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Myelodysplastic Syndrome - An underserved population offers commercial opportunity

SuperGen/MGI Pharma's Dacogen and Celgene's Revlimid are in pre-registration for treatment of myelodysplastic syndrome (MDS). However, the former's similar efficacy and toxicity to Pharmion's Vidaza, the first drug indicated for MDS, coupled with the limited target population of the Revlimid, will leave a significant proportion of the MDS population underserved by pharmacotherapy.

Scope

Overview of MDS epidemiology, classification and staging, prognosis and risk factors

Examination of unmet needs in MDS treatment and market opportunities for drug developers

Review of current treatment controversies and physician opinion of existing and future treatment strategies

Profile of the therapeutic and commercial potential of pipeline drugs

Report Highlights
MDS can affect all ages but is predominantly found in the elderly, with the Aplastic Anemia & MDS International Foundation estimating that 80% of those affected are over 60 years of age. Consequently as a result of the elderly suffering more co-morbidities and poorer prognosis, the current treatment of MDS consists mainly of supportive care.

In the years following Dacogen's anticipated US launch in 2006, Datamonitor predicts the sales margin between it and Vidaza will narrow as physicians gain familiarity with Dacogen and SuperGen/MGI Pharma establish more convenient dosing regimens. However, Vidaza is still predicted to maintain a market lead over its closest direct competitor.

Recently recommended by the FDA's Advisory Committee for accelerated approval, Revlimid looks certain to enter the MDS market in 2006. Indicated for lower-risk MDS in the presence of a chromosome abnormality known as 5q-, Revlimid will quickly become the standard treatment in this patient cohort with additional off-label use also predicted.

Reasons to Purchase

Understand current controversies in MDS treatment and adopt knowledge from this report to drive strategic planning for novel MDS therapeutics

Assess opportunities and risks for innovative treatments within the MDS market

Gain insight into current treatment paradigms, as reported by leading oncologists/ hematologists

