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Update on PNH: The Consequences of Chronic Hemolysis

Update on PNH: The Consequences of Chronic Hemolysis. MARTY WELTZ, DO, MPH,MBA,FACP ASST PROFESSOR, CLIN MEDICINE & PHARMACOLOGY JOHNS HOPKINS UNIVERSITY SIDNEY KIMMEL COMPREHENSIVE CANCER CENTER BLOOMBERG SCHOOL OF PUBLIC HEALTH CAREY BUSINESS SCHOOL BALTIMORE, MD. Objectives.

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Update on PNH: The Consequences of Chronic Hemolysis

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  1. Update on PNH: The Consequences of Chronic Hemolysis MARTY WELTZ, DO, MPH,MBA,FACP ASST PROFESSOR, CLIN MEDICINE & PHARMACOLOGY JOHNS HOPKINS UNIVERSITY SIDNEY KIMMEL COMPREHENSIVE CANCER CENTER BLOOMBERG SCHOOL OF PUBLIC HEALTH CAREY BUSINESS SCHOOL BALTIMORE, MD

  2. Objectives • Discuss paroxysmal nocturnal hemoglobinuria (PNH) and the role of chronic hemolysis • Describe the serious morbidities and mortality associated with chronic hemolysis in PNH patients

  3. Estimated 4,000 – 6,000 patients in U.S.1 5 year mortality: 35%2 Diagnosed at all Ages – Median age early 30’s3,4 Quality of life diminished5 Progressive disease5 Actuarial Survival From the Time ofDiagnosis in 80 Patients With PNH1 100 80 Age- and sex-matched controls 60 Patients Surviving (%) 40 Patients with PNH 20 0 0 5 10 15 20 25 Years After Diagnosis The expected survival of an age- and sex-matched control group is shown for comparison (Hillmen et al 1995). In a patient population where ½ the patients have <30% clone, 1 in 7 patients died by 5 years (de Latour et al. Blood. 2008; 112: 3099-3106) Paroxysmal Nocturnal Hemoglobinuria:A Chronic Disabling and Life-Threatening Disease 1. Hill A et al. Blood. 2006;108(11): 290a. Abstract 985 2. Hillmen, 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;348:573-77. 5. Hill A et al. Br J Haematol. 2007;137:181-92.

  4. Paroxysmal Nocturnal Hemoglobinuria • It’s not paroxysmal • Even in the absence of symptoms, destructive progression of hemolysis is ongoing • It’s not nocturnal • Hemolysis in PNH is subtle and constant, 24 hours a day • Hemoglobinuria is a less commonly seen complication • ¾ patients present without hemoglobinuria1 1. Parker, et al. Blood. 2005;106:3699-3709

  5. Thrombosis RenalFailure Significant Impact on Survival Pulmonary Hypertension Abdominal Pain Dyspnea Fatigue Significant Impact on Morbidity Reduced Red Cell Mass Dysphagia Hemoglobinuria Erectile Dysfunction PNH is a Progressive Disease of Chronic Hemolysis 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 ComplementActivation Intact RBC Hemoglobin in the Blood from Destroyed PNH RBCs Anemia Parker C et al. Blood. 2005;106:3699-3709; 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; p. 419-427; Rother RP et al. JAMA. 2005;293:1653-1662; Socie G et al. Lancet. 1996;348:573-577; Hill A et al. Br J Haematol. 2007;137:181-92.

  6. THROMBOSIS Venous • PE/DVT • Cerebral • Dermal • Hepatic/Portal • Abdominal ischemia Arterial • Stroke/TIA • MI Pulmonary Hypertension • Dyspnea • Cardiac Dysfunction End Organ Damage • Brain • Liver • GI Chronic Kidney Disease • Renal insufficiency • Dialysis • Anemia Anemia • Transfusions • Hemosiderosis Chronic Hemolysis is the Underlying Cause of Progressive Morbidities and Mortality of PNH Fatigue / Impaired Quality of Life • Abdominal pain • Dysphagia • Poor physical functioning • Erectile dysfunction Parker, et al. Blood. 2005;106:3699-3709; Brodsky. 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; p. 419-427; Hillmen P et al. N Engl J Med. 1995;333:1253-1258; Rosse W et al. Hematology (Am Soc Hematol Educ Program). 2004:48-62; Rother RP et al. JAMA. 2005;293:1653-1662; Socie G et al. Lancet. 1996;348:573-577. Hill A et al. Br J Haematol. 2007;137:181-92.

