Sepsis Management New Frontiers and Evolving Perspectives

Sepsis Management New Frontiers and Evolving Perspectives
The Science and Medicine of Sepsis Management The Role of Inflammation, Signaling Cascades, and Immune Modulation on the Natural History and Treatment of the Sepsis Syndrome Dr. Steven Opal, MD Program Chair and Moderator Chairman Elect, International Sepsis Forum Professor of Medicine at Brown Medical School Director of the Infectious Disease Division Memorial Hospital of Rhode Island Pawtucket, Rhode Island, USA

Welcome and Program Overview
CME-certified symposium jointly sponsored by the Postgraduate Institute of Medicine and CMEducation Resources, LLC Commercial Support: Sponsored by an independent educational grant from Eisai, Inc. Faculty disclosures: Listed in program syllabus

Distinguished Program Faculty
Dr. Pierre-Francois Laterre Professor of Critical Care St Luc University Hospital Universite Catholique de Louvain Brussels, Belgium Program Chair and Moderator Dr. Steven Opal, MD Chairman Elect, International Sepsis Forum Professor of Medicine at Brown Medical School Director of the Infectious Disease Division Memorial Hospital of Rhode Island Pawtucket, Rhode Island, USA Dr. Jean-Paul Mira, MD, PhD Professor of Critical Care Medicine Chair, Medical Intensive Care Unit Head, Variability of Innate Immunity Research Laboratory Cochin-St. Vincent de Paul University Hospital Paris, France

The Evolving Science and Medicine of
Sepsis Management Evolving Perspectives in Sepsis Research: The Pivotal Role of Immune Modulation and the Unregulated Inflammatory Cascade Dr. Steven Opal, MD Program Chair and Moderator Chairman Elect, International Sepsis Forum Professor of Medicine at Brown Medical School Director of the Infectious Disease Division Memorial Hospital of Rhode Island Pawtucket, Rhode Island, USA

Sepsis: Defining a Disease Continuum
Infection/Trauma SIRS Sepsis Severe Sepsis A clinical response arising from a nonspecific insult, including ³2 of the following: Temperature ≥38oC or ≤36oC HR ≥90 beats/min Respirations ≥20/min WBC count ≥12,000/mm3 or ≤4,000/mm3 or >10% immature neutrophils SIRS with a presumed or confirmed infectious process SIRS = systemic inflammatory response syndrome. Bone et al. Chest. 1992;101:1644 6

Sepsis: Defining a Disease Continuum
Infection/Trauma SIRS Sepsis Severe Sepsis Sepsis with ≥1 sign of organ failure Cardiovascular (refractory hypotension) Renal Respiratory Hepatic Hematologic CNS Unexplained metabolic acidosis Shock Bone et al. Chest. 1992;101:1644; Wheeler and Bernard. N Engl J Med. 1999;340:207. 7

Challenges to Research and Study
Infection/Trauma SIRS Sepsis Severe Sepsis High and variable mortality rate (20-60%) Heterogeneous patient population Unpredictable disease progression Unclear etiology and pathogenesis Based on inflammation as cause, regardless of source Knowledge base has progressed since 1992 8

Sepsis Resuscitation Bundle (6 Hours)
Serum lactate measured Blood cultures obtained prior to antibiotic administration From the time of presentation, broad-spectrum antibiotics administered within 3 hours for ED admissions and 1 hour for non-ED ICU admissions In the event of hypotension and/or lactate > 4 mmol/L (36 mg/dl): Deliver an initial minimum of 20 ml/kg of crystalloid (or colloid equivalent) Apply vasopressors for hypotension not responding to initial fluid resuscitation to maintain mean arterial pressure (MAP) > 65 mm Hg In the event of persistent hypotension despite fluid resuscitation (septic shock) and/or lactate > 4 mmol/L (36 mg/dl): Achieve ventral venous pressure (CVP) of > 8 mm Hg Achieve central venous oxygen saturation (ScvO2) of > 70%* * Achieving a mixed venous oxygen saturation (ScvO2) of 65% is an acceptable alternative Copyright 2007 by SCCM, ESICM, and the International Sepsis Forum

Sepsis Management Bundle (24 Hours)
Low-dose steroids administered for septic shock in accordance with a standardized ICU policy Recombinant Activated protein C administered in accordance with a standardized ICU policy Glucose control maintained > lower limit of normal, but < 150 mg/dl (8.3 mmol/L) Inspiratory plateau pressures maintained < 30 cm H2) for mechanically ventilated patients Copyright 2007 by SCCM, ESICM, and the International Sepsis Forum