Table of Contents

• ABOUT DATAMONITOR HEALTHCARE - page 2
  • About the Oncology pharmaceutical analysis team - page 2
    • Richard Faint, Director of Oncology - page 2
• CHAPTER 1 EXECUTIVE SUMMARY - page 5
  • Introduction - page 5
  • Scope and coverage of the brief - page 5
  • Key findings - page 6
    • MDS epidemiology is poorly monitored - page 6
    • Curative therapy is elusive and supportive care remains the mainstay of treatment for the majority of patients - page 6
    • The adverse effect profile of Pharmion's Vidaza is a key barrier to its widespread use - page 6
    • SuperGen/MGI Pharma's Dacogen fails to improve upon Vidaza's efficacy and is associated with a more cumbersome administration schedule - page 7
    • Sales between Vidaza and Dacogen will narrow following the latters' launch but Vidaza is still predicted to maintain a market lead - page 7
    • Celgene's Revlimid can expect rapid uptake, both on- and off-label, following its predicted US launch in 2006 - page 7
    • Further opportunities exist for developers wanting to join this niche market - page 7
• CHAPTER 2 DISEASE OVERVIEW - page 9
  • MDS is a clonal hematopoietic stem cell disorder - page 9
  • MDS diagnosis, classification and staging: unresolved controversies remain - page 9
    • The French-American-British (FAB) system involves five subgroups - page 10
    • The World Health Organization (WHO) system incorprates new diagnostic information to stratify MDS patients - page 11
    • The International Prognostic Scoring System (IPSS) provides the most accurate prognostic assessment - page 13
  • MDS epidemiology: a poorly monitored disease on the rise - page 15
  • Range of risk factors linked to MDS - page 18
  • MDS prognosis is particularly poor for Int-2/high-risk patients - page 19
• CHAPTER 3 CURRENT TREATMENT CONTROVERSIES - page 21
  • Bone marrow transplantation: potentially curative MDS treatment only available to small patient subgroup - page 21
  • MDS treatment goals highlight major unmet needs - page 22
  • The three treatment approaches to MDS - page 22
  • Supportive care therapies address MDS symptoms only - page 22
  • Low-intensity therapies may improve hematological status - page 23
  • High-intensity therapies are associated with increased morbidity and mortality - page 24
  • Supportive care alone is the standard treatment for the majority of MDS patients - page 24
    • Review of supportive care treatments used by surveyed physicians - page 25
      • Blood transfusions prove problematic - page 25
    • Cytokines improve hematological status - page 26
      • Management of anemia with erythropoietin-stimulating factors is key - page 26
      • Amgen's Aranesp (darbepoietin alfa) may improve patient compliance with more convenient administration schedule - page 27
      • EPO and G-CSF combination therapy improves response rate but is economically-challenging - page 28
      • Management of neutropenia and thrombocytopenia is a major unmet need - page 28
  • Pharmion's Vidaza (azacitadine): the first FDA approved MDS therapeutic - page 29
    • Vidaza demonstrates response rate of 16% across all FAB subtypes in Phase III study - page 30
      • Phase III study shows Vidaza improves time to AML progression or death for intermediate and high-risk patients - page 31
      • Vidaza's early activity in MDS emerges from Phase II data - page 31
    • Vidaza's adverse-effect profile limits treatment to high-risk patients - page 33
    • Confusion regarding Vidaza's duration of treatment exists - page 34
    • Vidaza's administration schedule unappealling to patients and physicians - page 35
    • Despite Vidaza's launch significant market opportunites still exist in Int-2/high-risk patient population - page 37
  • Toxicity of Celgene/Pharmion's Thalomid (thalidomide) limits it's utility in refractory low or Int-1MDS treatment - page 38
    • Efficacy demonstration limited to low or Int-1 MDS - page 38
    • Thalomid may have a role in growth-factor refractory patients who seek an orally administered alternative to Vidaza - page 39
  • Cephalon's Trisonex (arsenic trioxide) may confer improved hematological improvement over Thalomid in refractory high-risk MDS - page 39
    • Trisenox yields transfusion independence in low- and high-risk MDS, but few complete or partial remissions - page 40
    • Grade III and IV adverse effects necessitate close patient monitoring - page 40
• CHAPTER 4 THE TWO NEWCOMERS: SUPERGEN/MGI PHARMA'S DACOGEN AND CELEGENE'S REVLIMID - page 42
  • FDA approval of SuperGen/MGI Pharma's Dacogen (decitabine) deferred pending analysis of transfusion data - page 42
    • Dacogen is a pro-drug that incorporates into DNA to inhibit DNA methyltransferase - page 42
    • Dacogen misses Phase III trial endpoint of time to AML progression, while demonstrating similar response rate to Vidaza - page 43
    • Dacogen demonstrates promising Phase II results, especially in high-grade MDS - page 45
    • What does Dacogen offer over Vidaza? - page 46
      • Dacogen has similar efficacy and safety profile to Vidaza - page 46
      • Dacogen fails to improve on inconvenience of Vidaza's administration schedule - page 46
      • Physicians believe Dacogen may be preferred to Vidaza in Int-2 and high-risk MDS patients - page 48
  • Celgene's Revlimid (lenalidomide) NDA under review for 5q- MDS - page 49
    • Revimid is a novel immunomodulatory analogue of thalidomide - page 50
    • Revlimid demonstrates impressive transfusion-independence Phase II data but toxicity concerns exist - page 50
      • Upto 80% of patients in the MDS-003 trial required the doses of Revlimid to be held or reduced - page 50
      • Physicians view Revlimid's toxicity as manageable - page 51
    • With convenient oral delivery, Revlimid uptake will be quick in low-risk/Int-1 groups - page 52
    • Lack of treatment options for advanced MDS may lead to off-label Revlimid use for Int-2/high-risk patients - page 52
  • The market impact of Revlimid and Dacogen upon Vidaza sales - page 53
    • Vidaza to remain US market leader for Int-2/high-risk MDS following Dacogen's launch, though EU market more evenly matched - page 53
    • Revlimid to achieve significant on- and off-label market penetration in low-risk/Int-1 MDS - page 53
• CHAPTER 5 MDS PIPELINE FOCUSED ON HEMATOLOGICAL IMPROVEMENT RATHER THAN AML PROGRESSION - page 58
  • Review of MDS pipeline drugs in Phase III development - page 60
    • Vion Pharmaceutical's Cloretazine (VNP-40101M) requires more explicit demonstration of MDS activity - page 60
      • Phase III clinical trials focus on AML - page 60
      • No breakdown of response in MDS sub-group provided in Phase II study - page 60
    • Johnson & Johnson's Zarnestra (tipifarnib) holds promise with further MDS development eagerly anticipated - page 61
      • Zarnestra demonstrates impressive MDS Phase II results, though whether J&J will enter Phase III MDS trials remains unclear - page 62
    • Pfizer's Atgam (Antithymocyte Globulin (ATG) has potent immunosuppressive activity - page 63
      • Phase III study open to recruitment - page 63
      • Phase II results demonstrate statistically significant clinical benefit compared with historic cohorts - page 63
    • Schering Plough's Sarasar (lonafarnib) to challenge Johnson and Johnson's Zarnestra - page 64
      • Clinical trials: main focus of Sarasar development is MDS, where greatest antitumor activity is shown - page 64
      • Sarasar and Zarnestra race to commercialization - page 65
  • Opportunities exist for developers wanting to join this niche market - page 65
• APPENDIX - page 66
  • Bibliography - page 66
  • Disclaimer - page 73


