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Signs and Symptoms Predictive of Morbidities and Mortality in PNH

Signs and Symptoms Predictive of Morbidities and Mortality in PNH. Jack Goldberg, MD Clinical Professor of Medicine Chief , Division of Hematology and Medical Oncology, Penn Presbyterian Medical Center. Actuarial Survival From the Time of Diagnosis in 80 Patients With PNH 2. 100. 80.

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Signs and Symptoms Predictive of Morbidities and Mortality in PNH

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  1. Signs and Symptoms Predictive of Morbidities and Mortality in PNH Jack Goldberg, MD Clinical Professor of Medicine Chief, Division of Hematology and Medical Oncology, Penn Presbyterian Medical Center

  2. Actuarial Survival From the Time ofDiagnosis in 80 Patients With PNH2 100 80 Age- and Gender-Matched Controls 60 Patients Surviving (%) 40 Patients with PNH 20 0 0 5 10 15 20 25 Years After Diagnosis Paroxysmal Nocturnal Hemoglobinuria: A Chronic, Systemic and Life-Threatening Disease • Prevalence: 15.9 / million1 • Diagnosed at all Ages • Median age early 30’s3,4 • Progressive disease2-4 • Uncontrolled complement activation underlies the morbidities and mortality • Despite best supportive care • 5 year mortality: 35%2 1. Hill A et al. Blood. 2006;108(11):290a. Abstract 985. 2. Hillmen P et al. N Engl J Med. 1995;333:1253-1258. 3. Nishimura JI, et al. Medicine. 2004;83:193-207. 4. Socié G et al. Lancet. 1996;348:573-577.

  3. Paroxysmal Nocturnal Hemoglobinuria • It’s not paroxysmal1 • Even in the absence of symptoms, destructive progression of hemolysis is ongoing • It’s not nocturnal1 • Hemolysis in PNH is subtle and constant, 24 hours a day • Hemoglobinuriais a less commonly seen complication • ¾ patients present without hemoglobinuria2 1. Rother, R et al. Nature Biotechnology. 2007;25,11:1256-1264. 2. International PNH Interest Group. Blood. 2005;106:3699-3709.

  4. The Defect in PNH PNH is an acquired hemolytic disorder characterized by the somatic mutation of the PIG A gene which prevents all GPI anchored proteins from binding to the cell surface1 • CD59 • Forms a defensive shield for RBCs from complement-mediated lysis • Inhibits the assembly of the membrane attack complex • CD55 • Prevents formation and augments instability of the C3 convertases, attenuating the complement cascade CD55 CD59 GPI-anchor 1. McKeage K. Drugs. 2011;71(17):2327-2345. Adapted from: Johnson RJ et al. J ClinPathol: MolPathol. 2002;55:145-152. 2. Brodsky R. Paroxysmal Nocturnal Hemoglobinuria. In: Hematology - Basic Principles and Practices. 4th ed. R Hoffman; EJ Benz; S Shattil et al. eds. Philadelphia, PA: Elsevier Churchill Livingstone; 2005;419-427.

  5. PNH is a Disease of Chronic Complement DysregulationLeading to Hemolysis and Progressive Morbidities and Mortality Thrombosis Normal red blood cells are protected from complement attack by a shield of terminal complement inhibitors Without this protective complement inhibitor shield, PNH red blood cells are destroyed Renal Failure Significant Impact on Survival Pulmonary Hypertension Abdominal Pain ComplementActivation Dyspnea Dysphagia Fatigue Significant Impact on Morbidity Free Hemoglobin/Anemia Intact RBC Hemoglobinuria NO↓ Erectile Dysfunction 1. International PNH Interest Group. Blood. 2005;106:3699-3709. 2. Brodsky R. Paroxysmal Nocturnal Hemoglobinuria. In: Hematology - Basic Principles and Practices. 4th ed. R Hoffman; EJ Benz; S Shattil et al, eds. Philadelphia, PA: Elsevier Churchill Livingstone; 2005;419-427. 3. Rother RP et al. JAMA. 2005;293:1653-1662. 4. Socie G et al. Lancet. 1996;348:573-577. 5. Hill A et al. Br J Haematol.2007;137:181-192. 6. Lee JW et al. Hematologica2010;95(s2): Abstract #505 and 506. 7. Hill A et al. Br J Haematol. 2010; May;149(3):414-425. 8. Hillmen P et al. Am J Hematol. 2010;85:553-559.