Pathophysiology of Sepsis
Riedemann NC et al. Nature Medicine 2003;9:

The Apoptosis Theory of Sepsis
Massive apoptosis of lymphocytes is seen in lymphoid tissues of animals and humans with sepsis Later phase of immunosuppression may in part be due to apoptosis Secondary nosocomial infection and/or viral re-activation Hotchkiss RS et al

Schemata for Pathophysiology of Sepsis
Rittirsch D et al. 2008

What do we know about the immunopathophysiology of sepsis?
The Science and Medicine of Sepsis What do we know about the immunopathophysiology of sepsis? All encompassing single mechanism still elusive Host inflammation hypothesized to be the cause of the syndrome Natural experiment with mice suggests that we may be able to reduce inflammation without compromising host defense, perhaps through manipulation of TLRs

DAMPs PAMPs PRRs NOD-LRRs TLRs RLHs
SEPSIS: A Dynamic, Complex Host Response to PAMP/DAMPs DAMPs PAMPs HSP Heparan Sulfate Hyaluronic acid Fibrinogen Biglycan Surfactant A HMGB-1 Heme MRP8/14 Microorganisms PRRs Immune cells NOD-LRRs TLRs RLHs ASC Signalosome Pathway Inflammasome Pathway Specific host immune response to each pathogen is mediated by various sets of pathogen associated molecular patterns (PAMPs) and pattern recognition receptors (PRRs) as detailed in Figure 1. PRRs are essential for initiating the host's immune defenses against invading pathogens, yet they can also contribute to persistent and deleterious systemic inflammation. PRRs also serve as receptors for endogenous danger signals, hemodynamic changes in sepsis (tissue hypoperfusion and ischemia/reperfusion phenomenon), thus same signaling systems that alerts the highly advantageous, host defense mechanisms, also contributes to the disadvantageous, pathological events of systemic inflammation, coagulation, tissue damage in target organs in sepsis. Heat shock proteins, fibrinogen, fibronectin, hyaluran, biglycans and high mobility group box-1 (HMGB-1) have been defined as danger associated molecular patterns (DAMPs) which are likely relevant for sepsis. Toll-like receptors (TLRs), especially TLR4, are involved in the recognition of these endogenous or harmful self-antigens ligands which are released during non-infectious injury, such as trauma or ischemia/reperfusion suggesting their function may not be restricted to the recognition of extrinsic pathogens. NF-κB Caspase-1 & 5 ASC NALP1 & 3 Pyrin Host-derived mediators INFLAMMATION Cinel& Opal CCM 2009;37:291

Incidence of Severe Sepsis by Age
120,000 30 100,000 Number of cases 25 Incidence rate 80,000 20 Cases Incidence/1,000 Population 60,000 15 40,000 10 20,000 5 <1 1 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85+ Age/Years Angus DC, at al. Crit Care Med 2001; 29:

Hotchkiss and Karl NEJM 2003;348:138
Sepsis-targeting the host response Receptor downregulation (TLR 4, TNFR, HLA-DR) Soluble (sIL1,6,TNFr) and decoy receptors (IL-1R2) Receptor antagonists (IL-1ra) Anti-inflammatory cytokines (IL-4,10,13) Intracellular inhibitors (SOCS, IkB, Tollip, MyD88s) Cellular apoptosis of B cells CD4 T cells and FDCs Sepsis-induced immunosuppression Hotchkiss and Karl NEJM 2003;348:138

Sepsis-targeting microbial mediators-LPS
4 million LPS molecules/cell - 75% of outer membrane

Increasing Levels of Endotoxemia Aggravates Severity of Illness
<0.4 (n=367) (n=228) >0.6 (n=262) P* ICU LOS (days) 5 7 P=0.04 APACHE II 13.3 15.3 17.6 P<0.001 % Hospital Death 16 23 P=0.05 % ICU Death 11 13 17 WBC (% abnormal) 42 48 56 % with Shock 12 21 % Hypoxemic 52 P=0.005 *p values compare < 0.4 vs > 0.6 Marshall et al. the Medic trial J Infect Dis 2004;190:527

LPS Mj LPS Mj Early Signaling Events of Innate Immunity are now increasingly understood 3’ 5’ nuclear localization sequence DNA NFkB DNA NFkB Host response-antimicrobial defense programs

