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Sepsis - Under reaction to an overreaction

Sepsis, a complex and rapidly progressing disease with up to 80% associated mortality, presents major challenges with regard to its epidemiology, definition and management. Rising disease incidence has been fuelled by the growing number of surgical interventions and an increase in immunocompromization. Disease management is predominantly non-specific, relying on a range of interventions.

Scope

Assessment of sepsis epidemiology, disease progression, and approaches to diagnosis and management

In-depth case study of Xigris, the only sepsis-specific drug on the market

Discussion of the challenges associated with the development of a sepsis drug and reasons for the failure of past R&D programs

Overview of immunomodulators currently in clinical development for the treatment of the sepsis response

Report Highlights
Sepsis is widely regarded as the most challenging problem in intensive care, a direct consequence of the complexity of the disease, its rapid progression and heterogeneity of the patient population. Current diagnostics fail to allow for rapid and accurate diagnosis.

The execution of more than 60 randomized trials involving more than 15,000 subjects and costing more than $1 billion has produced only one sepsis-specific drug, Eli Lilly's Xigris. However, due to the drug's high price point, the narrow label and its contraindications, Xigris has failed to meet expectations, with global 2005 sales totaling $214.6m.

Successful development of the sepsis pipeline might lead to the first new drug, Takeda's TAK-242, reaching the market in 2009. Due to the high level of redundancy regarding molecular mediators in the sepsis response, future approaches are likely to focus on intervening at multiple points in the sepsis cascade.

Reasons to Purchase

Understand the challenges associated with the definition and epidemiology of sepsis, both of which impact on effective drug development

Identify unmet needs in sepsis diagnosis and treatment

Optimize R&D strategies for sepsis based on the analysis of past developmental failures

