1. 1 Drotrecogin alfa activated (Xigris ® ) in the treatment of adult patients with severe sepsis GENERAL OVERVIEW

2. 2 I.Severe Sepsis II.Activated Protein C Mode of Action III.Clinical Trials IV.Learning Curve V.Conclusions OVERVIEW DrotAA: Drotrecogin alfa (activated) = recombinant human Activated Protein C (rhAPC) = Xigris ®

3. 3 I. Sepsis: Defining a Disease Continuum 1 Adult Criteria A clinical response arising from a nonspecific insult, including  2 of the following: –Temperature >38 o C, or <36 o C –Heart Rates >90 /min –Respiratory rate >20 /min –White Blood Cell count > 12000 cells/μL or < 4000 cells/μL SIRS = Systemic Inflammatory Response Syndrome SIRS with a presumed or confirmed infectious process Sepsis SIRS Infection or Trauma Severe Sepsis 1. Levy M et al., Crit Care Med. 2003;31(4),1250-1256

4. 4 Sepsis with organ dysfunction, for example: - Cardiovascular (acute circulatory failure with persistent arterial hypotension unexplained by other causes) - Renal - Respiratory - Hepatic - Hematologic - Central Nervous System - Hypoperfusion Shock Sepsis: Defining a Disease Continuum 1 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference Cardiovascular: arterial hypotension, systolic blood pressure <90mmHg, mean arterial blood pressure <70mmHg Renal: acute oliguria, urine output 0.5mg/dL Respiratory: Arterial hypoxemia PaO 2 /FiO 2 ratio <300 Hepatic: hyperbilirubinemia, plasma total bilirubin >4mg/dL or 70mmol/L Haematological: Thrombocytopenia, platelet count <100,000/μL Central Nervous System: altered mental status Hypoperfusion parameters: hyperlactatemia (>1 mmol/L) Sepsis SIRS Infection or Trauma Severe Sepsis

5. 5 Incidence of Different Pathologies in Europe 1-2 11.6 13.0 13.2 14.0 30.0 * 0 10 20 30 Incidence (%) Lung Cancer Colon Cancer Prostate Cancer Breast Cancer Severe Sepsis 1. Ferlay J et al Annals of Oncology. 2007;18:581-592, 2. Vincent JL et al Crit Care Med. 2006;34:344-353 * During the ICU stay

6. 6 Mortality of Different Pathologies in Europe 1-2 1. Ferlay J et al Annals of Oncology. 2007;18:581-592, 2. Vincent JL et al Crit Care Med. 2006;34:344-353 5.8 7.3 12.0 20.2 32.2 * 0 20 40 Deaths (%) Prostate Cancer Breast Cancer Colon Cancer Lung Cancer Severe Sepsis * During the ICU stay

7. 7 198 Intensive Care Units (ICU) in 24 European Countries 3147 adult patients Sepsis in European Intensive Care Units: The SOAP study 1 IncidenceICU MortalityHospital Mortality Sepsis37%27%36% Severe Sepsis30%32.2%NA Septic Shock15%54.1%NA 1: Adapted from Vincent JL et al. Crit Care Med. 2006;34:344-353 0 10 20 30 40 50 60 70 0123≥ 4 Mortality (%) Numbers of failing organs SOAP: Sepsis Occurrence in Acutely Ill Patients NA = Not Available

8. 8 Severe Sepsis Pathophysiology 1 1. Adapted from Smithies MN et al. Blood Coagul Fibrinolysis. 2004;15(suppl 1):S11–S20 Tissue injury Microvascular coagulation/ thrombosis Organ dysfunction Death Mitochondrial dysfunction Activation of coagulation Inhibition of fibrinolysis Endothelial dysfunction Tissue factor expression Microvascular flow redistribution Inflammation Leucocyte activation Anti-inflammatory mediators e.g. IL-10, IL-1 receptor antagonists Pro-inflammatory mediators e.g. Tumour necrosis factor, IL-1, IL-6, IL-8, nitric oxide Pathogen Infection Host responses