  7. THROMBOSIS Venous • PE/DVT • Cerebral • Dermal • Hepatic/Portal • Abdominal ischemia Arterial • Stroke/TIA • MI Pulmonary Hypertension • Dyspnea • Cardiac Dysfunction End Organ Damage • Brain • Liver • GI Chronic Kidney Disease • Renal insufficiency • Dialysis • Anemia Fatigue / Impaired Quality of Life Anemia • Abdominal pain • Dysphagia • Poor physical functioning • Erectile dysfunction • Transfusions • Hemosiderosis Consequences of Hemolysis in PNH:Anemia Parker, et al. Blood. 2005;106:3699-3709; Brodsky. 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; p. 419-427; Hillmen, et al. N Engl J Med. 1995;333:1253-1258; Rosse, et al. Hematology (Am Soc Hematol Educ Program). 2004:48-62; Rother, et al. JAMA. 2005;293:1653-1662; Socie, et al. Lancet. 1996;348:573-577. Hill A et al. Br J Haematol. 2007;137:181-92.

  8. In cases where both are present, they can/should be addressed concomitantly Causes of Anemia in PNH Adapted from: Parker et al. Blood 2005;106:3699-3709 and Rother et al. JAMA 2005;293:1653-1662

  9. Anemia in PNH • Hemolysis is a key factor causing anemia in PNH1 • In individual patients other factors may contribute to anemia2: • Bone marrow dysfunction with AA or MDS • Kidney function/erythropoiesis • Extravascular hemolysis • Autoimmune factors • Anemia is common in PNH • 91% of patients have anemia3 • One symptom in multi-factorial disease 1.Parker C et al. Blood 2005;106:12:3699-3709. 2. Brodsky. 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; p. 419-427. 3. Nishimura JI, et al. Medicine. 2004;83:193-207

  10. THROMBOSIS Venous • PE/DVT • Cerebral • Dermal • Hepatic/Portal • Abdominal ischemia Arterial • Stroke/TIA • MI Pulmonary Hypertension • Dyspnea • Cardiac Dysfunction End Organ Damage • Brain • Liver • GI Chronic Kidney Disease • Renal insufficiency • Dialysis • Anemia Fatigue / Impaired Quality of Life Anemia • Abdominal pain • Dysphagia • Poor physical functioning • Erectile dysfunction • Transfusions • Hemosiderosis Consequences of Hemolysis in PNH: Fatigue and Impaired Quality of Life Parker, et al. Blood. 2005;106:3699-3709; Brodsky. 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; p. 419-427; Hillmen, et al. N Engl J Med. 1995;333:1253-1258; Rosse, et al. Hematology (Am Soc Hematol Educ Program). 2004:48-62; Rother, et al. JAMA. 2005;293:1653-1662; Socie, et al. Lancet. 1996;348:573-577. Hill A et al. Br J Haematol. 2007;137:181-92.

  11. Hemolysis Causes Fatigue Independent of Anemia • Rosse (Hoffman-Hematology)1 • “Many patients note a feeling of fatigue that may be disabling during periods of hemoglobinuria.” • This is not related to hemoglobin level (anemia), as it disappears when the hemoglobinuria stops.” • Brodsky (Hoffman-Hematology)2 • “PNH patients frequently complain of disabling fatigue that is often out of proportion to the degree of anemia.” • Univariate analyses indicate hemolysis and anemia associated with fatigue3 • Multivariate analysis indicates hemolysis drives fatigue in PNH – not anemia3 1. Rosse. Paroxysmal nocturnal hemoglobinuria In: R Hoffman; EJ Benz; SJ Shattil et al., eds. Hematology: Basic Principles andPractice. 3rd ed. New York: Churchill-Livingstone; 2000:331-342. 2. Brodsky. Paroxysmal nocturnal hemoglobinuria. In: R Hoffman; EJ Benz; SJ Shattil et al., eds. Hematology. Basic Principles andPractice. 4th ed. Philadelphia: Elsevier Churchill Livingstone; 2005:419-427. 3. Hill A et al. Haematologica. 2008;93(s1):359. Abstract 0903 and Presentation at: European Hematology Association 15th Annual Meeting; June 15th, 2008; Copenhagen, Denmark.