LBP LPS CD 14 MONOCYTE-MACROPHAGE LPS-mediated gene induction MD-2
3714 genes (12% of the human transcriptome) is altered over 24 hours upon exposure to LPS TLR4 TIR tk, mapk NFkB Signal transduction MONOCYTE-MACROPHAGE Cytokines Chemokines Nitric oxide Acute phase proteins Pro-coagulants Lowry et al. Nature 2005;437:1032-7

The Hexameric TLR4–MD-2–LPS
Signalling Complex Lipid A BS Park et al. Nature 2009; 7830:1-5

The main trimerization interface
of the TLR4–MD-2–LPS complex BS Park et al. Nature (2009);7830

Structural Comparison of LPS with Antagonists
TLR4 binding site BS Park et al. Nature (2009); 7830:1-5

Current Anti-LPS projects for severe infection
• Currently in use-PMX B hemoperfusion columns • Phase 3 trials-E5564 • Phase 2 trials-recombinant Lactoferrin • Preclinical/early clinical study: AOAH transgenes, rAlkaline phosphatase, small molecule inhibitors, cationic peptides, heme absorption columns, monoclonal antibodies, receptor fusion constructs O-side chain Inner core Outer core oligosaccharide Lipid A E. coli Lipopolysaccharide 25

With gentamicin and ceftriaxone
Prophylactic and Salvage Rx with anti-TLR4 antibodies protect mice from lethal Gram-negative bacterial sepsis (E. coli 018 given i.p.) -15 min 109cfu -15 min 109cfu -15 min 109cfu Prophylactic and therapeutic administration of anti-TLR4 antibodies protect mice from lethal Gram-negative bacterial sepsis. (A–D) BALB/c mice were injected i.p. with anti-TLR4 or control antibodies (160 mg/kg for A–C and 200 mg/kg for D) given before (prophylactically; A and B) or after (therapeutically; C and D) an i.p. injection of a high (2 × 109 cfu) inoculum (A–C) or low (2 × 105 cfu) inoculum (D) of E. coli O18. (A) Plasma concentrations of TNF and IL-6 were measured 4 h after the bacterial challenge. The horizontal line represents the median cytokine concentration. P < .005 for TNF and IL-6. (B–D) Survival of mice treated prophylactically (B) (at −4, −0.5, and + 4 h) or therapeutically either early (+1 and + 4 h) (C) or late (+13 h) (D). P < .0001, .02, and .03, respectively. Data points are from 1 experiment (n = 10–12 mice per treatment group). +13 hr 105cfu +13 hr 109cfu +13 hr 105cfu Roger T et al. PNAS 2009;106: With gentamicin and ceftriaxone

Packed Crystal Structure of Human Lactoferrin
Suzuki et al J Mol Biol 2003; 331:485 27

Lactoferrin LF11 Peptide Bound to LPS
Cationic region Lactoferrin Cationic LPS binding protein-competes for LPS with LBP, CD14 Fe++ chelator, limits oxidant tissue injury Bacteristatic Promotes neutrophil binding and activity Promotes efficient antigen presentation and clearance by GALT Phase 2 clinical trials in prevention of neonatal sepsis positive, adult study results completed LPS Phosphoryl group Lipid A Japelj et al. J. Biol. Chem. 2005;280:16955 28

Phase II Results with Oral Talactoferrin in Severe Sepsis
No cardiovascular dysfunction (n=69) Total (n=190) Agennix AG Press Release Dec. 1, 2009

PMX Cartridge for Clinical Application
Approved for use in Japan for many years and available on a limited basis in several European countries

Estimation of Survival Rate According to Treatment Group
Polymyxin B hemoperfusion therapy 1.00 0.75 0.50 0.25 Survival Proportion Conventional therapy Log-rank P=.03 Time, d No. at risk Polymyxin B hemoperfusion therapy Conventional therapy Patients with septic shock secondary to Peritonitis Cruz, D. N. et al. JAMA 2009;301:2445

Physiological End Points by Treatment Group at Baseline and 72 Hours
Severely septic patients with peritonitis Cruz, D. N. et al. JAMA 2009;301:2445

Jung et al. PLoS One 2009;4(1):e704

Conclusions New Approaches for Treating Sepsis Using
Novel Interventions Against Old Targets The discovery of the TLRs and other pattern recognition receptors of the innate immune system offers new treatment options to the initiating events in severe sepsis Targeting microbial mediators and their signaling receptors is a rational and probably safe approach to treat sepsis The results of current ongoing clinical trials targeting microbial ligands and their receptors will answer longstanding questions about adjuvant therapies to improve the outcome in sepsis We will next hear from two experts in sepsis research: Jean-Paul Mira (Toll like receptors) Pierre-Francois Laterre (Clinical development of TLR4 inhibitors)