9. 9 Thrombin Coagulation cascade Prothrombin ┴ inflammatory Cell activation Fibrin/platelets PAR1 VIIIa Va Th V VIII IXa Xa PC APC Thrombin Thrombomodulin Th ┴ Pro-inflammatory ┴ Pro-apoptotic PAR1 Signals for cytoprotection Apoptotic balance ↓ Inflamm cell adhesion ↓ Chemokine/cytokine ↓ Vascular function EDG-1 - ┴ Thrombin generation  Cytoprotection APC CD1 MHC EPCR transactivation II. Activated Protein C (APC) Mechanism of Action 1-5 1. Esmon CT. et al. Sem.Thromb.Hemost. 2006;32,(Suppl1):49-60 2. Feistritzer C et al. J Allergy Clin Immunol. 2003:112:375-381 3. Adapted from Macias WL et al. Crit Care. 2005;9(suppl 4):S38-S45 4. McClintock et al. Crit Care. 2008;12:R41 5. Abraham E et al. Crit Care Med. 2007;35(10):2408-2416

10. 10 APC Mode of Action in Sepsis 1 Protects against disruption of the endothelial cell barrier Improves microcirculatory perfusion Has anti-inflammatory activity Has anti-coagulation activity Has pro-fibrinolytic activity Has anti-apoptotic activity 1. Levi M et al. Crit Care. 2007;11(suppl 5):S3

11. 11 DrotAA: Molecular Properties 1-3 DrotAA is a recombinant version of the natural plasma-derived activated Protein C, from which it differs only by unique oligosaccharides in the carbohydrate portion of the molecule 1 DrotAA has similar properties to those of endogenous human Activated Protein C 1 DrotAA has a molecular weight of 55 kDa and is not eliminated by hemofiltration or dialysis 2 Simulated structure of human Activated Protein C 3 1. EMEA: http://www.emea.europa.eu/humandocs/PDFs/EPAR/xigris/H-396-PI-en.pdf accessed 29 August 2008, 2. Laterre PF et al. Critical Care 2003;7:445-450, 3. Protein Data Bank: http://nist.rcsb.org/pdb/explore.do?structureId=1AUT accessed 29 August 2008http://www.emea.europa.eu/humandocs/PDFs/EPAR/xigris/H-396-PI-en.pdfhttp://nist.rcsb.org/pdb/explore.do?structureId=1AUT

12. 12 Xigris Therapeutic Indications 1 Xigris is indicated for the treatment of adult patients with severe sepsis with multiple organ failure when added to best standard care. The use of Xigris should be considered mainly in situations when therapy can be started within 24 hours after the onset of organ failure 1. EMEA: http://www.emea.europa.eu/humandocs/PDFs/EPAR/xigris/H-396-PI-en.pdf accessed 29 August 2008http://www.emea.europa.eu/humandocs/PDFs/EPAR/xigris/H-396-PI-en.pdf

13. 13 III. Evidence from Clinical Trials of DrotAA in the Treatment of Severe Sepsis in Adult Patients 1. Bernard GR et al. Crit. Care Med. 2001;29:2051-2059, 2. Bernard GR et al. N Engl J Med. 2001;344:699-709, 3. Vincent JL et al. Crit Care Med. 2005;33:2266-2277, 4. Abraham E et al. N Engl J Med. 2005;353(13):1332-1341, 5. Levi M et al. Am J Respir Crit Care Med. 2007;176:483–490, 6. Dhainaut JF et al. Crit Care. 2008;12(2):P205 Study Study Objectives EVAA 1 (Phase II) To determine an effective dose and duration of DrotAA ( 24  g/Kg/h for 96 h) PROWESS 2 (Phase III) To asses whether treatment with DrotAA reduced the rate of death from any cause among patients with severe sepsis ENHANCE 3 (Phase IIIB) To provide further evidence for the efficacy and safety of DrotAA treatment in severe sepsis (single-arm, open-label) ADDRESS 4 (Phase IIIB) To evaluate the efficacy of DrotAA for adults who had severe sepsis and a low risk of death (APACHE II score <25 or single organ dysfunction) XPRESS 5 (Phase IV) To demonstrate that in adult patients with severe sepsis receiving DrotAA treatment, concomitant treatment with prophylactic heparin is equivalent to treatment with placebo EXTEND 6 (Phase IV) To investigate whether, in severe sepsis patients with persistent vasopressor dependency at the end of 96 h commercial DrotAA treatment, continued administration of DrotAA for up to a further 72 h results in more rapid resolution of vasopressor dependency compared with placebo