  12. Impact of PNH on Quality of Life • 59% patients were transfusion-free for at least 12 mo or had never been transfused • 76% were forced to modify their daily activities to manage their PNH • 17% were unemployed due to PNH Meyers G et al. Blood. 2007;110 (11): Abstract 3683. *Moderate to severe; N=29.

  13. Abdominal Pain and Ischemia in PNH • Abdominal pain is associated with hemolysis1 • Hemolysis causes nitric oxide consumption leading to vasoconstriction, smooth muscle contraction, and ischemia1,2 • Severe abdominal pain observed with intestinal ischemia:3,4 • Marked elevation of d-dimers5,6 • Electron microscopic findings of ischemia on biopsy3 • Venous blockage by angiography or MRI6 1. Hill A et al. Haematologica. 2005;90(e-case)40. 2. Rother RP et al. JAMA.2005;293:1653-62. 3. Adams T et al. Digestive Diseases and Sciences. 2002; 47(1):58–64. 4. Quentin V et al. Gastroenterol Clin Biol. 2003;27(10):927-31. 5. Weitz I et al. Blood. 2008; 112: Abstract 407. 6. Khoshini R et al. Med Gen Med. 2004; 6(1): 23.published online: January 6, 2004.

  14. Fatigue and Quality of Life Conclusions • 96% of patients report fatigue • Fatigue/QoL independent of anemia/transfusion requirements • 76% of patients with PNH have disruptions in daily activities • 17% of patients were unemployed due to PNH • 66% of patients report shortness of breath • 57% of patients report abdominal pain • Fatigue, QoL and abdominal pain are linked by underlying hemolysis and the threat of ischemia Meyers G et al. Blood. 2007;110(11):Abstract 3683.

  15. THROMBOSIS Venous • PE/DVT • Cerebral • Dermal • Hepatic/Portal • Abdominal ischemia Arterial • Stroke/TIA • MI Pulmonary Hypertension • Dyspnea • Cardiac Dysfunction End Organ Damage • Brain • Liver • GI Chronic Kidney Disease • Renal insufficiency • Dialysis • Anemia Fatigue / Impaired Quality of Life Anemia • Abdominal pain • Dysphagia • Poor physical functioning • Erectile dysfunction • Transfusions • Hemosiderosis Consequences of Hemolysis in PNH:Chronic Kidney Disease Parker, et al. Blood. 2005;106:3699-3709; 2. Brodsky. 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; p. 419-427; Hillmen, et al. N Engl J Med. 1995;333:1253-1258; Rosse, et al. Hematology (Am Soc Hematol Educ Program). 2004:48-62; Rother, et al. JAMA. 2005;293:1653-1662; Socie, et al. Lancet. 1996;348:573-577. Hill A et al. Br J Haematol. 2007;137:181-92.

  16. BackgroundRenal Damage in PNH • Chronic hemolysis and cell-free plasma hemoglobin lead to chronic kidney disease in PNH1-3 • Renal damage in PNH may be due to repetitive exposure of tissue to cell-free hemoglobin3,4 • 64% of patients with PNH have chronic kidney disease4 • Renal failure has been identified as the cause of death in approximately 8 – 18% of PNH patients5 1. Brodsky RA. Hematology: Basic Principles and Practice. Churchill Livingstone; 2005:419-427. 2. Rother RP, et al. JAMA. 2005;293:1653-1662. 3. Clark DA et al. Blood. 1981 Jan;57(1):83-9. 4. Hillmen et al. Blood. 2007; 110 (11): Abstract 3678; Poster at: American Society of Hematology 49th Annual Meeting; December 10, 2007; Atlanta, GA. 5. Nishimura JI, et al. Medicine. 2004;83:193-207.