  6. Thrombosis Chronic Kidney Disease Common Symptoms of PNH Thrombosis in PNH1 Is the leading cause of death2 Accounts for 40-67% of deaths1 First thrombotic event can be fatal1,3 First TE increases risk for death 5 to 10-fold1 Up to 44% of patients experience clinical thrombotic events1 Occurs in typical and atypical sites4 Is not adequately managed with anticoagulation1 All patients with PNH are at risk for thrombosis1 1. Hillmen et al.Blood. 2007;110:4123-4128. 2. International PNH Group et al. Blood. 2005;106(12):3699-3709. 3. AudebertHJ et al. J Neurol. 2005;252:1379-1386. 4. Lee JW et al. Hematologica2010;95(s2): Abstract #506.

  7. Thrombosis Chronic Kidney Disease Common Symptoms of PNH Mechanisms for Thrombosis in PNH 1. Hill A et al. Br J Haematol. 2007;137:181-192. 2. Weitz I. Thrombosis Research. 2010;125:S106-S107.3. Helley D et al. Hematologica. 2010;95(4):574-581. 4. Markiewski MM et al. Trends Immunology.2007;28(4):184-192. Multifactorial pathogenesis of thrombosis in PNH: • Hemolysis • Reduced nitric oxide1-3 • Platelet hyperreactivity • Hypercoagulability • Prothrombotic membranes2 • Impaired fibrinolysis1,3 • Excessive platelet activation from CD59 deficiency1,3 • Complement C5a also contributes to increased thrombotic risk1,4 • Tissue factor initiated coagulation1,2,4

  8. Thrombosis Chronic Kidney Disease Common Symptoms of PNH Thrombosis is Associated With Risk of Early Mortality TE increases risk of death 7-15 fold over patients with no TE (N=286) (n=415) • TE was a strong predictor of mortality (OR 6.99; 95% CI 3.2-15.2; P<0.0001) in a South Korean PNH registry • 21% of TE patients presented with a TE prior to PNH diagnosis • TE was an independent prognostic factor related to poor survival (HR 15.4; 95% CI 9.3-25.4; P<0.001) in a large cohort of French PNH patients 1. Lee JW et al. Hematologica. 2010;95(s2): Abstract #505.2. de Latour RP et al. Blood. 2008;112(8):3099-3106.

  9. Thrombosis Chronic Kidney Disease Common Symptoms of PNH Thrombosis Can Occur Regardless of Clone Size % TE (n=43) PNH Granulocyte Clone Size (%) South Korean National Registry. Lee JW et al. Hematologica. 2010;95(s2): Abstract #505.

  10. Thrombosis Chronic Kidney Disease Common Symptoms of PNH Common Clinical Symptoms are Predictive of Thrombosis (P=0.0004) (P=0.002) (P=0.015) (P=0.046) South Korean National Registry. Lee JW et al. Hematologica. 2010;95(s2): Abstract #505 and 506.

  11. Thrombosis Chronic Kidney Disease Common Symptoms of PNH Thrombosis in PNH Conclusions 1. Hillmen P et al. Blood. 2007;110:12:4123-4128. 2. International PNH Group et al. Blood. 2005;106(12):3699-3709. 3. Lee JW et al. Hematologica. 2010;95(s2): Abstract #506. 4. Hall C et al. Blood. 2003;102:3587-3591. • 40-67% mortality in PNH results from thrombosis1 • Thrombosis is the leading cause of death in PNH2 • First TE increases risk for death 5 to 10-fold1 • DVT or PE most common clinical presentation1 • Arterial thromboses are also common1 • Anticoagulant therapy may not be adequate to control thrombosis in PNH1 • Anticoagulant therapy also associated with higher risk of fatal hemorrhage in PNH4 • Clinical thrombosis evident in PNH patients:1 • Minimal hemolysis • No transfusion history • Smaller clone size3

