Market Report Source

Overview

Introduction
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

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

TABLE OF CONTENTS

CHAPTER 1 EXECUTIVE SUMMARY

Introduction

Scope and coverage of the report

Objective of the analysis

Datamonitor insight into the sepsis market

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.

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.

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.

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.

CHAPTER 2 SEPSIS DISEASE INSIGHT

Sepsis is a devastating killer

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

Focus on the ICU

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

Sepsis-associated mortality is unacceptably high

Sepsis can rapidly progress to organ failure and death

Sepsis is defined as a systemic inflammatory response resulting from infection

Systemic inflammation and activation of the coagulation cascade are key hallmarks

Bacterial infection is the leading cause of sepsis

The lung is the most common focus of the original infection

A weakened immune system increases the risk for sepsis

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

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

Late diagnosis contributes to high sepsis-associated mortality

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

The management of sepsis currently relies on three major pillars

Anti-infective therapy

Supportive and other care

Sepsis therapy represents a significant economic burden

CHAPTER 3 SEPSIS MARKET OVERVIEW

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

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

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

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

Clinical breakthrough leads to rising expectations

Narrow use and high price point limit sales

Price reduction may lead to wider use

CHAPTER 4 THE SEPSIS PIPELINE

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

‘Surviving Sepsis Campaign’ – a key driving force

The five-point action plan

Evidence-based management guidelines encourage new product use

Disease complexity hampers drug development

Developing drugs for sepsis is not a trivial exercise

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

Despite past failures, endotoxin scavengers are still being considered

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

Several other approaches have also proven fruitless

Current pipeline activity focuses predominantly on the inflammatory response

Takeda’s TLR4 antagonist TAK-242

Protherics’s CytoFab anti-TNF-alfa polyclonal antibody

Eisai’s TLR4 antagonist eritoran (E5564)

GSK’s GR-270773 neutralizes endotoxin

AM-Pharma’s bovine intestine-derived alkaline phosphatase

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

GTC Biotherapeutics’s transgenic antithrombin III

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

The future sepsis-treatment landscape remains uncertain

CHAPTER 5 KEY OPINION LEADER TRANSCRIPTS

Key Opinion Leader 1

Key Opinion Leader 2

Key Opinion Leader 3

Key Opinion Leader 4

Key Opinion Leader 5

APPENDIX

Bibliography

Journal articles

Press releases

Datamonitor reports

Websites

Miscellaneous

Report methodology

About Datamonitor

About Datamonitor Healthcare

About the Infectious Disease analysis team

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