  17. 64% of Patients Exhibit Clinical Chronic Kidney Disease (CKD) 50 43.1% 40 35.4% 30 Proportion of Patients (%) 20.5% 20 • 59% of patients with minimal (0-1) transfusion history with CKD (n=22) 10 0 Stage 3 - 5 CKD(n=40) Stage 1 - 2 CKD(n=84) No CKD (n=69) Hillmen et al. Blood. 2007; 110 (11): Abstract 3678; Poster at: American Society of Hematology 49th Annual Meeting; December 10, 2007; Atlanta, GA.

  18. Kidney Disease Conclusions • Kidney disease in PNH is caused by hemolysis1 • 64% of patients with PNH exhibit chronic kidney disease at any one time2 • Renal insufficiency prevalence in PNH is 5 times higher than reported for the general population3 • Only 25% of cases of pre-dialysis CKD or ESRD identified at screening had been clinically diagnosed previously2 1. Clark DA et al. Blood. 1981 Jan;57(1):83-9. 2. Hillmen et al. Blood. 2007; 110 (11): Abstract 3678; Poster at: American Society of Hematology 49th Annual Meeting; December 10, 2007; Atlanta, GA. 3. Stevens LA. et al. N Engl J Med. 2006;354:2473-83.

  19. THROMBOSIS Venous • PE/DVT • Cerebral • Dermal • Hepatic/Portal • Abdominal ischemia Arterial • Stroke/TIA • MI Pulmonary Hypertension • Dyspnea • Cardiac Dysfunction End Organ Damage • Brain • Liver • GI Chronic Kidney Disease • Renal insufficiency • Dialysis • Anemia Fatigue / Impaired Quality of Life Anemia • Abdominal pain • Dysphagia • Poor physical functioning • Erectile dysfunction • Transfusions • Hemosiderosis Consequences of Hemolysis in PNH:Pulmonary Hypertension Parker, et al. Blood. 2005;106:3699-3709; Brodsky. 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; p. 419-427; Hillmen, et al. N Engl J Med. 1995;333:1253-1258; Rosse, et al. Hematology (Am Soc Hematol Educ Program). 2004:48-62; Rother, et al. JAMA. 2005;293:1653-1662; Socie, et al. Lancet. 1996;348:573-577. Hill A et al. Br J Haematol. 2007;137:181-92.

  20. Hemolysis and Nitric Oxide • Red blood cell destruction during hemolysis releases cell-free hemoglobin • Cell-free hemoglobin scavenges NO • Reduced nitric oxide can cause pulmonary hypertension: • Vasoconstriction • Clotting • Platelet hyperreactivity • Impaired fibrinolysis • Hypercoagulability Rother R. et al. JAMA. 2005; 293: 1653-1662

  21. 40 35 30 25 20 NO Consumption (µM) 15 10 5 0 PNH(n=32) Normal(n=9) Severe Nitric Oxide (NO) Consumption in PNH P<0.0001 • 15-fold elevation in NO consumption in PNH vs normal volunteers Hill A et al. Br J Haematol. 2006;133 (suppl 1):119. Abstract 316.

  22. Symptoms of Pulmonary Hypertension Commonly Found in Patients With PNH • 66% of patients report shortness of breath • 72% of patients qualified shortness of breath as moderate to severe • 88% report distress due to shortness of breath Meyers G et al. Blood. 2007;110(11): Abstract :3683.

  23. Elevated BNP is Predictive of Pulmonary Hypertension • Elevated plasma BNP (brain natriuretic peptide) highly predictive of pulmonary hypertension1 • Plasma BNP correlated negatively with RV ejection fraction (r=0.71)1 • NT-proBNP level >160 pg/ml2 • 78% positive predictive value for pulmonary hypertension diagnosis • Independent predictor of mortality 1. Nagaya et al. JACC. 1999;31:202-208.2. Machada et al. JAMA. 2006;296:310-318.