14. 14 1. Bernard GR et al. Crit. Care Med. 2001;29:2051-2059, 2. Bernard GR et al. N Engl J Med. 2001;344:699-709, 3. Vincent JL et al. Crit Care Med. 2005;33:2266-2277, 4. Abraham E et al. N Engl J Med. 2005;353(13):1332-1341, 5. Levi M et al. Am J Respir Crit Care Med. 2007;176:483–490, 6. Dhainaut JF et al. Crit Care. 2008;12(2):P205 StudyPatients (n)28-day Mortality (%)Relative Risk DrotAAPlacebo EVAA* 1 (Phase II) 13128.934.10.85 PROWESS 2 (Phase III) 169024.730.80.81 ENHANCE 3 (Phase IIIB) 237825.3N/A ADDRESS 4 (Phase IIIB) 264018.517.01.08 XPRESS 5 (Phase IV) 193531.9N/A EXTEND #6 (Phase IV) 20139.832.31.23 N/A: Not Applicable, * Patients received intravenous infusion of DrotAA (12, 18, 24, or 30 μg/kg/h) or placebo for 48 or 96 h, # All patients received the 96 h commercial treatment of DrotAA followed by a continued administration of DrotAA or placebo for up to a further 72 h Evidence from Clinical Trials of DrotAA in the Treatment of Severe Sepsis in Adult Patients

15. 15 Study Synopsis: ENHANCE 1 and PROWESS 2 PROWESS 1 ENHANCE 2 (Adult) Design Global, single-arm, open label study, 25 Countries, 361 Sites (n=2378) Enrollment initiated March 2001 to Dec. 2002 Population Severe Sepsis -Presence of a known or suspected infection -Evidence of a systemic response to the infection (≥3 SIRS criteria) -At least one sepsis-associated organ dysfunction of no greater than 48 h duration DrotAA Dosage 24 µg/kg/h for 96 h Objective Provide further evidence for the efficacy and safety of DrotAA treatment in severe sepsis 1. Adapted from Bernard GR et al. N Engl J Med. 2001;344:699-709, 2. Adapted from Vincent JL et al. Crit Care Med. 2005;33(10):2266-2277 Design Global, randomized, double-blind, placebo-controlled trial 11 countries at 164 sites (n=1690, planned n=2280) Enrollment initiated July 1998 to June 2000 Objective 28-day all-cause mortality

16. 16 DrotAA is not approved for the treatment of patients with single organ dysfunction 2 Study Description: ADDRESS 1-2 Design International, multi-center, randomized, double-blind, parallel placebo-controlled study 34 Countries, 516 Sites (n=2640, Planned n >11000) Enrollment initiated Sep. 2002 to Feb. 2004 Population Adult patients with low risk of death: EU: patients with single organ failure US: patients with an APACHE II score <25) Dosage 96 h infusion of placebo or DrotAA 24 µg/kg/h Primary Endpoint 28-day all-cause mortality  1. Abraham E et al. N Engl J Med. 2005;353(13):1332-1341, 2. EMEA: http://www.emea.europa.eu/humandocs/PDFs/EPAR/xigris/H-396-PI-en.pdf accessed 29 August 2008http://www.emea.europa.eu/humandocs/PDFs/EPAR/xigris/H-396-PI-en.pdf