Table of Contents

• ABOUT DATAMONITOR HEALTHCARE - page 2
  • About the Infectious Disease pharmaceutical analysis team - page 2
• CHAPTER 1 EXECUTIVE SUMMARY - page 3
  • Introduction - page 3
  • Scope and coverage of the report - page 3
  • Objective of the analysis - page 3
  • Datamonitor insight into the sepsis market - page 4
    • Sepsis is a complex, multifactorial and rapidly progressing disease characterized by an excessive inflammatory response to infection that leads to organ failure and death, with severe forms of sepsis such as septic shock being associated with up to 80% mortality. In the US, sepsis is the 10th leading cause of death, killing over 200,000 people annually, more than some common forms of cancer. The dramatic rise in the incidence of sepsis during the past decades has been fuelled by an increase in the number of invasive surgical procedures and growing immunocompromization. - page 5
    • Sepsis is widely regarded as the most challenging problem in intensive care, where more than half of all severe cases are treated. This is a direct consequence of the complexity of the disease and its rapid progression; the heterogeneity of the patient population; current diagnostics failing to allow for rapid and accurate diagnosis; and treatment consisting in predominantly non-specific therapy focusing on the control of the infection, hemodynamic stabilization, and modulation of the sepsis response. - page 7
    • Despite the execution of more than 60 randomized trials involving more than 15,000 subjects and costing more than $1 billion (Shulman, 2002), the development of a drug for the treatment of sepsis has remained elusive. Following the completion of the PROWESS trial for Xigris, the first drug to demonstrate a reduction in mortality in severe sepsis patients at high risk of mortality, Eli Lilly first launched Xigris in the US in November 2001. However, despite high expectations and strong first-year sales, Xigris has failed to meet analysts' blockbuster expectations, with global 2005 sales totaling $214.6m. Key reasons for the limited uptake have been the drug's high price point, the narrow label and its contraindications, in particular the increased risk for bleeding. - page 9
    • The current sepsis pipeline has dwindled to a mere seven candidates, with approaches ranging from TLR4 signal transduction inhibitors/antagonists to small molecule anti-nitric oxide (NO) agents. Although experts are confident about some of these products, the first of which might reach the market by 2009, there is still uncertainty regarding the overall benefit of single-drug therapy in sepsis. Future approaches are therefore likely to focus either on the combination of two or more immunomodulators, or the identification of compounds able to intervene at multiple points in the sepsis cascade. - page 11
• CHAPTER 2 SEPSIS DISEASE INSIGHT - page 18
  • Sepsis is a devastating killer - page 18
    • The real incidence of sepsis is far from being clear-cut - page 18
      • Focus on the ICU - page 22
      • The past few decades have seen a dramatic rise in the incidence of sepsis - page 26
    • Sepsis-associated mortality is unacceptably high - page 28
  • Sepsis can rapidly progress to organ failure and death - page 31
    • Sepsis is defined as a systemic inflammatory response resulting from infection - page 31
      • Systemic inflammation and activation of the coagulation cascade are key hallmarks - page 35
    • Bacterial infection is the leading cause of sepsis - page 36
      • The lung is the most common focus of the original infection - page 39
    • A weakened immune system increases the risk for sepsis - page 40
  • Identification and effective management of severe sepsis remains a key challenge in intensive care - page 42
    • Sepsis is currently regarded as the most challenging problem encountered in the ICU - page 42
    • Late diagnosis contributes to high sepsis-associated mortality - page 42
      • The severity of the disease can be either scored or translated into 'predicted mortality' - page 45
    • The management of sepsis currently relies on three major pillars - page 46
      • Anti-infective therapy - page 47
      • Supportive and other care - page 52
    • Sepsis therapy represents a significant economic burden - page 53
• CHAPTER 3 SEPSIS MARKET OVERVIEW - page 54
  • Only one drug is currently on the complex, high-risk sepsis market - page 54
    • Despite the high level of unmet need, the sepsis market has been hard to conquer - page 54
    • Xigris, the first and so far only drug launched for severe sepsis, has failed to impress - page 55
      • Activated protein C has various, yet incompletely-understood, mechanisms of action - page 57
      • Clinical breakthrough leads to rising expectations - page 61
      • Narrow use and high price point limit sales - page 64
      • Price reduction may lead to wider use - page 70
• CHAPTER 4 THE SEPSIS PIPELINE - page 72
  • 'One of the world's oldest and most virulent diseases' attracts little commercial interest - page 72
    • 'Surviving Sepsis Campaign' - a key driving force - page 72
      • The five-point action plan - page 73
      • Evidence-based management guidelines encourage new product use - page 73
  • Disease complexity hampers drug development - page 74
    • Developing drugs for sepsis is not a trivial exercise - page 74
    • Lack of efficacy has forced the discontinuation of numerous late-stage clinical programs - page 76
      • Despite past failures, endotoxin scavengers are still being considered - page 77
      • More recent approaches have targeted the inflammatory and blood-clotting cascades - page 79
      • Several other approaches have also proven fruitless - page 82
    • Current pipeline activity focuses predominantly on the inflammatory response - page 83
      • Takeda's TLR4 antagonist TAK-242 - page 85
      • Protherics's CytoFab anti-TNF-alfa polyclonal antibody - page 87
      • Eisai's TLR4 antagonist eritoran (E5564) - page 88
      • GSK's GR-270773 neutralizes endotoxin - page 91
      • AM-Pharma's bovine intestine-derived alkaline phosphatase - page 92
      • Medinox's Norathiol (NOX-100) neutralizes nitric oxide - page 93
      • GTC Biotherapeutics's transgenic antithrombin III - page 95
    • The first new sepsis drug is unlikely to reach the market before 2009 - page 96
  • The future sepsis-treatment landscape remains uncertain - page 97
• CHAPTER 5 KEY OPINION LEADER TRANSCRIPTS - page 100
  • Key Opinion Leader 1 - page 100
  • Key Opinion Leader 2 - page 115
  • Key Opinion Leader 3 - page 132
  • Key Opinion Leader 4 - page 145
  • Key Opinion Leader 5 - page 157
• APPENDIX - page 161
  • Bibliography - page 161
    • Journal articles - page 161
    • Press releases - page 163
    • Datamonitor reports - page 165
    • Websites - page 165
    • Miscellaneous - page 165
  • Report methodology - page 166
  • About Datamonitor - page 167
    • About Datamonitor Healthcare - page 167
    • About the Infectious Disease analysis team - page 168
    • Disclaimer - page 169