  24. Evidence of Pulmonary Hypertension in PNH Three different patient cohorts all show high prevalence of pulmonary hypertension using three different measurements: • 47% of patients with elevated NT-proBNP ≥160 pg/ml1 • 43% of patients with mild to moderate and 7% severe pulmonary hypertension as evidenced by cardiac doppler2 • 100% of patients with elevated BNP3 • 80% with reduced right ventricular ejection fraction (RVEF) • 60% had evidence of subclinical PE • 50% had no history of transfusions 1, Hill A et al. Blood. 2008;112 (11):Abstract 486. 2. Hill et al. Br J Haematol. 2006;133 (suppl 1):119:Abstract 316. 3. Hill et al. Blood. 2006;108(11): Abstract 979.

  25. Pulmonary Hypertension Conclusions • Hemolysis results in cell-free hemoglobin and NO consumption leading to pulmonary hypertension1 • 66% of PNH patients report dyspnea2 • 47% of PNH patients may have increased risk of pulmonary hypertension3 • PNH patients with pulmonary hypertension have cardiac dysfunction3 1. Rother R. et al. JAMA. 2005; 293: 1653-1662. 2. Meyers G et al. Blood. 2007;110(11):Abstract 3683. 3. Hill et al. Br J Haematol. 2006;133 (suppl 1):119:Abstract 316.

  26. THROMBOSIS Venous • PE/DVT • Cerebral • Dermal • Hepatic/Portal • Abdominal ischemia Arterial • Stroke/TIA • MI Pulmonary Hypertension • Dyspnea • Cardiac Dysfunction End Organ Damage • Brain • Liver • GI Chronic Kidney Disease • Renal insufficiency • Dialysis • Anemia Fatigue / Impaired Quality of Life Anemia • Abdominal pain • Dysphagia • Poor physical functioning • Erectile dysfunction • Transfusions • Hemosiderosis Consequences of Hemolysis in PNH:Thrombosis Parker, et al. Blood. 2005;106:3699-3709; Brodsky. 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; p. 419-427; Hillmen, et al. N Engl J Med. 1995;333:1253-1258;. Rosse, et al. Hematology (Am Soc Hematol Educ Program). 2004:48-62; Rother, et al. JAMA. 2005;293:1653-1662; Socie, et al. Lancet. 1996;348:573-577. Hill A et al. Br J Haematol. 2007;137:181-92.

  27. Thrombosis in PNH: Common and Frequent Cause of Death • 40% of patients with clinical thrombotic events1 • 60% of patients with evidence of undiagnosed thrombosis2 • Leading cause of death3 • Accounts for 40–67% of deaths1 • First thrombotic event can be fatal3 • First TE increases risk for death 5 to 10-fold1 • Risk of thrombosis with smaller clone size4 • Risk increases with increasing clone size5 • Clinical thrombosis evident in PNH patients with:1 • Minimal hemolysis • No transfusion history • Less severe anemia 1. Hillmen et al. Blood 2007; 110: 4123-4128. 2. Hill A et al. Blood. 2006;108(11):Abstract 979. 3. Parker C et al. Blood. 2005;106(12):3699-3709. 4. Audebert HJ et al. J Neurol. 2005;252:1379-1386. 5. Moyo V et al. Br J Haematol. 2004;126:133-138.

  28. Mechanisms for Thrombosis in PNH • Hemolysis • Reduced Nitric Oxide1 • Platelet hyperreactivity • Impaired fibrinolysis • Hypercoagulability • Prothrombotic membranes2 • Platelet activation from reduced CD591 • Tissue factor initiated coagulation independent of hemolysis - C5a2 • Hill A et al. Br J Haematol. 2007;137:181-192. • Weitz I et al. Blood. 2008; 112: Abstract 407.

  29. Hillmen 1995 (N=80)1 DVT or PE = 33% of 49 thrombotic events CVA/MI = 16% of thrombotic events – All fatal Atypical VTE more common in PNH than in the general population3 Typical VTE most common VTE in PNH Hillmen 2007 (N=195)2 DVT or PE = 40% of 124 thrombotic events CVA/MI = 15% of thrombotic events Atypical VTE more common in PNH than in the general population3 Typical VTE most common VTE in PNH Patterns of Thrombosis inLarge PNH Cohorts High proportion of PE and/or DVT sites of thrombosis consistently found in PNH patients – Socie et al. 1996 (29%)4 and Nishimura and Rosse. 2004 (27%)5 1. Hillmen P et al. N Engl J Med. 1995;333:1253-8. 2. Hillmen P et al. 12. Blood. 2007; 100:4123-8. 3. Fowkes FJI et al. Eur J Vasc Endovasc Surg. 2003;25:1-5. 4. Socie G et al. Lancet. 1996;348:573-7. 5. Nishimura J et al. Medicine.2004;83(3):193-207.

