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The Science and Medicine of Sepsis Management The Role of Inflammation, Signaling Cascades, and Immune Modulation on the Natural History and Treatment.

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Presentation on theme: "The Science and Medicine of Sepsis Management The Role of Inflammation, Signaling Cascades, and Immune Modulation on the Natural History and Treatment."— Presentation transcript:

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2 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 New Frontiers and Evolving Perspectives 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

3 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 Welcome and Program Overview

4 Distinguished Program Faculty 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 Dr. Jean-Paul Mira, MD, PhD Professor of Critical Care Medicine Professor of Critical Care Medicine Chair, Medical Intensive Care Unit Chair, Medical Intensive Care Unit Head, Variability of Innate Immunity Head, Variability of Innate Immunity Research Laboratory Research Laboratory Cochin-St. Vincent de Paul University Hospital Cochin-St. Vincent de Paul University Hospital Paris, France Paris, France Dr. Pierre-Francois Laterre Professor of Critical Care St Luc University Hospital Universite Catholique de Louvain Brussels, Belgium

5 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 The Evolving Science and Medicine of Sepsis Management

6 SIRS = systemic inflammatory response syndrome. Infection/TraumaSIRSSepsis 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 Bone et al. Chest. 1992;101:1644 Sepsis: Defining a Disease Continuum

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

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

9 1.Serum lactate measured 2.Blood cultures obtained prior to antibiotic administration 3.From the time of presentation, broad-spectrum antibiotics administered within 3 hours for ED admissions and 1 hour for non-ED ICU admissions 4.In the event of hypotension and/or lactate > 4 mmol/L (36 mg/dl): a)Deliver an initial minimum of 20 ml/kg of crystalloid (or colloid equivalent) b)Apply vasopressors for hypotension not responding to initial fluid resuscitation to maintain mean arterial pressure (MAP) > 65 mm Hg 5.In the event of persistent hypotension despite fluid resuscitation (septic shock) and/or lactate > 4 mmol/L (36 mg/dl): a)Achieve ventral venous pressure (CVP) of > 8 mm Hg b)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 Resuscitation Bundle (6 Hours)

10 1.Low-dose steroids administered for septic shock in accordance with a standardized ICU policy 2.Recombinant Activated protein C administered in accordance with a standardized ICU policy 3.Glucose control maintained > lower limit of normal, but lower limit of normal, but < 150 mg/dl (8.3 mmol/L) 4.Inspiratory plateau pressures maintained < 30 cm H2) for mechanically ventilated patients Copyright 2007 by SCCM, ESICM, and the International Sepsis Forum Sepsis Management Bundle (24 Hours)

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

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

13 Rittirsch D et al Schemata for Pathophysiology of Sepsis

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

15 Microorganisms Immune cells Host-derived mediators PRRs PAMPs DAMPs HSP Heparan Sulfate Hyaluronic acid Fibrinogen Biglycan Surfactant A HMGB-1 Heme MRP8/14 Caspase-1 & 5 ASC NALP1 & 3 Pyrin ASC NF-κB TLRs NOD-LRRs RLHs Cinel& Opal CCM 2009;37:291 SEPSIS: A Dynamic, Complex Host Response to PAMP/DAMPs

16 Incidence of Severe Sepsis by Age Cases 0 20,000 40,000 60,000 80, , ,000 < Age/Years Number of cases Incidence rate Incidence/1,000 Population Angus DC, at al. Crit Care Med 2001; 29:

17 Hotchkiss and Karl NEJM 2003;348:138 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 Sepsis-targeting the host response

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

19 Increasing Levels of Endotoxemia Aggravates Severity of Illness Marshall et al. the Medic trial J Infect Dis 2004;190:527 <0.4(n=367) (n=228)>0.6(n=262)P* ICU LOS (days) 557P=0.04 APACHE II P<0.001 % Hospital Death P=0.05 % ICU Death P=0.04 WBC (% abnormal) P<0.001 % with Shock P<0.001 % Hypoxemic P=0.005 *p values compare 0.6

20 nuclear localization sequence LPS M DNA NF B Early Signaling Events of Innate Immunity are now increasingly understood Host response-antimicrobial defense programs LPS M DNA NF B

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

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

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

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

25 Lipid A O-side chain Inner coreOuter core oligosaccharide 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 E. coli Lipopolysaccharide

26 Prophylactic and Salvage Rx with anti-TLR4 antibodies protect mice from lethal Gram-negative bacterial sepsis (E. coli 018 given i.p.) Roger T et al. PNAS 2009;106: min 10 9 cfu +13 hr 10 5 cfu With gentamicin and ceftriaxone -15 min 10 9 cfu +13 hr 10 9 cfu -15 min 10 9 cfu +13 hr 10 5 cfu

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

28 Japelj et al. J. Biol. Chem. 2005;280:16955 Lactoferrin LF11 Peptide Bound to LPS LPS Cationic region Phosphoryl group Lipid Lipid A 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