• List of Tables
• Table 1: French-American-British (FAB) MDS classification system - page 10
• Table 2: WHO classification and criteria for MDS - page 12
• Table 3: International Prognostic Scoring System: derivation of patient score - page 14
• Table 4: MDS patient subtype breakdown by IPSS score - page 14
• Table 5: Population forecast of under and over 65 year olds in the seven major markets, 2005-2010 - page 16
• Table 6: MDS incidence forecast in the seven major markets, 2005-2010 - page 17
• Table 7: Median survival, interval & risk to AML by IPSS category - page 20
• Table 8: NCCN MDS supportive care recommended drugs - page 23
• Table 9: NCCN MDS low-intensity guidelines - page 24
• Table 10: Current treatment of MDS by severity - page 25
• Table 11: EPO clinical studies of erythroid response - page 27
• Table 12: Response rates in Vidaza-treated patients in Phase II and III studies - page 33
• Table 13: Dacogen's Phase III (0007) response rates - page 44
• Table 14: Dacogen's Phase III results of median time to AML or death (days) - page 45
• Table 15: Dacogen's Phase II trial response rates (CR +PR) - page 45
• Table 16: Revlimid Phase II response rate data - page 51
• Table 17: MDS market forecast ($m), 2005-10 - page 54
• Table 18: MDS Prevalence Forecast, 2005-2010 - page 55
• Table 19: Product market penetration forecast 2005-2010 (EU and US) - page 56
• Table 20: Product price, US and EU ($) - page 57
• Table 21: MDS pipeline, September 2005 - page 58


• List of Figures
• Figure 1: MDS incidence forecast in the seven major markets, 2005-2010 - page 17
• Figure 2: Median survival & interval to AML by IPSS category - page 19
• Figure 3: National Comprehensive Cancer Network MDS Treatment Guidelines - page 21
• Figure 4: Barriers to use of Vidaza in low/Int-1 risk MDS (1 = low barrier, 6 = high barrier) - page 36
• Figure 5: Barriers to use of Vidaza in Int-2/high risk MDS (1=low barrier 6=high barrier) - page 37

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