  30. 70 60 50 40 Proportion of Patients (%) 30 20 10 0 Pulmonary Embolism* MI* Undiagnosed Thrombosis Identified by MRI in PNH • 50% of patients never transfused • Average age = 32 yo; Median disease duration = 2 yrs (n=10) *Pulmonary Embolism = sub-segmental perfusion defects; MI = myocardial scars. Hill et al. Blood. 2006;108:Abstract 979.

  31. Elevated Risk for Thrombosis Even in Patients With Minimal Transfusion 6 (n=22) 4.87 5 4 Thrombosis Rate(TE Per 100 Pt-Yrs) 3 2 1 0 0-1 Transfusion/12m Hillmen et al. Blood 2007; 110: 4123-4128

  32. Thrombosis Risk at All Levels of Hemolysis 12.00 N=187 10.79 9.53 10.00 8.00 5.70 Thrombosis Events(TE per 100 Pt-Years) 6.00 3.96 4.00 2.00 0.00 Lowest LDH Highest LDH (n=47) (n=47) (n=47) (n=46) Quartiles Bessler M et al. Blood. 2007;110(11): Abstract 840.

  33. Elevated Thrombotic Rate in Antithrombotic-Treated Patients (n=103) 12.00 10.61 10.00 8.00 Thrombosis Event Rate(TE per 100 patient-years) 6.00 4.00 2.00 0.00 Antithrombotic-Treated Patients 91 were receiving anticoagulants Hillmen et al. Blood. 2007;110:4123-4128.

  34. Thrombosis in PNH Conclusions • 40-67% mortality in PNH results from thrombosis1 • 5- to10- fold increased risk of death following first thrombotic event1 • Thrombosis is the leading cause of death in PNH2 • DVT or PE most common clinical presentation1 • Unusual sites more common in PNH patient population3 • Undiagnosed thrombosis present in most hemolytic patients by MRI4 • Anticoagulant therapy may not be adequate to control thrombosis in PNH1 • Anticoagulant therapy also associated with higher risk of fatal hemorrhage in PNH5 1. Hillmen et al. Blood. 2007;110:12:4123-4128. 2. Parker C et al. Blood. 2005; 106(12):3699-3709. 3. Rosse. Paroxysmal nocturnal hemoglobinuria In: R Hoffman; EJ Benz; SJ Shattil et al., eds. Hematology: Basic Principles and Practice. 3rd ed. New York: Churchill-Livingstone; 2000:331-342. 4. Hill et al. Blood. 2006;108:Abstract 979. 5. Hall C etal. Blood. 2003;102:3587 3591.

  35. DVT Acute Renal Failure Hepatic Failure Chronic Kidney Disease Cardiac Dysfunction Stroke / TIA Ischemic Bowel Pulmonary Hypertension Common Symptoms of Hemolysis Signal the Underlying Threat of Catastrophic Consequences Fatigue Impaired QoL Hemoglobinuria Dyspnea Erectile Dysfunction Dysphagia Anemia Abdominal Pain

  36. Historical Management of PNH Palliative options do not impact progression and risk for severe morbidities and mortality • Transfusions • Risk of iron overload • Transient treatment of anemia • Anticoagulants • Risk of hemorrhage • Ineffective in many patients* • Red cell supplements • ESAs may expand clones and elevate hemolysis • Folic acid, iron, erythropoiesis-stimulating agents • Steroids/androgen hormones • No controlled clinical trials ESA=erythropoietin stimulating agents Parker C et al. Blood. 2005;106(12):3699-3709. *Hillmen P et al. Blood. 2007;110:4123-8.