29 Phase II Results with Oral Talactoferrin in Severe Sepsis Total (n=190) No cardiovascular dysfunction (n=69) p<0.04 p=0.06 Agennix AG Press Release Dec. 1, 2009

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

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

32 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

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

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35 Conclusions 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 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 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 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: We will next hear from two experts in sepsis research: Jean-Paul Mira (Toll like receptors) Jean-Paul Mira (Toll like receptors) Pierre-Francois Laterre (Clinical development of TLR4 inhibitors) Pierre-Francois Laterre (Clinical development of TLR4 inhibitors) New Approaches for Treating Sepsis Using Novel Interventions Against Old Targets

36 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 The Science and Medicine of Sepsis Management

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

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

40 Akira S, 2009

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

42 Known Endogenous TLR Ligands Bianchi M. J Leuk Biol 2007

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

44 Canonical model of sepsis New model of sepsis

45 Animal Models of Sepsis

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

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

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

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

50 Relevance of Polymorphisms in TLR and TLR Adapters for Sepsis

51 Understanding the Role of TLR Signaling in Susceptibility to Human Infections Clinical immunodeficiency Mutated gene Mutated protein Immunological pathways affected Infectious susceptibility X-lined recessive EDA-ID IKBKG IKK ƴ (NE MO) Multiple innate and adaptive pathways Pyogenic bacterial infections (Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae) Atypical mycobacteria (Mycobacterium avium intracellulare) Autosomal dominant EDA-ID NFKBIA IκBαIκBαIκBαIκBα Multiple innate and adaptive pathways As above IRAK4 deficiency IRAK4IRAK4 TLR signaling Pyogenic bacterial infections (Streptococcus pneumoniae, Staphylococcus aureus) Human monogenic immunodeficiencies affecting Toll-like receptor function

52 Pyogenic Bacterial Infections in Humans with IRAK-4 Deficiency

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55 40 20 IL-1 (pg/ml) WT/WT WT/Asp299Gly & Thr399Ile

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

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

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

59 Legionnaires Disease and TLR5

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

61 TLR5 Polymorphisms and Legionnaires Disease C C T T A G A G P = 0.02 P = 0.02 P = 0.03 Cases n=109 CTL n=508 Paired CTL n=89 Hawn TR. J Exp Med 2003; 198: 1563 SNPSmokersNonsmokersP No. BP Allele OR (95% CI)POR (95% CI) Haplotype CA CG (0.55, 3.25) (1.04, 3.80) 0.04 TA (0.19, 3.05) (1.00, 5.89) 0.005

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

63 IRAK-1 Haplotype Increases Morbidity of Sepsis Arcoli J. Am J Respir Crit Care Med 2006;175: septic Caucasians patients OR:2.6 (95% CI, ) Wildtype % Variant P=0.047 IRAK-1 Haplotype Shock Pulmonary Infection Wildtype VFD Variant P=0.03 IRAK-1 Haplotype Wildtype VFD Variant P=0.02 IRAK-1 Haplotype

64 IRAK-1 Haplotype Increases Mortality of Sepsis Arcoli J. Am J Respir Crit Care Med 2006;175:1335 Wildtype % Variant P=0.03 IRAK-1 Haplotype 60-Day Mortality Pulmonary Infection Wildtype % Variant P=0.05 IRAK-1 Haplotype 60-Day Mortality

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

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

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

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

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

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

72 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) * * **

73 Lauer S. Cell Immunol 2009;255:8 LPS decreases TLR4 cell expression Soluble MD2 Increases TLR4 Levels on the Epithelial Cell Surface TLR4 cell surface expression Mean fluorescence TLR4/vectorTLR4/vector(noLPS) LPS (ug/ml)

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

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

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

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

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

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

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

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82 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 100 and 250 mg doses of eritoran completely blocked all clinical signs and symptoms of LPS toxicity Chills Chills Fever Fever Headache Headache Myalgia Myalgia Tachycardia Tachycardia 100 and 250 mg doses of eritoran completely blocked all biochemical effects of LPS challenge 100 and 250 mg doses of eritoran completely blocked all biochemical effects of LPS challenge Lynn M, et al. J Infect Dis Feb 15;187(4):631-9 Placebo 60, 100, 260 ug E6684 Time after LPS infusion (hrs) Plasma TNF α (pg/mL)

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

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

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

86 Characteristics of Infection: P2 Eritoran (continued) Tidswell et al. Crit Care Med 2010; 38:72-83 CharacteristicPlacebo(n=96) Eritoran tetrasodium 45mg (n=103) Eritoran tetrasodium 105 mg (n=94) Overall p Value Infection type, m (%).6944 Gram-negative Gram-negative 26 (27.1) 23 (22.3) 29 (31.2) Gram-positive Gram-positive 30 (31.3) 38 (36.9) 29 (31.2) Mixed bacterial Mixed bacterial 10 (10.4) 7 (6.8) 13 (14.0) Fungal Fungal 1 (1.0) 4 (3.9) 1 (1.1) Viral Viral 1 (1.0) 2 (1.9) 0 (0) Unkown 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)