17. 17 Baseline Characteristics of DrotAA Treated Patients: Disease Severity 1. Adapted from Vincent JL et al. Crit Care Med. 2005;33(10):2266-2277, 2. Abraham E et al. N Engl J Med. 2005;353(13):1332-1341 APACHE II Score (Mean ± SD) 24.6 ± 7.622.0 ± 7.418.2 ± 5.8 Vasopressor Support n (%) 1750 (73.7%)516 (60.7%)638 (47.9%) Ventilatory Support n (%) 1948 (82.0%)623 (73.3%)751 (56.3%) PROWESS 1 (n = 850) ENHANCE 1 (n = 2378) ADDRESS 2 (n = 1333) No of Organ Dysfunctions (Mean ± SD) 2.4 ± 1.12.7 ± 1.1≤ 2 (92.2%)

18. 18 Baseline Characteristics of DrotAA Treated Patients: Site of Infection 1. Adapted from: Vincent JL et al. Crit Care Med. 2005;33(10):2266-2277, 2. Abraham E et al. N Engl J Med. 2005;353(13):1332-1341 Lung461 (54.2%)1112 (46.8%) Intra-Abdominal170 (20.0%)588 (24.7%) Urinary Tract 85 (10.0%) 204 (8.6%) Other89 (10.5%)310 (13.0%) 685 (51.4%) 275 (20.6%) 133 (10.0%) 240 (18.0%) PROWESS 1 (n = 850) ENHANCE 1 (n = 2378) ADDRESS 2 (n = 1333) Values given as n (%)

19. 19 Mortality 1 PROWESS: 28-Day All-Cause Mortality 1 1. Adapted from Bernard GR et al. N Engl J Med. 2001;344:699-709 ARR: Absolute Risk Reduction RRR: Relative Risk Reduction Primary Analysis Results p-value = 0.005 DrotAAPlacebo ARR: 6.1% 0 5 10 15 20 25 30 35 28-Day mortality (%) RRR: 19.4% n = 840 n = 850 30.8% 24.7%

20. 20 Survival Rate in PROWESS and ENHANCE 1 *Absolute risk reduction of PROWESS DrotAA group vs. Placebo is 6.1% (p= 0.005) 2 1. Adapted from Vincent JL et al. Crit Care Med. 2005;33(10):2266-2277, 2. Bernard GR et al. N Engl J Med. 2001;344:699-709 The pattern of the survival curve was essentially identical for ENHANCE patients and PROWESS DrotAA-treated patients 1 Survival Rate (%) 60 70 80 90 100 Days After the Start of the Infusion 07142128 PROWESS Placebo (n=840) 28-day all cause mortality*: 30.8% 2 PROWESS DrotAA (n=850) 28-day all cause mortality*: 24.7% 2 ENHANCE DrotAA (n=2375) 28-day all cause mortality: 25.3%

21. 21 ADDRESS: 28-Day and In-Hospital Mortality 1-2 1. Adapted from Abraham E et al. N Engl J Med. 2005;353(13):1332-1341, 2. EMEA: http://www.emea.europa.eu/humandocs/PDFs/EPAR/xigris/H-396-PI-en.pdf accessed 29 August 2008http://www.emea.europa.eu/humandocs/PDFs/EPAR/xigris/H-396-PI-en.pdf The number of patients refers to the total number of patients who completed the study and were included in the analysis DrotAA Placebo RR (95% CI) p-value 28-Day Mortality 1.08 (0.92-1.28) 18.5%17.0% 20.6%20.5% 0.98 0.34 1.00 (0.86-1.16) In-Hospital Mortality DrotAA is not approved for the treatment of patients with single organ dysfunction 2