  37. Historical Management of PNH (cont) • Allogeneic bone marrow transplant • 44% mortality at 2 yrs with HLA-matched sibling donor1 • Acute GVHD in 34%; chronic GVHD in 33%1 • GVHD-free survival in 14% of patients2 Bone Marrow Transplant 1. Saso R et al. Brit J Haem. 1999;104:392-6. 2. Hegenbart U et al. Biology of Blood and Marrow Tplt. 2003;9(11):689-97.

  38. 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; 2009.

  39. Human Framework Regions Hinge CH1 CL Complementarity Determining Regions (murine origin) CH2 Human IgG4 Heavy Chain Constant Regions 2 and 3 Human IgG2 Heavy Chain Constant Region 1 and Hinge CH3 SOLIRIS® (eculizumab) Humanized First in Class Anti - C5 Antibody Rother RP et al. Nature Biotech. 2007;25(11):1256-64.

  40. SOLIRIS® Blocks Terminal Complement Complement Cascade SOLIRIS® • SOLIRIS® binds with high affinity to C5 C3 C3a Proximal • Terminal complement activity is blocked C3b • Proximal functions of complement remain intact • Weak anaphylatoxin • Immune complex clearance • Microbial opsonization C5a C5 Terminal C5b-9 Cause of Hemolysis in PNH C5b Figueroa JE, Densen P. Clin Microbiol Rev. 1991;4(3):359-395. Walport MJ. N Engl J Med. 2001;344(14):1058-66. SOLIRIS® (eculizumab) [package insert]. Alexion Pharmaceuticals; 2009. Rother RP et al. Nature Biotech. 2007;25(11):1256-64.

  41. Dosing Schedule • In clinical trials all patients were vaccinated against Neisseria meningitidis • Concomitant medications allowed: • Steroids, immunosuppressant drugs, anti-clotting agents and hematinics1 • SOLIRIS® should be administered via IV infusion over 35 minutes every 7 days during induction and every 14 days during maintenance • SOLIRIS® dose adjustment to every 12 days may be necessary for some patients to maintain LDH reduction SOLIRIS® (eculizumab) [package insert]. Alexion Pharmaceuticals; 2009. 1. Hillmen P et al. N Engl J Med. 2004;350(6):552-9.

  42. SOLIRIS® PNH Clinical Studies Pilot Study – NEJM. 2004 N = 11 Long-Term Extension Trial Hillmen Blood. 2007 Evaluated long-term safety, efficacy and effect on thrombosis; Placebo patients switched to SOLIRIS® N = 187 TRIUMPH – NEJM. 2006 Pivotal Phase III, Double-Blind, Placebo-Controlled Trial, N = 87 SHEPHERD – Blood. 2008 Broader patient population, including those receiving minimal transfusions or with thrombocytopenia, N = 97

  43. TRIUMPH – Placebo/Extension TRIUMPH – SOLIRIS®/Extension SHEPHERD – SOLIRIS® 0 4 8 12 16 20 24 28 32 36 40 44 48 52 Time, Weeks TRIUMPH and SHEPHERD:86% Reduction in LDH 3000 2500 2000 Lactate Dehydrogenase (U/L) 1500 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):4123-8.

  44. Reducing Hemolysis is Central to Improving Morbidity in PNH • SOLIRIS® results in a sustained reduction in hemolysis (LDH) • 100% response rate in trials beginning with the first dose1, 2 • Demonstrated sustained reduction (54 months) in hemolysis (LDH) results in a reduced need for RBC transfusions and less fatigue3 • Monitor hemolysis (LDH) not anemia (Hgb) when determining a response to SOLIRIS® 5 • Chronic hemolysis is central to the serious morbidities and contributes to mortality in PNH4 • LDH may assist in monitoring SOLIRIS® effect5 1. Hillmen P et al. N Engl J Med. 2006;355:1233-43; 2. Brodsky RA et al. Blood. 2008;111(4):1840-7. 3. Socie G et al. [abstract] Blood. 2007;110(11):3672. 4. Rother RP et al. JAMA. 2005;293:1653-62. 5. SOLIRIS® (eculizumab) [package insert]. Alexion Pharmaceuticals; 2009.