87 Endotoxin in Critically Ill J Marshall JID 2004

88 Endotoxin in Critically Ill J Marshall JID 2004 EA Level Gram-negative infection Gram-positive infection All infections Prevalence, % (no./total) OR (95% CI) Prevalence, % (no./total) OR (95% CI) Prevalence, % (no./total) OR (95% CI) Low (<0.40) 1.4 (5/367) (14/367) (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) 2.2( )

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

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

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

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

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

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

95 Infectious Adverse Events: P2 Eritoran Tidswell et al. Crit Care Med 2010; 38:72-83 Infectious Adverse Events Placebo(n=96) Eritoran Tertrasodium 45 mg (n=103) Eritoran Tetrasodium 105 mg (n=94) Overall p value Investigator- reported infectious complication Clinical evaluation committee determination of infectious complication 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.

96 Eritoran P2 Clinical Trial: No Effect on Circulating IL-6 Concentration Tidswell et al. Crit Care Med 2010; 38:72-83 Placebo 45 mg 105 mg 0 12 hr 48 hr IL-6 lvel (pg/mL)

97 ACCESS Trial: P3 Eritoran Trial 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 159 worldwide study locations 2000 patients enrolled in trial 2000 patients enrolled in trial Contr olled Comparison of Eritoran Tetrasodium and Placebo in Patients with Severe Sepsis Controlled Comparison of Eritoran Tetrasodium and Placebo in Patients with Severe Sepsis

98 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: 1.Length of ICU stay within 28 days 2.Length of Hospital stay within 28 days 3.Duration of dialysis within 28 days 4.Duration of mechanical ventilation within 28 days 5.Duration of use of vasopressors within 28 days 6.Measurement of cytokine inflammatory panel and procalcitonin 7.Quality of Life 8.SOFA assessment 9.Incidence of infection episodes subsequent to randomization 10.Pharmacoeconomics 11.Mortality at 3 and 6 months

99 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 Objective evidence of infection – likely bacterial or fungal pathogen Examples of objective evidence: Clinical findings (i.e. cellulitis or abscesses) Clinical findings (i.e. cellulitis or abscesses) Cultures Cultures Gram stains Gram stains X-rays X-rays Surgical pathology specimens Surgical pathology specimens ** Note: A positive culture is not a requirement for entry into the trial ACCESS Trial Entry Criteria Inclusion Criteria

100 ACCESS Trial Entry Criteria Inclusion Criteria Presence of at least 3 of 4 SIRS criteria: Presence of at least 3 of 4 SIRS criteria: Core Temperature > 38 C or 38 C or < 36 C Heart Rate > 90 beats/min 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 PaCO 2 20 breaths/min OR a PaCO 2 < 32 mmHg, or mechanical ventilation WBC Count > 12,000 cells/ L, 10% band forms. WBC Count > 12,000 cells/ L, 10% band forms.

101 III.At least 1 of the following organ dysfunctions: A. Acute Lung Injury (ALI)/Acute Respiratory Distress A. Acute Lung Injury (ALI)/Acute Respiratory Distress Syndrome (ARDS) Syndrome (ARDS) Acute Onset of the following: Acute Onset of the following: 1. PaO 2 /FiO m, then PaO 2 /FiO m, then PaO 2 /FiO 2 < 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 Criteria 1-4 must occur together within 24-hour interval ACCESS Trial Entry Criteria Inclusion Criteria

102 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 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 ACCESS Trial Entry Criteria Inclusion Criteria

103 E. Shock Acute onset of systolic BP 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. ACCESS Trial Entry Criteria Inclusion Criteria

104 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 patients family has not committed to aggressive management of patients 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. ACCESS Trial Entry Criteria Inclusion Criteria

105 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 Inclusion Criteria

106 12 hrs Onset of 1st Organ Failure Study Drug Infusion Onset of Organ Failure < 12 hrs between documentation of the 1 st qualifying organ dysfunction and administration of study drug ACCESS Trial Entry Criteria: Time Window

107 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 Initial resuscitation goals Use of low tidal volumes for mechanical ventilation Use of low tidal volumes for mechanical ventilation Control of blood glucose levels Control of blood glucose levels Maintenance of target hemoglobin levels Maintenance of target hemoglobin levels Source control 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.

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

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

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

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

112 Summary and Conclusions TLR-4 inhibition represents a potentially promising strategy for treatment of severe sepsis 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 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 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 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 * Three interim analyses have been conducted for the Phase III ACCESS study and the DSMB has given authorization to complete the study

113 Summary and Take Home Message

114 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 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. 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 Polymorphisms of TLRs and related adaptor and signaling molecules are associated with susceptibility or protection from a number of infectious diseases Conclusions

115 TLR4 is the signal receptor for LPS along with MD2 and CD 14 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. 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 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 Conclusions


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