  12. Thrombosis Chronic Kidney Disease Common Symptoms of PNH Kidney Pathology in PNH • Chronic hemolysis and cell-free plasma hemoglobin lead to chronic kidney disease in PNH1-4 • Repetitive exposure of tissue to cell-free hemoglobin may lead to renal damage in PNH3,4 • 80% of PNH patients (median age of 31.5 years) had MRI evidence of significant renal hemosiderosis1,5 • Marked hemosiderin deposits in the proximal renal tubule are a common feature in all autopsy and biopsy reports dealing with PNH • Demonstrable by MRI even when no overt hemoglobinuriais seen • Autopsy and biopsy often show interstitial nephritis and fibrosis3,4 1. Brodsky R. Hematology: Basic Principles and Practice. Churchill Livingstone; 2005:419-427. 2. Rother R et al. JAMA. 2005;293:1653-1662. 3. Clark DA et al. Blood. 1981;57(1):83-89. 4. Hillmen P et al. Am J Hematol. 2010; 85:553-559. 5. Hill A et al. Blood. 2006;108:Abstract 979.

  13. Thrombosis Chronic Kidney Disease Common Symptoms of PNH Kidney Disease in PNH Conclusions • Kidney failure is the cause of 8-18% of PNH-related deaths1 • Kidney disease in PNH is caused by hemolysis2 • 64% of patients with PNH exhibit chronic kidney disease at any one time3 • Late stage renal impairment in PNH is predictive of mortality4 • Kidney disease is underappreciated in PNH3 1. Nishimura JI et al. Medicine. 2004;83:193-207. 2. Clark DA et al. Blood. 1981 Jan;57(1):83-89. 3. Hillmen P et al. Am J Hematol. 2010;85:553-559. 4. Kim JS et al. Hematologica. 2011;96(S2): Abstract #271.

  14. Thrombosis Chronic Kidney Disease Common Symptoms of PNH Common Symptoms Have a Significant Impact on Quality of Life ~75% of Patients Reported Symptoms as Moderate to Very Severe 59% patients were transfusion-free for at least 12 months or had never been transfused 76% were forced to modify their daily activities to manage their PNH 17% were unemployed due to PNH *Moderate to severe; N=29. Meyers G et al. Blood. 2007;110(11): Abstract 3683.

  15. Soliris® (eculizumab) Soliris is a Complement Inhibitor Indicated for the Treatment of Patients With PNH to Reduce Hemolysis Soliris is the First and Only Approved Therapy for PNH Soliris® (eculizumab) [package insert]. Alexion Pharmaceuticals; 2011.

  16. Human Framework Regions • No mutations • Germline Complementarity Determining Regions (murine origin) Human IgG4 Heavy Chain Constant Regions 2 and 3 (Eliminates complement activation) Human IgG2 Heavy Chain Constant Region 1 and Hinge (Eliminates Fc receptor binding) Soliris Humanized First in Class Anti - C5 Antibody Hinge CH1 CL CH2 CH3 Rother R et al. Nat Biotech. 2007;25:1256.

  17. Soliris Blocks Terminal Complement1,2 Complement Cascade2,3 Soliris • Soliris binds with high affinity to C51,2 C3 C3a Proximal • Terminal complement - C5a and C5b-9 activity blocked1,2 C3b • Proximal functions of complement remain intact1,2 • Weak anaphylatoxin2,4 • Immune complex clearance2 • Microbial opsonization2 C5 C5a Terminal C5b C5b-9 1. Soliris® (eculizumab) [package insert; 2011. 2. Rother RP et al. Nature Biotech. 2007;25(11):1256-1264. 3. Walport MJ. N Engl J Med. 2001;344(14):1058-1066. 4. Figueroa JE, Densen P. Clin Microbiol Rev. 1991;4(3):359-395.