  45. 18 Patients not on SOLIRIS® (n=44) 16 SOLIRIS® (n=43) 14 12 10 Median Units Transfused 8 6 4 * * 2 * * 0 (n=87) (n=30) (n=35) (n=22) Overall 4-14 15-25 >25 Pre-treatment Transfusion Strata‡ 73% Reduction in Mean Units Transfused Across all Subgroups1 *P<0.001. ‡Transfusion data obtained during 12 months before treatment; values were normalized for a 6-month period 1. Hillmen P et al. N Engl J Med. 2006;355;1233-1243. 2. Schubert J. Br. J Haematol. 2008;142(2):263-72.

  46. 78% Patients Reported Significant Improvement in Fatigue • Reduction in hemolysis is the best predictor of improvement in fatigue as measured by FACIT-Fatigue and EORTC-Fatigue and relevant measures of QoL (EORTC)1,2 • Established instrument1,2 • Improvements in fatigue and QoL seen in all patient subgroups, and regardless of level of hemolysis at baseline1 • Improvement began in the induction phase (3 weeks) and maintained2,3 The fatigue in PNH is often disproportionate to the nominal hemoglobin level, fatigue impacted by hemolysis4 1. Brodsky RA et al. Blood. 2008;111(4):1840-7. 2. Hillmen P et al. N Engl J Med. 2006;355:1233-43. 3. SOLIRIS® (eculizumab) [package insert]. Alexion Pharmaceuticals; 2009. 4. Brodsky RA. Paroxysmal Nocturnal Hemoglobinuria. In: Hematology - Basic Principles and Practices. 4th ed. Elsevier Churchill Livingstone; 2005;419-427.

  47. TRIUMPH: Improvement in Fatigue Independent of Hemoglobin 12.0 8 11.5 6 11.0 4 10.5 2 Change from Baseline FACIT-Fatigue Score Hemoglobin, g/dL 0 10.0 -2 9.5 -4 9.0 -6 8.5 0 2 4 6 8 10 12 14 16 18 20 22 24 26 Time, Weeks SOLIRIS® (n=43) Patients not on SOLIRIS® (n=44) SOLIRIS® Hgb P<0.001 FACIT-Fatigue Score Hgb Level FACIT-Fatigue Score FACIT = Functional Assessment of Chronic Illness Therapy. Adapted from: Hillmen P et al. NEJM. 2006;355:1233-43. Data on file. Alexion Pharmaceuticals; 2009.

  48. Patients Report Rapid and Sustained Improvement Across Broad Range of Measures 1.2 Large Impact 1 0.8 Moderate Impact FACIT-Fatigue† EORTC Fatigue† Global Health† Physical† Role† Cognitive* Social* Emotional* Dyspnea† Pain* Appetite loss† Financial Insomnia* Constipation Nausea Diarrhea 0.6 Standard Effect Size (SES) Small Impact 0.4 0.2 0 EORTC Functioning EORTC Symptoms *P<0.05.†P<0.001. Brodsky R et al. Blood.2006;108(11): Abstract 3770. Data on file. Alexion Pharmaceuticals.

  49. SOLIRIS® PNH Clinical Studies Pilot Study – NEJM. 2004 N = 11 Long-Term Extension Trial Hillmen Blood. 2007 Evaluated long-term safety, efficacy and effect on thrombosis; Placebo patients switched to SOLIRIS® N = 187 TRIUMPH – NEJM. 2006 Pivotal Phase III, Double-Blind, Placebo-Controlled Trial, N = 87 SHEPHERD – Blood. 2008 Broader patient population, including those receiving minimal transfusions or with thrombocytopenia, N = 97

  50. Long-Term Extension Results Patient (n) 187/149 173 171 171 68 21 10 *P<0.001 †P=0.002 † * * * * Study Year • All patients sustained a reduction in hemolysis as measured by LDH • Patients followed for up to 54 months Socié G et al. Blood. 2007;110(11): Abstract 3672; Presentation at: American Society of Hematology 49th Annual Meeting; December 10th, 2007; Atlanta, GA SOLIRIS® (eculizumab) [package insert]. Alexion Pharmaceuticals; 2009.

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