Toll-Like Receptors in Sepsis
The Science and Medicine of Sepsis Management Toll-Like Receptors in Sepsis Emerging Implications for Critical Care Management Dr. Jean-Paul Mira, MD, PhD Professor of Critical Care Medicine Chair, Medical Intensive Care Unit Head, Variability of Innate Immunity Research Laboratory Cochin-St. Vincent de Paul University Hospital Paris, France

Recognition of PAMPs from Different Classes of Microbial Pathogens
Mogensen TH. Clin. Microbiol. Rev.2009; 22 :

Kumar H. Biochem Biophys Res Comm. 2009;388:621

Akira S, 2009

TLRs: Receptors of Alarmins
EMBO reports 2006;7:775 41

Known Endogenous TLR Ligands
Bianchi M. J Leuk Biol 2007

TLR Recognition of Exogenous versus
Endogenous Ligands Iwasaki A. Science 2010; 327:291

Canonical model of sepsis New model of sepsis

Animal Models of Sepsis

TLR2 and Streptococcus pneumoniae Meningitis
WT TLR2 -/- Echchannaoui H et al. JID 2002;186:798

Tissieres P. Curr Opinion Infect Dis 2009;22:285

Essential Role of MD2 in LPS Responsiveness
8 4 2 Days Surivival (# of mice) MD-2 -/- WT 10 8 6 4 2 Surivival (# of mice) MD-2 -/- WT Hours LPS IP + D-galactosamine IP LPS IP Nagai H. Nat Immunol 2002;3:667

Gram Negative Infection
Essential Role of MD2 in Gram Negative Infection WT 10 8 6 4 2 Survival (# of mice) MD-2 -/- Days Salmonella Peritonitis Nagai H. Nat Immunol 2002;3:667

Relevance of Polymorphisms in TLR and TLR Adapters for Sepsis

Understanding the Role of TLR Signaling in Susceptibility to Human Infections
Human monogenic immunodeficiencies affecting Toll-like receptor function Clinical immunodeficiency Mutated gene Mutated protein Immunological pathways affected Infectious susceptibility X-lined recessive EDA-ID IKBKG IKKƴ(NEMO) Multiple innate and adaptive pathways Pyogenic bacterial infections (Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae) Atypical mycobacteria (Mycobacterium avium intracellulare) Autosomal dominant EDA-ID NFKBIA IκBα As above IRAK4 deficiency IRAK4 TLR signaling Pyogenic bacterial infections (Streptococcus pneumoniae, Staphylococcus aureus)

Pyogenic Bacterial Infections in Humans with IRAK-4 Deficiency

40 20 IL-1a (pg/ml) WT/WT WT/Asp299Gly & Thr399Ile

TLR4 Polymorphisms and Septic Shock
Control % TLR4 mutated patients Gram negative Septic shock Lorenz , Arch. Intern. Med :1028

Toll-like Receptor 4 Polymorphisms and Aspergillosis in Stem-Cell Transplantation
Hypothesis : polymorphisms in TLR genes from the donor and the recipient may influence susceptibility to invasive aspergillosis in stem cell transplantation Discovery study: DNA from 336 patients and their unrelated donors (1995 – 2003) 33 cases of aspergillosis Validation study: matched case-control study with recipients of donors 103 patients with invasive aspergillosis and 263 recipients without aspergillosis. Genes: 20 SNPs in TLR2, TLR3, TLR4 and TLR9 Bochud PY. N Engl J Med 2008; 359:1766

Toll-like Receptor 4 Polymorphisms and Aspergillosis in Stem-Cell Transplantation
Bochud PY. N Engl J Med 2008; 359:1766

Legionnaire’s Disease and TLR5

Common TLR5 Stop Codon Polymorphism
1174 1775 C T A G Hawn TR. J Exp Med 2003; 198: 1563

TLR5 Polymorphisms and Legionnaire’s Disease
SNP Smokers Nonsmokers P No. BP Allele OR (95% CI) OR (95% CI) Haplotype CA 00 1 1 CG (0.55, 3.25) 0.53 1.99 (1.04, 3.80) 0.04 TA (0.19, 3.05) 0.70 2.43 (1.00, 5.89) 0.005 Cases n=109 CTL n=508 Paired CTL n=89 P = 0.02 1174 1775 C T A G P = 0.03 Hawn TR. J Exp Med 2003; 198: 1563