22. 22 Organ Dysfunction Definition in Clinical Trials 1 Cardiovascular system dysfunction: –arterial systolic blood pressure had to be ≤90 mm Hg or the mean arterial pressure ≤70 mm Hg for at least 1 hour despite adequate fluid resuscitation, adequate intravascular volume status or the use of vasopressors in an attempt to maintain a systolic blood pressure of ≥90 mm Hg or a mean arterial pressure of ≥70 mm Hg Kidney dysfunction: –urine output had to be to be <0.5 ml/kg of body weight/h for 1 hour, despite adequate fluid resuscitation Respiratory-system dysfunction: –the ratio of PaO 2 to FiO 2 had to be ≤250 in the presence of other dysfunctional organs or systems or ≤200 if the lung was the only dysfunctional organ Hematologic dysfunction: –platelet count had to be <80,000/mm 3 or to have decreased by 50% in the 3 days preceding enrollment Metabolic acidosis: –the pH had to be ≤7.30 or the base deficit had to be ≥5.0 mmol/liter in association with a plasma lactate level that was >1.5 times the upper limit of the normal value for the reporting laboratory 1. Bernard GR et al. N Engl J Med. 2001;344:699-709

23. 23 PROWESS: 28-Day Mortality: Two or More Organ Dysfunctions 1 1. Adapted from Dhainaut JF et al. Intensive Care Med. 2003;29:894-903 ARR: Absolute Risk Reduction RRR: Relative Risk Reduction p-value = 0.006 28-Day mortality (%) RRR: 21.8% ARR: 7.4% PlaceboDrotAA 0 5 10 15 20 25 30 35 40 n = 637 n = 634 33.9% 26.5%

24. 24 PROWESS: Resolution of Respiratory Dysfunction by Day 7 1 1. Adapted from Vincent JL et al. Crit Care Med. 2003;31:834-840

25. 25 PROWESS: Resolution of Cardiovascular Dysfunction by Day 7 1 1. Adapted from Vincent JL et al. Crit Care Med. 2003;31:834-840 Cardiovascular Resolution (%) p-value = 0.009 Study Day 012345678 0 20 40 60 80 DrotAA n = 746 Placebo n = 736

26. 26 28-Day All-Cause Mortality by Organ Dysfunctions 1 1. Adapted from Vincent JL et al. Crit Care Med. 2005;33(10):2266-2277 Number of Organ Dysfunctions PROWESS ENHANCE Placebo DrotAA DrotAA (n=840) (n=850) (n=2375) 1 21.2% (203) 19.5% (215) 15.4% (370) 26.0% (273) 20.7% (270) 17.7% (706) 2 34.4% (218) 26.2% (214) 27.3% (703)3 46.6% (116) 38.7% (119) 39.0% (436) 4 53.3% (30) 32.3% (31) 35.0% (160) 5 Values given as % (n)

27. 27 Patients Treated within 24 h of their First Organ Dysfunction in ENHANCE trial 1-2 The use of DrotAA should be considered mainly in situations when therapy can be started within 24 h after the onset of organ failure Treatment should be started within 48 hours, and preferably within 24 h, of onset of the first documented sepsis-induced organ dysfunction 1. Vincent JL et al. Crit Care Med. 2005;33(10):2266-2277, 2. EMEA: http://www.emea.europa.eu/humandocs/PDFs/EPAR/xigris/H-396-PI-en.pdf accessed 29 August 2008http://www.emea.europa.eu/humandocs/PDFs/EPAR/xigris/H-396-PI-en.pdf 25.3 22.9 27.4 0 5 10 15 20 25 30 35 ENHANCE DrotAA ENHANCE DrotAA < 24h ENHANCE DrotAA ≥ 24h 28-day all-cause mortality (%) p-value = 0.01

28. 28 Xigris Therapeutic Indications 1 Xigris is indicated for the treatment of adult patients with severe sepsis with multiple organ failure when added to best standard care. The use of Xigris should be considered mainly in situations when therapy can be started within 24 hours after the onset of organ failure 1. EMEA: http://www.emea.europa.eu/humandocs/PDFs/EPAR/xigris/H-396-PI-en.pdf accessed 29 August 2008http://www.emea.europa.eu/humandocs/PDFs/EPAR/xigris/H-396-PI-en.pdf

