CHAPTER 1 EXECUTIVE SUMMARY

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Introduction

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Scope and coverage of the report

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Objective of the analysis

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Datamonitor insight into the sepsis market

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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.

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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.

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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.

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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.

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CHAPTER 2 SEPSIS DISEASE INSIGHT

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Sepsis is a devastating killer

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The real incidence of sepsis is far from being clear-cut

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Focus on the ICU

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The past few decades have seen a dramatic rise in the incidence of sepsis

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Sepsis-associated mortality is unacceptably high

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Sepsis can rapidly progress to organ failure and death

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Sepsis is defined as a systemic inflammatory response resulting from infection

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Systemic inflammation and activation of the coagulation cascade are key hallmarks

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Bacterial infection is the leading cause of sepsis

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The lung is the most common focus of the original infection

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A weakened immune system increases the risk for sepsis

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Identification and effective management of severe sepsis remains a key challenge in intensive care

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Sepsis is currently regarded as the most challenging problem encountered in the ICU

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Late diagnosis contributes to high sepsis-associated mortality

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The severity of the disease can be either scored or translated into 'predicted mortality'

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The management of sepsis currently relies on three major pillars

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Anti-infective therapy

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Supportive and other care

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Sepsis therapy represents a significant economic burden

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CHAPTER 3 SEPSIS MARKET OVERVIEW

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Only one drug is currently on the complex, high-risk sepsis market

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Despite the high level of unmet need, the sepsis market has been hard to conquer

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Xigris, the first and so far only drug launched for severe sepsis, has failed to impress

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Activated protein C has various, yet incompletely-understood, mechanisms of action

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Clinical breakthrough leads to rising expectations

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Narrow use and high price point limit sales

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Price reduction may lead to wider use

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CHAPTER 4 THE SEPSIS PIPELINE

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'One of the world's oldest and most virulent diseases' attracts little commercial interest

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'Surviving Sepsis Campaign' - a key driving force

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The five-point action plan

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Evidence-based management guidelines encourage new product use

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Disease complexity hampers drug development

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Developing drugs for sepsis is not a trivial exercise

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Lack of efficacy has forced the discontinuation of numerous late-stage clinical programs

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Despite past failures, endotoxin scavengers are still being considered

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More recent approaches have targeted the inflammatory and blood-clotting cascades

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Several other approaches have also proven fruitless

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Current pipeline activity focuses predominantly on the inflammatory response

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Takeda's TLR4 antagonist TAK-242

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Protherics's CytoFab anti-TNF-alfa polyclonal antibody

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Eisai's TLR4 antagonist eritoran (E5564)

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GSK's GR-270773 neutralizes endotoxin

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AM-Pharma's bovine intestine-derived alkaline phosphatase

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Medinox's Norathiol (NOX-100) neutralizes nitric oxide

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GTC Biotherapeutics's transgenic antithrombin III

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The first new sepsis drug is unlikely to reach the market before 2009

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The future sepsis-treatment landscape remains uncertain

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CHAPTER 5 KEY OPINION LEADER TRANSCRIPTS

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Key Opinion Leader 1

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Key Opinion Leader 2

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Key Opinion Leader 3

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Key Opinion Leader 4

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Key Opinion Leader 5

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APPENDIX

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Bibliography

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Journal articles

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Press releases

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Datamonitor reports

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Websites

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Miscellaneous

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Report methodology

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About Datamonitor

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About Datamonitor Healthcare

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About the Infectious Disease analysis team

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Disclaimer

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List of Tables

Table 1: There is significant regional variation with regard to the reported incidence of severe sepsis

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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

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Table 3: Incidence of sepsis and severe sepsis in European ICUs, 2002

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Table 4: Severe sepsis kills more individuals than some of the most common types of cancer

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Table 5: Mortality due to sepsis increases rapidly with progressing disease

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Table 6: Rates of sepsis mortality versus overall hospital mortality in Europe, 2002

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Table 7: A range of lab tests are usually performed when (severe) sepsis or septic shock is suspected

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Table 8: Disease-severity scoring systems and predicted mortality

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Table 9: Overview of antibacterials commonly used for empirical antibiotic therapy in sepsis

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Table 10: Xigris: key facts

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Table 11: Xigris's US, non-US and global sales and yearly sales growth, 2001-2005

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Table 12: Past sepsis programs were discontinued predominantly due to lack of efficacy

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Table 13: Only a handful of compounds are currently in development for the treatment of sepsis

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Table 14: Compounds undergoing development for the treatment of sepsis

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Table 15: Compounds undergoing development for the treatment of sepsis

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Table 16: Compounds undergoing development for the treatment of sepsis

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List of Figures

Figure 1: Severe sepsis and septic shock are commonly treated in the ICU

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Figure 2: According to a 22-year period US study, the incidence and mortality of sepsis have been increasing

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Figure 3: Sepsis is a progressive disease that can lead to multi-organ failure and death

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Figure 4: The presence of SIRS is manifested by two or more of four conditions

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Figure 5: Severe sepsis leads to multi-organ failure

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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

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Figure 7: Sepsis is triggered by infection

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Figure 8: Bacterial infections account for the vast majority of all cases of sepsis

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Figure 9: The lung is the most common site of infection leading to sepsis

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Figure 10: Results of the pan-European SOAP study

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Figure 11: A weakened immune system is the key risk factor for sepsis

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Figure 12: Sepsis therapy rests on three non-hierarchical pillars

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Figure 13: Numerous criteria influence the choice of empirical antibacterial therapy

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Figure 14: Guidelines for antibiotic therapy in severe sepsis and septic shock

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Figure 15: Activated Protein C has (at least) three distinct mechanisms of action

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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

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Figure 17: Combined clinical, commercial and regulatory factors supported Xigris's blockbuster potential

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Figure 18: Despite a promising start, Xigris sales have failed to impress

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Figure 19: A range of setbacks has prevented Xigris from achieving blockbuster status

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Figure 20: The Surviving Sepsis Campaign five-point action plan

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Figure 21: LPS-activated macrophages release pro-inflammatory cytokines including TNF-alfa and IL-6

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Figure 22: Thrombin is a key mediator in the pro-coagulation cascade

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Figure 23: Macrophages activated by LPS through the TLR4 release inflammatory cytokines

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Figure 24: Eritoran Phase II trial demonstrates significant reduction in mortality

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Figure 25: Potential US launches of developmental sepsis drugs

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