IRAK-1 Haplotype Increases
NF-kB Activation Wildtype AUC Variant P=0.0009 IRAK-1 gene located on X chromosome 2 haplotypes: htSNP = IRAK-1 532LS IRAK-1 Haplotype Arcoli J. Am J Respir Crit Care Med 2006;175:1335

Morbidity of Sepsis Wildtype VFD 20 10 Variant P=0.03 IRAK-1 Haplotype 155 septic Caucasians patients Wildtype % 70 60 50 40 30 20 10 Variant P=0.047 IRAK-1 Haplotype Shock Pulmonary Infection Wildtype VFD 20 10 Variant P=0.02 IRAK-1 Haplotype OR:2.6 (95% CI, ) Arcoli J. Am J Respir Crit Care Med 2006;175:1335

Mortality of Sepsis Wildtype % 70 60 50 40 30 20 10 Variant P=0.03 IRAK-1 Haplotype 60-Day Mortality Pulmonary Infection Wildtype % 70 60 50 40 30 20 10 Variant P=0.05 IRAK-1 Haplotype 60-Day Mortality Arcoli J. Am J Respir Crit Care Med 2006;175:1335

Contribution of Toll-like receptor-mediated responses to sepsis pathogenesis

TLR signaling pathway: 84 genes expression analyzed
Mononuclear cells: down regulation in septic shock patients Neutrophils: up-regulation throughout the stages of sepsis Salamao R. Crit Care Med 2009; 37:132

Tissieres P. Curr Opinion Infect Dis 2009;22:285

Endotoxin Responsiveness of Human Airway Epithelia is Limited by Low Expression of MD-2
Jia HP. Am J Physiol Lung Cell Mol Physiol 2004;287:L428

Soluble MD-2 Activity in Plasma from Patients with Severe Sepsis and Septic Shock
Pugin J. Blood 2004; 104:4071

Increased Release of sMD-2 During Human Endotoxemia and Sepsis: A Role for Endothelial Cells
WB anti-MD2 Healthy Septic Wolfs TG. Mol Immunol 2008;45:3268

Increased Release of sMD-2 During Human Endotoxemia and Sepsis: A Role for Endothelial Cells
Endotoxemia in human volunteers Time (hours) sMD-2 (mg/ml) * Wolfs TG. Mol Immunol 2008;45:3268

Soluble MD2 Increases TLR4 Levels on the Epithelial Cell Surface
LPS decreases TLR4 cell expression 1.2 1 0.8 0.6 0.4 0.2 TLR4 cell surface expression TLR4/vector(noLPS) TLR4/vector Mean fluorescence LPS (ug/ml) Lauer S. Cell Immunol 2009;255:8

Endotoxin Responsiveness of Human Airway Epithelia is Limited by Low Expression of MD-2
sMD2 may prime epithelial cells for enhanced immunoresponsive function Jia HP. Am J Physiol Lung Cell Mol Physiol 2004;287:L428

Conclusions Cell response to pathogen stimulation is a complex phenomenon! During sepsis, both exogenous and endogenous ligands stimulate TLRs Effects of TLRs stimulation are cell-dependent Consequences of TLRs stimulation are host-dependent TLRs coreceptors and signaling molecules play a pivotal role in the regulation of the inflammatory response Toll Like Receptors and TLR adaptors: attractive drug targets

Emerging Perspectives in
Sepsis Management Clinical Trials with TLR inhibition in Sepsis The Journey from the Bench to the Bedside Dr. Pierre-Francois Laterre Professor of Critical Care St Luc University Hospital Universite Catholique de Louvain Brussels, Belgium

TLR4 Ligands Pathogen-associated pattern molecules
LPS Mannan Danger-associated pattern molecules HMGB1 Heat shock proteins Hyaluronan Biglycans Fibronectin

Clinical Trials of Anti-TLR4 Agents
Agents targeting LPS Antibodies against LPS Polymyxin B Bactericidal/Permeability-Increasing Protein Agents targeting TLR4 or the TLR Signalsome TAK-242 Eritoran

Eschericia coli Lipopolysaccharide
O-side chain Inner core Outer core Oligosaccharide Lipid A

Clinical Trials of Antibodies against LPS Core Region Epitopes
Ann Intern Med 1994;120:771-78

P1 Proof-of-Concept Trial of Eritoran in Normal Human Volunteers Challenged with LPS
100 and 250 mg doses of eritoran completely blocked all clinical signs and symptoms of LPS toxicity Chills Fever Headache Myalgia Tachycardia 100 and 250 mg doses of eritoran completely blocked all biochemical effects of LPS challenge 400 350 300 250 200 150 100 50 Plasma TNF α (pg/mL) Placebo 60, 100, 260 ug E6684 Time after LPS infusion (hrs) Lynn M, et al. J Infect Dis Feb 15;187(4):631-9 82

