGCD0103 in MDS, 2007 99
Table 36: Romiplostim: key historical events 100
Table 37: Ongoing clinical trials for Romiplostim in MDS, 2007 101
Table 38: Ceflatonin: Key historical events 103
Table 39: Zarnestra: Key historical events 105
Table 40: Ongoing clinical trials involving Zarnestra in MDS, 2007 105
Table 41: Final results from a Phase II study of Zarnestra in Intermediate- and High-risk MDS 107
Table 42: Cloretazine: Key historical events 109
Table 43: Ongoing clinical trials involving Cloretazine in MDS, 2007 110
Table 44: Clolar: Key historical events 113
Table 45: Ongoing clinical trials involving Clolar in MDS, 2007 114
Table 46: Telintra: key historical events 117
Table 47: Ongoing clinical trials involving Telintra in MDS, 2007 117
Table 48: Abbreviations used in Stakeholder Opinions: Myelodysplastic Syndromes 132
List of Figures
Figure 1: Risk factors implicated in the onset of MDS 9
Figure 2: The hematopoiesis process 10
Figure 3: Hypercellularity and peripheral blood cytopenias in MDS 11
Figure 4: The pathophysiology of MDS 15
Figure 5: Median survival for each WHO MDS subtype 20
Figure 6: Cumulative risk of progressing to AML after 2 years for each MDS WHO subtype 21
Figure 7: International Prognostic Scoring System (IPSS) for MDS 23
Figure 8: Male and female incidence of MDS in the US over and under 65 years of age as a percentage of the total US patient population, 2007 26
Figure 9: MDS incidence in the seven major markets, 2007 and 2016 30
Figure 10: Incidence of MDS subtypes in the seven major markets, 2007 31
Figure 11: Factors complicating the management of MDS 32
Figure 12: Summary of supportive care, low-intensity and high-intensity therapies available for the management of MDS 33
Figure 13: Summary of current trends in the management of lower-risk MDS 35
Figure 14: Summary of current trends in the management of higher-risk MDS 36
Figure 15: NCCN treatment guidelines for lower-risk MDS patients (IPSS Low/Intermediate-1) 38
Figure 16: The implications of long-term transfusion dependence 40
Figure 17: Thrombocytopenia in MDS 48
Figure 18: Phase II study of Revlimid in MDS patients with del(5q) 54
Figure 19: Phase II study of Revlimid in MDS patients without del(5q) 55
Figure 20: Phase II study of Revlimid in Intermediate-2/High-risk MDS with del(5q): Interim results 57
Figure 21: Phase III study of Lymphoglobuline with cyclosporine versus best supportive care in Low/Intermediate-1 MDS 60
Figure 22: NCCN treatment guidelines for IPSS Intermediate-2/High-risk MDS patients 64
Figure 23: Phase III study of Vidaza versus supportive care in MDS patients 68
Figure 24: Phase III study of Vidaza versus conventional care regimens in higher-risk MDS 70
Figure 25: Phase III study of Dacogen versus supportive care in patients with MDS 74
Figure 26: US sales of Vidaza and Dacogen, Q1 2006-Q3 2007 76
Figure 27: Summary of unmet needs in the treatment of MDS 84
Figure 28: Clinical development pipeline for MDS, 2007 86
Figure 29: Proteins undergoing farnesylation by farnesyltransferase 94
Figure 30: Phase I/II study of Sarasar in advanced MDS and CMML 96
Figure 31: Phase I/II study of Romiplostim in Low-risk/Intermediate-1 MDS 102
Figure 32: Proteins undergoing farnesylation by farnesyltransferase 104
Figure 33: Phase II study of Zarnestra in Intermediate and High-risk MDS 106
Figure 34: Phase II study of Cloretazine in AML and high-risk MDS 111
Figure 35: Phase II studies of intravenous and oral Clolar in higher-risk MDS 115
Figure 36: Phase I/II study of intravenous Telintra (liposomes for injection) in MDS 118