  18. Soliris Experience in PNH Clinical Trials Pilot Study – Hillmenet al. NEJM, 2004 N = 11 Long-Term Extension Trial HillmenBlood. 2007 Evaluated long-term safety, efficacy and effect on thrombosis; Placebo patients switched to Soliris N = 187 TRIUMPH – Hillmenet al. NEJM, 2006 Pivotal Phase III, Double-Blind, Placebo-Controlled Trial, N = 87 SHEPHERD – Brodsky et al.Blood. 2008 Broader patient population, including those receiving minimal transfusions or with thrombocytopenia, N = 97 195 Patients With >250 Patient Years of Soliris Exposure

  19. TRIUMPH – Placebo/Extension TRIUMPH – Soliris/Extension SHEPHERD – Soliris 0 4 8 12 16 20 24 28 32 36 40 44 48 52 Time, Weeks 86% Reduction in LDH:TRIUMPH and SHEPHERD 3000 2500 2000 1500 100% response after the first dose Lactate Dehydrogenase (U/L) 1000 500 0 • TRIUMPH placebo patients switched to Soliris after Week 26 • All TRIUMPH patients entered the long-term extension study P<0.001 at all measured time points. Hillmen P et al. Blood. 2007;110(12):4123-4128.

  20. 63% of patients received concomitant anticoagulants1 The effect of anticoagulant withdrawal was not studied2 Events observed in both venous and arterial sites3 There were fewer thrombotic events with Soliris treatment than during the same period of time prior to treatment2 N=195 45 39 40 35 30 25 Thrombotic Events (#) 20 15 P=0.0001 10 3 5 0 Soliris Treatment Pre-Soliris Treatment 92% Reduction in Thrombotic Events 1. Brodsky R et al. Blood. 2008;111(4):1840-1847. 2. Soliris® (eculizumab) [package insert]. Alexion Pharmaceuticals; 2011. 3. Hillmen P, et al. Blood. 2007;110:4123-4128.

  21. Soliris Treatment Results in Large and Clinically Meaningful Improvements in Patient-Reported Outcomes 1.2 1.13 1.12 Large Clinical Impact 1 0.8 Moderate Clinical Impact 0.69 0.65 0.6 Standard Effect Size (SES) Small Clinical Impact 0.4 0.2 0 FACIT-Fatigue* EORTC Fatigue* Dyspnea* Pain† (P<0.001) (P<0.001) (P=0.002) (P<0.001) 1. Brodsky R et al. Blood. 2006;108(11): Abstract 3770. 2. Data on file. Alexion Pharmaceuticals.

  22. What is the Impact of Long-term Soliris Treatment on Clinical Outcomes and Survival? Uncontrolled Complement Activation Soliris Decreased Mortality ? Hemolysis End Organ Damage Poor Outcomes • TE • Renal • Gastrointestinal • Pulmonary • Cardiac • Hepatic Increased Mortality ComplicationsAssociated With ElevatedHemolysis(LDH)

  23. Long-term Treatment With Soliris in Paroxysmal Nocturnal Hemoglobinuria: Sustained Efficacy and Improved Survival • 79 consecutive patients with PNH • Treated with Soliris between May 2002 and July 2010 • Mortality and disease symptoms were evaluated

  24. Paroxysmal Nocturnal Hemoglobinuria: A Chronic, Systemic and Life-Threatening Disease Improved Overall Survival in Patients Treated With Soliris Pre-Eculizumab from time ofDiagnosis in 80 Patients With PNH1 100 100 N=79 P<0.46 80 80 Age- and sex-matched controls 60 Age- and gender-matched healthy UK population Cumulative Surviving (%) 60 Patients Surviving (%) 40 Soliris treated 40 20 Patients with PNH 20 0 5 0 1 2 3 4 6 7 8 9 0 Time (years) 0 5 10 15 20 25 • 96% (76/79) patient survival • There was no difference in mortality between patients on eculizumab and the healthy population (P=0.46) • 2 patients over 70 years of age had worse survival (P=0.0042). No patients under the age of 50 years died Years After Diagnosis Kelly RJ et al. Blood. 2011;117:6786-6792.