Phase 2 Study of Eritoran
Multicentric, randomized, double-blind trial Tidswell et al. Crit Care Med 2010; 38:72-83

Baseline Characteristics: P2 Eritoran
Tidswell et al. Crit Care Med 2010; 38:72-83

Characteristics of Infection: P2 Eritoran
Placebo (n=96) Eritoran tetrasodium 45mg (n=103) Eritoran tetrasodium 105 mg (n=94) Overall p Value Primary focus of infection, n (%) .5054 Pulmonary 38 (39.6) 39 (37.9) 29 (31.2) Intra-abdominal/gynecologic 20 (20.8) 14 (13.6) 15 (16.1) Urinary tract 13 (13.5) 13 (12.6) 19 (19.4) Skin/soft tissue 5 (5.2) 7 (6.8) 7 (7.5) Indwelling catheter 2 92.1) 8 (7.8) 5 (5.4) Unknown 3 (3.1) 9 (9.7) Other 7 (7.2) 4 (3.9) No evidence of infection 8 (8.3) 10 (9.7) Tidswell et al. Crit Care Med 2010; 38:72-83

Characteristics of Infection: P2 Eritoran
(continued) Characteristic Placebo (n=96) Eritoran tetrasodium 45mg (n=103) Eritoran tetrasodium 105 mg (n=94) Overall p Value Infection type, m (%) .6944 Gram-negative 26 (27.1) 23 (22.3) 29 (31.2) Gram-positive 30 (31.3) 38 (36.9) Mixed bacterial 10 (10.4) 7 (6.8) 13 (14.0) Fungal 1 (1.0) 4 (3.9) 1 (1.1) Viral 2 (1.9) 0 (0) Unkown 17 (17.7) 18 (17.5) 15 (16.1) Bacteremia, without focal infection, n (%) 3 (3.1) 10 (9.7) 8 (8.5) Bacteremia, with focal infection, n )%) 25 (26.1) 29 (28.1) 26 (27.7) Adequate antimicrobial therapy, n (%) 87 (91) 91 (88) 85 (90) Tidswell et al. Crit Care Med 2010; 38:72-83

Endotoxin in Critically Ill
J Marshall JID 2004

Endotoxin in Critically Ill
EA Level Gram-negative infection Gram-positive infection All infections Prevalence, % (no./total) OR (95% CI) Prevalence, % (no./total) Low (<0.40) 1.4 (5/367) -- 3.8 (14/367) 5.2 (19/367) Intermediate ( ) 4.8 (11/228) 3/7 ( ) 7.9 (18/228) 2.2 ( ) 11.4 (26/228) 2.4 ( ) High (>0.60) 6.9 (18/262) 5.3 ( ) 5.7 (15/262) 1.5 ( ) 10.7 (28/262) ( ) J Marshall JID 2004

Phase 2 Study of Eritoran
Treatment Group Percent 28-day Mortality Mortality in modified intent-to-treat population (n=293) p = 0.846 p = 0.335 Multicentric, randomized, double-blind trial Placebo versus two eritoran dosing regimens (45 mg/6 d or 105 mg/6 d) Patients with severe sepsis and predicted risk of mortality (PROM) of 20-80% based on APACHE II score Study drug started within 12 h of recognition of severe sepsis 300 patients randomized; 293 included in the intent to treat (ITT) analysis Tidswell et al. Crit Care Med 2010; 38:72-83

Eritoran P2 Clinical Trial
Prospectively Defined Subgroups Mortality by APACHE II Quartile Mortality by Presence of Shock P-0.105 P=0.598 P=0.434 P-0.913 P-0.503 Percent 28-day Mortality Percent 28-day Mortality P-0.083 APACHE II Quartile Presence of Shock at Baseline Tidswell et al. Crit Care Med 2010; 38:72-83

Mortality in Important Subpopulations: P2
Clinically Evaluable Population (n=235) N DAA (Xigris) Population (n=225) p = 0.036 p = 0.094 Percent 28-day Mortality Treatment Group Tidswell et al. Crit Care Med 2010; 38:72-83

Kaplan-Meier Survival-Time Curves: P2
Tidswell et al. Crit Care Med 2010; 38:72-83