29. 29 Study Description: XPRESS 1 Design International, multicenter, randomized, double-blind, parallel placebo- controlled Phase IV equivalence-design trial, all receiving DrotAA 20 countries, 224 sites (n=1935) Enrollment initiated Dec. 2002 to Aug. 2005 Population Adult patients, indicated for the treatment with DrotAA under the approved label of the country in which the patients enrolled Study drug was either heparin or placebo Dosage 96 h infusion of DrotAA 24 µg/kg/h UFH (5000 U subcutaneously twice per day) or LMWH (enoxaparin, 40 mg subcutaneously once per day) Primary Endpoint 28-day all-cause mortality 1. Levi M et al. Am J Respir Crit Care Med. 2007;176:483-490 UFH: Unfractionated Heparin LMWH: Low Molecular Weight Heparin

30. 30 XPRESS: 28-Day All-Cause Mortality 1-2 Compared with placebo, concomitant prophylactic heparin did not increase 28- day mortality in patients with severe sepsis receiving DrotAA Early discontinuation of prophylactic heparin may be harmful in patients with severe sepsis receiving DrotAA No dose adjustments are required in adult patients with severe sepsis with regard to co-administration of prophylactic heparin Unable to conclude superiority of DrotAA/Heparin over DrotAA/Placebo 1. Adapted from Levi M et al. Am J Respir Crit Care Med. 2007;176:483-490, 2. EMEA: http://www.emea.europa.eu/humandocs/PDFs/EPAR/xigris/H-396-PI-en.pdf accessed 29 August 2008http://www.emea.europa.eu/humandocs/PDFs/EPAR/xigris/H-396-PI-en.pdf DrotAA AD90% ARD CIp-value PlaceboHeparinEquivalence Overall31.9%28.3%3.6%-0.071, -0.0020.08No AD: Absolute Difference, ARD: Absolute Risk Difference

31. 31 Safety in DrotAA Clinical Trials 1 1. Adapted from Fumagalli R et al. Critical Care. 2007;11(suppl 5):S6 Placebo-controlled studiesOpen-label a PROWESSADDRESSENHANCEXPRESS Adverse events DrotAA (n=850) Placebo (n=840) DrotAA (n=1317) Placebo (n=1293) DrotAA (n=2378) DrotAA (n=1935) Study drug infusion period* Serious events 58 (6.8)55 (6.5)75 (5.7)78 (6.0)166 (7.0)128 (6.6) Serious bleeds 20 (2.4)8 (1.0)31 (2.4)15 (1.2)85 (3.6)46 (2.4) CNS bleeds 2 (0.2)04 (0.3)3 (0.2)15 (0.6)6 (0.3) Days 0 trough 28 Serious events 106 (12.5) 102 (12.1)182 (13.8)183 /(14.2)319 (13.4)256 (13.2) Serious bleeds 30 (3.5)17 (2.0)51 (3.9)28 (2.2)155 (6.5)88 (4.5) CNS bleeds 2 (0.2)1 (0.1)6 (0.5)5 (0.4)35 (1.5)17 (0.9) Values are expressed as n (%). CNS: Central Nervous System *In PROWESS and ENHANCE, the study drug infusion period was defined as the actual infusion plus 1 day. In ADDRESS, RESOLVE and XPRESS, the study drug infusion period was defined as study days 0 through 6 a ENHANCE was an open-label study. XPRESS was a placebo-controlled study of the co-administration of heparin with drotrecogin alfa (activated); the drug under study was heparin; open-label drotrecogin alfa (activated) was administered to all patients

32. 32 Bleeding Events in PROWESS 1 PROWESS involved 850 DrotAA-treated and 840 placebo-treated patients. The percentage of patients experiencing at least one bleeding event in the two treatment groups was 24.9% and 17.7%, respectively In both treatment groups, the majority of bleeding events were ecchymosis or gastro-intestinal tract bleeding The difference in the incidence of serious bleeding events between the two treatment groups occurred primarily during study drug administration Serious bleeding events included any intracranial haemorrhage, any life- threatening or fatal bleed, any bleeding event requiring the administration of  3 units of packed red blood cells per day for 2 consecutive days, or any bleeding event assessed as serious by the investigator 1. EMEA: http://www.emea.europa.eu/humandocs/PDFs/EPAR/xigris/H-396-PI-en.pdf accessed 29 August 2008http://www.emea.europa.eu/humandocs/PDFs/EPAR/xigris/H-396-PI-en.pdf