  25. Soliris has a Major Impact on Survival in PNH N=79 100 P<0.46 Age- and gender-matched healthy UK population Soliris treated 80 Cumulative Surviving (%) 60 40 20 0 5 0 1 2 3 4 6 7 8 9 Time (years) Kelly RJ et al. Blood. 2011;117:6786-6792.

  26. Improved Overall Survival in Patients Treated With Soliris 100 Soliris n = 79 80 Untreated n = 30 60 Cumulative Surviving (%) 40 20 0 1 2 3 4 5 6 7 8 9 Time (years) Kelly RJ et al. Blood. 2011;117:6786-6792.

  27. Summary of Clinical Efficacy In clinical trials, Soliris significantly reduced hemolysis1 the underlying cause of morbities in PNH • 86% sustained reduction in hemolysis as measured by LDH2 • Fewer thrombotic events were observed with Soliris in clinical trials1,3 • The majority of patients (63%) received concomitant anticoagulant therapy1 • The effect of anticoagulant withdrawal during Soliris treatment has not been studied1 • 78% clinically meaningful improvement in fatigue • Fatigue in PNH impacted by hemolysis • Significant improvement noted in pain and dyspnea along with a broad range of QoL measures4 • 73% reduction in need for transfusions across all patient populations2 1. Soliris® (eculizumab) [package insert]. Alexion Pharmaceuticals; 2011. 2. Hillmen P et al. N Engl J Med. 2006;355:1233-1243. 3. Hillmen P et al. Blood. 2007;110(12):4123-4128. 4. Socie G et al. Blood. 2007;110(11):Abstract 3672.

  28. Sustained Complement Inhibition Leads to Reduced Hemolysis, Thrombosis and Improvements in Survival Uncontrolled Complement Activation Decreased Mortality Soliris • Reduction in LDH (P<0.0001) • 100% response rate in pivotal clinical trial programs (As measured by reduction in LDH) • 92% (P<0.0001) reduction in TE Hemolysis End Organ Damage Poor Outcomes • Significant reduction in abdominal pain • Improvement in dyspnea, dysphagia, fatigue, hemoglobinuria • Thrombosis • Renal • Gastrointestinal • Pulmonary • Cardiac • Hepatic Increased Mortality ComplicationsAssociated With ElevatedHemolysis(LDH) • 4 fold improvement in CKD over placebo (P<0.04) • Soliris appears to normalize survival in patients with PNH 1. Hillmen P et al. Blood. 2007;110(12):4123-4128. 2. Brodsky R et al. Blood. 2010;116(21): Abstract #4237. 3. Hill A et al. Blood. 2004;104:772: Abstract #2823. 4. Data on file. Alexion Pharmaceuticals, Inc. 5. Hillmen et al. N Engl J Med. 2004;350 552. 6. Brodsky et al. Blood. 2008;111:1840-1847. 7. Hillmen et al. Blood. 2007;110:4123-4128. 8. Hill A et al. Br J Haematol. 2010; May;149(3):414-425. 9. Hillmen P et al. Am J Hematol. 2010;85:553-559. 10. Hill et al. Blood. 2008;112: Abstract A486.

  29. Global, observational, non-interventional study to collect real world safety, effectiveness and QoL data Open to all physicians treating patients with PNH regardless of therapy Objectives Database for publications to enhance understanding of disease and improve outcomes Promote evidence-based medicine Current enrollment Over 1200 patients enrolled Participation in 21 countries, including Argentina, Australia, Belgium, Canada, Denmark, Finland, France, Germany, Netherlands, New Zealand, Russia, South Korea, Spain, Sweden, Switzerland, Taiwan, United Kingdom, United States Enrollment information: www.pnhsource.com

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