Relative Reduction in Risk of Death at 28 Days and 95% CI: P2 Eritoran
MITT population APACHE II predicted mortality Low (20-50%) High (51-80%) Type of pathogen Gran neg Gram pos Mixed bacterial Other/unknown Age 65 and younger 66 and older Stage of study Stage II Stage III Tidswell et al. Crit Care Med 2010; 38:72-83

Relative Reduction in Risk of Death
at 28 Days and 95% CI: P2 Eritoran (cont.) Xigra Used Yes No Baseline Endotoxin Detectable Elevated > 0.2 endotoxin status Baseline HDL < 25 mg/dL > 25 mg/dL Time to drug infusion 8 hours or less More than 8 hours Tidswell et al. Crit Care Med 2010; 38:72-83

Infectious Adverse Events: P2 Eritoran
Placebo (n=96) Eritoran Tertrasodium 45 mg (n=103) Eritoran Tetrasodium 105 mg (n=94) Overall p value Investigator-reported infectious complication 50.5 45.6 37.0 .2001 Clinical evaluation committee determination of infectious complication 36.8 35.0 38.0 .8967 Infectious adverse events were defined as either a) recurrent infection at the same site as the sepsis-initiating infection, either relapse of the same organism, or superinfection by a different organism; or b) new infection occurring at a different site that the sepsis-initiating infection. Tidswell et al. Crit Care Med 2010; 38:72-83

Eritoran P2 Clinical Trial:
No Effect on Circulating IL-6 Concentration Placebo 45 mg 105 mg hr 48 hr IL-6 lvel (pg/mL) 100000 10000 1000 100 10 1 Tidswell et al. Crit Care Med 2010; 38:72-83

ACCESS Trial: P3 Eritoran Trial
Controlled Comparison of Eritoran Tetrasodium and Placebo in Patients with Severe Sepsis A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Evaluating Eritoran Tetrasodium in Patients with Severe Sepsis: Can Inhibition of TL-4 Improve All-Cause Mortality in Patients with Severe Sepsis • 159 worldwide study locations • patients enrolled in trial

ACCESS Trial Protocol Overview: Study Objectives
Analysis of Efficacy Variables Primary Efficacy Endpoint: All-cause mortality at Day 28. The difference in mortality rates between treatment groups will be tested by chi-squared test Key Secondary Endpoint: Mortality at 1 year Other Endpoints of Interest: Length of ICU stay within 28 days Length of Hospital stay within 28 days Duration of dialysis within 28 days Duration of mechanical ventilation within 28 days Duration of use of vasopressors within 28 days Measurement of cytokine inflammatory panel and procalcitonin Quality of Life SOFA assessment Incidence of infection episodes subsequent to randomization Pharmacoeconomics Mortality at 3 and 6 months

ACCESS Trial Entry Criteria
Inclusion Criteria I. Age > 18 years; no upper age limit II. Confirmed early onset of severe sepsis defined as: • Objective evidence of infection – likely bacterial or fungal pathogen Examples of objective evidence: Clinical findings (i.e. cellulitis or abscesses) Cultures Gram stains X-rays Surgical pathology specimens ** Note: A positive culture is not a requirement for entry into the trial

Inclusion Criteria • Presence of at least 3 of 4 SIRS criteria: — Core Temperature > 38C or < 36C — Heart Rate > 90 beats/min **Note: Patients who cannot be assessed for sepsis-induced tachycardia due to another medical condition known to increase heart rate, or those receiving treatment that prevents tachycardia, must have 2 of the remaining 3 SIRS criteria. — Respiratory Rate > 20 breaths/min OR a PaCO2 < 32 mmHg, or mechanical ventilation — WBC Count > 12,000 cells/L, < 4,000 cells/L, OR > 10% band forms.

Inclusion Criteria At least 1 of the following organ dysfunctions: A. Acute Lung Injury (ALI)/Acute Respiratory Distress Syndrome (ARDS) — Acute Onset of the following: 1. PaO2/FiO2 < 300 (<200 in pts. with pneumonia). If altitude > 1000m, then PaO2/FiO2 < 300 x (PB/760) 2. Bilateral infiltrates consistent with pulmonary edema on frontal chest x-ray. (Infiltrates may be patchy, diffuse, homogeneous, or asymmetric) 3. Requirement for positive pressure ventilation via endotracheal tube 4. No clinical evidence of left atrial hypertension Criteria 1-4 must occur together within 24-hour interval