33. 33 Conclusions – Safety 1-2 1. Fumagalli R et al. Crit Care. 2007;11(suppl 5):S6, 2. Bernard GR Crit Care. 2003;7(2):155-163, 3. Barie et al. PS Curr Inf Dis Resp. 2008;10(5):368-376 DrotAA increases the risk for bleeding without increasing general adverse events, thus resulting in similar rates of serious adverse events in treated arms compared with placebo The only significant serious adverse event associated with DrotAA treatment is bleeding Serious bleeding events are most frequent on day 1 of therapy with DrotAA and rapidly decline on subsequent days Clinical experience indicates that invasive procedures are associated with a substantial percentage of these serious bleeding events Severe thrombocytopenia (for all bleeding events) and meningitis (for ICH only) may be risk factors for serious bleeding The risk for bleeding can be mitigated by following package inserts (approved labeling) and avoiding off-label use (in contraindicated patients) The intracranial hemorrhage rate in all of the studies is in accordance with the rate of spontaneous intracranial hemorrhage in critically ill patients

34. 34 Ongoing Trial: RESPOND 1-2 1. Vangerow B et al. Crit Care. 2007;11(suppl 5):S4, 2. ClinicalTrial-RESPOND: http://www.clinicaltrials.gov/ct2/show/NCT00386425?term=drotrecogin&recr=Open&rank=1#locn accessed 29 August 2008http://www.clinicaltrials.gov/ct2/show/NCT00386425?term=drotrecogin&recr=Open&rank=1#locn Design A randomized, double blind, phase II study Population Adult patients must have multiple sepsis-associated organ dysfunction and protein C deficiency (protein C level less than the lower limit of normal) Aiming to recruit 488 patients Enrollment initiated Nov. 2006 - Estimated Study Completion Date May 2009 Dosage Standard therapy: 24 mcg/kg/h for 24 h, followed by 24 mcg/kg/h for an additional 72 h Alternative therapy -moderate protein C deficiency: 24 mcg/kg/h for 24 h, followed by 24 mcg/kg/h for an additional 72 to 144 h Alternative therapy - severe protein C deficiency: 24 mcg/kg/hr for 24 h, followed by 30, 36, 42 or 48 mcg/kg/h for an additional 72 to 144 h Objective To establish serial plasma protein C measurements as a biomarker that will aid in the identification of those patients with severe sepsis who are most likely to benefit from DrotAA

35. 35 Ongoing Trial: PROWESS-SHOCK 1-2 Design A Randomized, Double-Blind, Placebo-Controlled, Multicenter, Phase III Study Population Adult patients must have evidence of infection, systemic inflammatory response syndrome (SIRS) and vasopressor-dependent septic shock Aiming to recruit 1500 patients Enrollment initiated March 2008 - Estimated Study Completion Date July 2010 Dosage 96 h infusion of placebo or DrotAA 24 µg/kg/h Objective To determine if DrotAA treatment provides significant mortality reduction improvement in patients with septic shock compared with placebo treatment in patients receiving the current standard of care for septic shock 1. Barie PS et al. Curr Inf Dis Resp. 2008;10(5):368-376, 2. ClinicalTrial-PROWESS-SHOCK: http://www.clinicaltrials.gov/ct2/show/NCT00604214?term=Drotrecogin+alfa&recr=Open&rank=2 accessed 29 August 2008http://www.clinicaltrials.gov/ct2/show/NCT00604214?term=Drotrecogin+alfa&recr=Open&rank=2