• List of Tables
• Table 1: There is significant regional variation with regard to the reported incidence of severe sepsis - page 19
• Table 2: The current incidence of severe sepsis in the general population might be over 2 million cases per year in the seven major markets - page 22
• Table 3: Incidence of sepsis and severe sepsis in European ICUs, 2002 - page 25
• Table 4: Severe sepsis kills more individuals than some of the most common types of cancer - page 28
• Table 5: Mortality due to sepsis increases rapidly with progressing disease - page 29
• Table 6: Rates of sepsis mortality versus overall hospital mortality in Europe, 2002 - page 30
• Table 7: A range of lab tests are usually performed when (severe) sepsis or septic shock is suspected - page 43
• Table 8: Disease-severity scoring systems and predicted mortality - page 45
• Table 9: Overview of antibacterials commonly used for empirical antibiotic therapy in sepsis - page 51
• Table 10: Xigris: key facts - page 56
• Table 11: Xigris's US, non-US and global sales and yearly sales growth, 2001-2005 - page 65
• Table 12: Past sepsis programs were discontinued predominantly due to lack of efficacy - page 77
• Table 13: Only a handful of compounds are currently in development for the treatment of sepsis - page 84
• Table 14: Compounds undergoing development for the treatment of sepsis - page 113
• Table 15: Compounds undergoing development for the treatment of sepsis - page 130
• Table 16: Compounds undergoing development for the treatment of sepsis - page 143


• List of Figures
• Figure 1: Severe sepsis and septic shock are commonly treated in the ICU - page 24
• Figure 2: According to a 22-year period US study, the incidence and mortality of sepsis have been increasing - page 26
• Figure 3: Sepsis is a progressive disease that can lead to multi-organ failure and death - page 32
• Figure 4: The presence of SIRS is manifested by two or more of four conditions - page 32
• Figure 5: Severe sepsis leads to multi-organ failure - page 34
• Figure 6: The predominance of the pro-inflammatory over the anti-inflammatory response, and coagulation over fibrinolysis, result in multi-organ injury and failure, and death of the patient - page 35
• Figure 7: Sepsis is triggered by infection - page 36
• Figure 8: Bacterial infections account for the vast majority of all cases of sepsis - page 37
• Figure 9: The lung is the most common site of infection leading to sepsis - page 39
• Figure 10: Results of the pan-European SOAP study - page 40
• Figure 11: A weakened immune system is the key risk factor for sepsis - page 41
• Figure 12: Sepsis therapy rests on three non-hierarchical pillars - page 47
• Figure 13: Numerous criteria influence the choice of empirical antibacterial therapy - page 48
• Figure 14: Guidelines for antibiotic therapy in severe sepsis and septic shock - page 50
• Figure 15: Activated Protein C has (at least) three distinct mechanisms of action - page 58
• Figure 16: The Phase III trial PROWESS demonstrated that drotrecogin alfa reduces 28-day all-cause mortality in severe sepsis patients with a high risk of death - page 60
• Figure 17: Combined clinical, commercial and regulatory factors supported Xigris's blockbuster potential - page 64
• Figure 18: Despite a promising start, Xigris sales have failed to impress - page 65
• Figure 19: A range of setbacks has prevented Xigris from achieving blockbuster status - page 70
• Figure 20: The Surviving Sepsis Campaign five-point action plan - page 73
• Figure 21: LPS-activated macrophages release pro-inflammatory cytokines including TNF-alfa and IL-6 - page 80
• Figure 22: Thrombin is a key mediator in the pro-coagulation cascade - page 81
• Figure 23: Macrophages activated by LPS through the TLR4 release inflammatory cytokines - page 85
• Figure 24: Eritoran Phase II trial demonstrates significant reduction in mortality - page 89
• Figure 25: Potential US launches of developmental sepsis drugs - page 97

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