Inclusion Criteria B. Thrombocytopenia Acute onset of platelet count <100,000 or a reduction of 50% or more from prior known levels, without past history of thrombocytopenia, and without attributable cause other than infection C. Lactic Acidemia Acute onset of serum lactate level > 4mmol/L (36 mg/dL) (Protocol amendment-lactic acidosis >2.2mmol/L (19.8 mg/dL) and evidence of metabolic acidosis: pH<7.30 or base deficit>5.0 mmol/L) D. Acute Renal Failure Urine output < 0.5 mL/kg/hr for at least 2 hrs, despite administration of at least 500 mL of crystalloid or 200 mL of colloid over a 30 minute period

Inclusion Criteria E. Shock Acute onset of systolic BP < 90 mmHg or MAP of < 65 mmHg. BP is poorly responsive to initial aggressive fluid resuscitation with a crystalloid or colloid, and vasopressors are required to maintain MAP > 65 mmHg despite initial fluid resuscitation for a least 1 hour. Mechanically ventilated patients must exhibit hypotension due to sepsis before the institution of mechanical ventilation or be hypotensive for at least 60 min following intubation to qualify for the study on basis of shock.

Inclusion Criteria IV. A reasonable likelihood that administration of study drug can be started within 12 hours of the time of recognition of organ dysfunction. V. Must be a commitment to full patient support **Note: If a patient’s family has not committed to aggressive management of patient’s condition or has requested the patient be classified as “Do not resuscitate” or “Do not treat”, the patient is excluded. If a family directive allows all resuscitative efforts other than chest compressions, the patient may be enrolled.

Inclusion Criteria VI. APACHE II Score Baseline APACHE II Score of 21-37, inclusive The Clinical Coordinating Centers will be responsible for calculating the APACHE II Scores and enrolment approval OSCCC (RI) and SLUCCC (Brussels).

ACCESS Trial Entry Criteria:
Time Window Onset of Organ Failure < 12 hrs between documentation of the 1st qualifying organ dysfunction and administration of study drug Study Drug Infusion 12 hrs Onset of 1st Organ Failure

ACCESS Trial Protocol Overview
Prior & Concomitant Therapy In addition to the appropriate antibiotic therapy, it is expected that all patients will receive evidence-based appropriate treatment of their severe sepsis. Appropriate treatment modalities include, but are not limited to: Initial resuscitation goals Use of low tidal volumes for mechanical ventilation Control of blood glucose levels Maintenance of target hemoglobin levels Source control In countries where recombinant human activated Protein C is approved for use, careful consideration should be given to contraindications and locally approved indications for use.

ACCESS Trial: Current Status
Over 1600 subjects randomized Enrolling ~40-60 subjects/month in recent months

At 1400 Subjects Mean APACHE II score ~27 in all regions of the world
Mean age= 65 Median time to treatment = 9.3 hrs Organ Dysfunctions: ~33% 1 ~33% 2 ~24% 3 50% Shock 25% Lactic Acidosis

Infection Site of Infection?
~50% lung ~20% genitourinary ~20% abdominal Incidence of new infection etc. (after 48 hours) ~43% …..similar to that reported by investigators in the Phase II study (~47%)

Data Monitoring Reviews of Study
DMC reviews at 375 and 750 and 1100 subjects resulted in recommendations to continue the study

Summary and Conclusions
TLR-4 inhibition represents a potentially promising strategy for treatment of severe sepsis Phase II Study with eritoran is completed, peer-reviewed, and published in JCCM There are signals in the Phase II eritoran study of improved mortality outcomes in high-risk subgroups; and safety profiles are acceptable Phase III ACCESS eritoran study is completing enrollment * Three interim analyses have been conducted for the Phase III ACCESS study and the DSMB has given authorization to complete the study

Summary and Take Home Message

Conclusions Despite its complexity and the multitude of pathogens that can cause sepsis, a limited number of pattern recognition receptors of the innate immune system activate the systemic host response in sepsis The Toll like receptors are now major targets for therapeutic intervention in sepsis. Polymorphisms of TLRs and related adaptor and signaling molecules are associated with susceptibility or protection from a number of infectious diseases

Conclusions TLR4 is the signal receptor for LPS along with MD2 and CD 14 A number of TLR 4 inhibitors show promise as adjuvant therapies for sepsis; one TLR4 inhibitor, known as eritoran or E5564, is now in late stage clinical development. If TLR inhibitors can improve survival in human sepsis, they will likely be most effective given early in the septic process. This is a major challenge in clinical trial design and implementation

Sepsis Management New Frontiers and Evolving Perspectives

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Sepsis Management New Frontiers and Evolving Perspectives

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