36. 36 Effects of DrotAA on Mortality in Clinical Practice Patients DrotAA treated (n) Absolute Risk Reduction p value PROWESS 1,2 850 6.1% a 5.2% b 0.005 a 0.027 b ICNARC study* 3 1079 4.1% a 1.3% b UK audit 4 3512.6%-13% b Polish Registry 5 30217.3% b Belgian Registry 6 43616.1% a Italian Survey 7 6688.5% c 0.0004 c French Study 8 5873.3% a 0.34 a 1. Bernard GR et al. N Engl J Med. 2001;344:699-709, 2. Laterre PF et al. Crit Care Med. 2004;32(11):2207-2218, 3: Rowan KM et al. Crit Care. 2008,12:R58, 4: Ridley S et al. Eur J Anaesthesiology. 2008,25:211-216, 5: Kübler A et al. Med Sci Monit. 2006;12(3):CR107-112, 6: Vincent JL et al. Acta Clinica Belgica. 2008;63-1:25-30, 7: Bertolini G et al. Intensive Care Med. 2007;33:426-434, 8: Dhainaut JF et al. Crit Care. 2007;11:R99 a 28-day mortality, b In Hospital mortality, c ICU mortality * Patients admitted with severe sepsis and ≥2 organ systems failing

37. 37 International INtegrated Database for the Evaluation of severe sePsis and DrotAA THerapy (INDEPTH) 1 Design 5 studies, 3 Phase II, 2 Phase III (n=4459) Studies conducted between July 1996- Jan. 2003 Population Adult patients with a suspected or confirmed infection with at least one organ dysfunction. In one of the phase II study, patients were required to have two organ dysfunctions Dosage 96 h infusion of placebo or DrotAA 24 µg/kg/h Objective To better understand the effects of DrotAA in severe sepsis patients and the natural progression of severe sepsis patients using the appropriate statistical analysis methods to integrate data from various trials 1. Sashegyi A et al. Curr Med Research Opin. 2006;22(5):1001-1012

38. 38 Results Patients treated with DrotAA had a significantly lower 28-day all-cause mortality rate (25.1%) than patients receiving placebo (31.8%) Patients treated earlier with DrotAA (0 to 24 h) had a significantly higher 28-day survival (76.4%) than patients treated later with DrotAA (more than 24 h; 73.5%) at day 28 Conclusions INDEPTH provides additional evidence that treatment of severe sepsis patients with DrotAA is associated with a sustained survival advantage throughout 28-day follow-up INDEPTH suggests that treatment with DrotAA within 24 h may carry a larger survival advantage for patients with severe sepsis, compared with those treated more than 24 h after organ dysfunction INDEPTH Provides Information on Mortality of the Patients with Severe Sepsis 1-2 1. Sashegyi A et al. Curr Med Research Opin. 2006;22(5):1001-1012, 2. Vincent JL et al. Crit Care. 2006;10:R74

39. 39 Patient order within a site All Patients nRelative Risk (95% CI) First 4 patients (164 sites)5590.91 (0.71-1.17) Patients 5-8 (105 sites)3620.81 (0.58-1.14) Patients 9-12 (72 sites)2490.80 (0.51-1.26) >12 patients (50 sites)5200.69 (0.52-.091) IV. Learning Curve from the PROWESS Study 1-2 A learning curve appeared to be present within the PROWESS trial such that the ability to demonstrate efficacy improved with increasing site experience In placebo controlled clinical trials, the treatment effect was most evident at sites enrolling larger numbers of patients 1. Adapted from Macias WL et al. Crit Care Med. 2004;32:2385 -2391, 2. EMEA: http://www.emea.europa.eu/humandocs/PDFs/EPAR/xigris/H-396-PI-en.pdf accessed 29 August 2008http://www.emea.europa.eu/humandocs/PDFs/EPAR/xigris/H-396-PI-en.pdf p=0.007

40. 40 DrotAA can reduce mortality in patients with severe sepsis at high risk for death (patients with multiple organ failure) This survival benefit is achieved at the expense of a slight increase in the risk for bleeding events Increase in the risk for bleeding events can be minimized by adequate patient selection If indicated, DrotAA should be used within the first 24 hours of sepsis-induced organ dysfunction 1. Laterre PF et al. Crit Care. 2007;11(suppl 5):S5 V. CONCLUSIONS 1

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