7/26/2013. The Defect in PNH PNH: NEW DIRECTIONS IN PNH TREATMENT. Paroxysmal Nocturnal Hemoglobinuria: Survival

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1 PNH: NEW DIRECTIONS IN PNH TREATMENT Jamile M. Shammo MD, FASCP, FACP Associate Professor of Medicine and Pathology Rush University Medical Center Chicago Paroxysmal Nocturnal Hemoglobinuria: Survival PNH is an acquired disorder of the hematopoietic stem cell Estimated 4, 6, patients in U.S.1 5 year mortality: 35%2 Diagnosed at all Ages Median age early 3 s3,4 Patients Surviving (%) Actuarial Survival From the Time of Diagnosis in 8 Patients With PNH Years After Diagnosis Age and Gender Matched Controls Patients with PNH 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 <3% clone, 1 in 7 patients died by 5 years. de Latour et al. Blood. 28; 112: Hill A et al. Blood. 26;18(11): 29a. Abstract Hillmen P et al. N Engl J Med. 1995;333: Nishimura JI, et al. Medicine. 24;83: Socié G et al. Lancet. 1996;348: Hill A et al. Br J Haematol. 27;137: The Defect in PNH The Somatic Mutation of the X chromosome PIG A Gene Prevents All GPI Anchored Proteins from Binding to Cell Surface 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 CD59 GPI anchor CD55 1. Adapted from: Johnson RJ et al. J Clin Pathol: Mol Pathol. 22;55: 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; 25;

2 Overview of Complement Complement Cascade Proximal C3 C3b C3a Terminal C5 C5b C5a Membrane Attack C5b 9 Cause Complex of Hemolysis Cause in of PNH Hemolysis in PNH Consequences of Complement Activation/MAC Complement activation has the potential to cause sere damage not only to microbes but also to host cells and tissues 1,2 Strict regulation is needed to avoid unnecessary damage to self due to overt or mistargeted activation 1,2 Tight control needed especially for the alternative pathway which is continuously turned on The most critical steps are controlled by several regulators Multimeric C9 Lesions on PNH Erythrocyte Photo: W Rosse Endothelial Cells Damaged by Complement Attack Photo: S. Meri, Univ. of Helsinki 1. Holers VM et al. Immunol Rev. 28;223: Zipfel PF et al. Curr Opin Nephrol Hypertens. 21;4: Chronic Uncontrolled Complement Activation Leads to Devastating Consequences in PNH Lectin Pathway Classical Pathway Alternative Pathway Proximal Terminal Anaphylaxis Inflammation Immune Complex Clearance Microbial Opsonization Consequences + Gain of Function Mutations: C3, CFB Thrombomodulin C5a Potent Anaphylatoxin Chemotaxis Proinflammatory Leukocyte Activation Endothelial Activation Prothrombotic C3 C5 C3 + H 2 O ALWAYS ACTIVE (chronic) Amplification Natural Inhibitors: Factor H, I, MCP, CD55 Natural Inhibitor: CD59 C5b 9 Membrane Attack Complex Cell Lysis Proinflammatory Platelet Activation Leukocyte Activation Endothelial Activation Consequences Cell Destruction Inflammation Prothrombotic Figueroa JE, Densen P. Clin Microbiol Rev. 1991;4: ; Walport MJ. N Engl J Med. 21;344: ; Rother RP et al. Nature Biotech. 27;25: ; Meyers G et al. Blood. 27; 11: Abstract 3683; Hill A et al. Br J Hematol. 21;149: ; Hillmen P et al. Am J Hematol 21;85: , International PNH Interest Group. Blood. 25;16: ; Hillmen P et al. N Engl J Med. 1995;333:1253; Nishimura J et al. Medicine. 24;83:193 27; Caprioli J et al. Blood. 26;18: ; Noris M et al. Clin J Am Soc Nephrol. 21;5: ; George JN et al. Blood. 21;116:46 469; Loirat C et al. Pediatr Nephrol. 28;23: ; Stahl A, et al Blood. 28;111: ; Hosler GA et al. Arch Pathol Lab Med. 23;127; ; Ariceta G et al. Pediatr Nephrol. 29;24:

3 Consequences 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 Renal Failure Pulmonary Hypertension Significant Impact on Survival Complement Activation Abdominal Pain Dyspnea Dysphagia Intact RBC Free Hgb/Anemia Fatigue Hemoglobinuria Significant Impact on Morbidity NO Erectile Dysfunction 1. International PNH Interest Group. Blood. 25;16: 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; 25; Rother RP et al. JAMA. 25;293: Socie G et al. Lancet. 1996;348: Hill A et al. Br J Haematol. 27;137: Lee JW et al. Hematologica 21;95 (s2):abstract #55 and Hill A et al. Br J Haematol. 21; May;149(3): Hillmen P et al. Am. J. Hematol. 21;85: Incidence of PNH Clones by Diagnostic Code in the Clinical Setting Utilizing High Sensitivity Flow Cytometry (HSFC) Objective: To use multiparameter HSFC to analyze the incidence of PNH clones in patients recommended for testing in the clinical setting Key Results: 7699 were screened for PNH clones utilizing HSFC 481 of 7699 (6.2%) across all high risk populations recommended for testing were found to be PNH positive PNH clinical clone (>1%) detection rate was 3.8% Subclinical clone (<1%) detection rate was 2.4% Movalia MK et al. Presented at ASH 212: Abstract Incidence of PNH Clones in High Risk Patient Populations PNH Clone Size Total <1% 1 2% >2% Aplastic anemia (n) % (111) MDS (n) % (36) Cytopenias (including pancytopenia, leukopenia, % (115) and non-hemolytic anemia) (n) Hemolysis (including hemolytic anemia and % (182) hemoglobinuria) (n) (n) % (21) Miscellaneous (n) % (22) Not provided (n) % (51) *Includes patients already diagnosed as having PNH. High risk patients may be included in more than 1 ICD 9 category. Movalia MK et al. Presented at ASH 212: Abstract

4 High Sensitivity Flow Cytometry is Needed for Accurate Diagnosis and Monitoring 1 4% of PNH+ Samples Show a Clone of <1% % PNH Clone Size >1% Number of Patients With PNH Clone PNH Clone Size 1. Movalia MK et al. Presented at the American Society of Hematology 53rd Annual Meeting; December 1 13, 211; San Diego, CA. in PNH: Accounts for 4 67% of deaths 2 First thrombotic event (TE) can be fatal 2,3 First TE increases risk for death 5 to 1 fold 2 Up to 44% of patients experience clinical thrombotic events 2 Occurs in typical and atypical sites 4 Is not adequately managed with anticoagulation 2 All patients with PNH are at risk for thrombosis 2 1. International PNH Group et al. Blood 25;16: ; 2. Hillmen et al. Blood 27;11: ; 3. Audebert HJ et al. J Neurol 25;252: ; 4. Lee JW et al. Hematologica 21;95(s2): Abstract 56. Sites: Superficial vein thrombosis Cerebral/internal jugular thrombosis Pulmonary embolus Myocardial Infarction/ unstable angina 13.7 ARTERIAL Cerebrovascular accident/ transient ischemic attack Hepatic/portal vein thrombosis Deep vein thrombosis* VENOUS 18.5 Mesenteric/splenic vein thrombosis *Includes 18.5% lower extremity and 14.5% other (inferior vena cava, bilateral lower extremity, pelvic, ureter, axillary, subclavian, and brachiocephalic veins). Hillmen P et al. Blood 27;11:

5 Chronic Kidney Disease Common Sites of Occur Frequently in PNH Common Symptoms of PNH TE Type Hillmen P et al (N=8) Hillmen P et al. 27 (N=195) DVT or PE 33% 4% CVA/MI 16% 15% Typical VTE most common VTE in PNH Atypical VTE more common in PNH than in the general population 3 Higher proportion of PE and/or DVT sites of thrombosis consistently found in PNH patients Socie et al (29%)4 and Nishimura and Rosse. 24 (27%)5 1. Hillmen P et al. N Engl J Med. 1995;333: Hillmen P et al. Blood. 27; 1: Fowkes FJI et al. Eur J Vasc Endovasc Surg. 23;25: Socie G et al. Lancet. 1996;348: Nishimura J et al. Medicine. 24;83(3): and PNH Clone Size TE (%) (n=43) <2 2 5 >5 PNH Granulocyte Clone Size (%) South Korean National Registry. Lee JW et al. Hematologica 21;95(s2): Abstract 55. Minimally Transfused PNH Patients: Risk of Rate (TE per 1 patient years) (n=91) Patients Treated With Anticoagulants 4.87 (n=22) Patients With 1 Transfusions Per Year Hillmen P et al. Blood 27;11:

6 Chronic Kidney Disease Common Symptoms of PNH Clinical Symptoms Predictive of TE South Korean National Registry. Lee JW et al. Hematologica (s2):Abstract #55 and 56. Predictors of thrombosis Risk: LDH Patients With TE (%) LDH 1.5x ULN 3.8 LDH <1.5x ULN Univariate analysis showed that the incidence of TE was significantly increased in patients with LDH 1.5x ULN at diagnosis (43/171; 25.1%) compared with patients with LDH <1.5x ULN (2/53; 3.8%; OR 8.57; P<.1) Lee JW et al. Presented at the 54th Annual Meeting of the American Society of Hematology; December 8 11, 212; Atlanta, GA. Abstract Predictors of thrombosis Risk: Elevated LDH and Clinical Symptoms LDH 1.5 ULN 7.1 LDH 1.5 ULN and Abdominal Pain LDH 1.5 ULN and Chest Pain LDH 1.5 ULN and Dyspnea LDH 1.5 ULN and Hemoglobinuria Odds Ratio for TE (Multivariate Analysis) The risk of TE in patients with LDH 1.5 ULN was 7.1 times greater than in patients with LDH <1.5 ULN (P=.13). The risk of TE was further increased in patients with both LDH 1.5 ULN and at least one of the four symptoms of abdominal pain, chest pain, dyspnea, and hemoglobinuria compared with patients with LDH 1.5 ULN alone (OR: 9.2; P=.32). Lee JW et al. Presented at the 54th Annual Meeting of the American Society of Hematology; December 8 11, 212; Atlanta, GA. Abstract

7 Chronic Kidney Disease Common Symptoms of PNH Potential Assessments to Identify Risk in PNH Baseline Platelet Count Proportion with History of TE 1 Thrombocytopenic <1, X 1 9 /L 45% Non-Thrombocytopenic 1, X 1 9 /L 27% Patients with thrombocytopenia have elevated incidence of TE 1 Evidence of platelet consumption in PNH 1,2 Platelet consumption may result from microthrombi 1,3 D dimer and other markers of elevated inflammatory response 3,4 61% and 82% of PNH patients in French and US studies demonstrated an elevated risk for TE as indicated by increased D dimer levels Chronic terminal complement activation leads to systemic inflammatory and hypercoagulable state in PNH 1. Socie G et al. Blood. 29;114:Abstract Hill A et al. Br J Haematol. 27;137: Weitz I et al. Research. 21;125:S Helley D et al. Hematologica.21;95(4): Chronic Kidney Disease Kidney Pathology in PNH Common Symptoms of PNH Chronic hemolysis and cell free plasma hemoglobin lead to chronic kidney disease in PNH 1 4 Repetitive exposure of tissue to cell free hemoglobin may lead to renal damage in PNH 3,4 8% of PNH patients (median age of 31.5 years) had MRI evidence of significant renal hemosiderosis 1,5 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 hemoglobinuria is seen Autopsy and biopsy often show interstitial nephritis and fibrosis 3,4 1. Brodsky R. Hematology: Basic Principles and Practice. Churchill Livingstone; 25: Rother R et al. JAMA. 25;293: Clark DA et al. Blood. 1981;Jan;57(1): Hillmen P et al. Am. J. Hematol. 21; 85: Hill A et al. Blood. 26;18:Abstract 979. Kidney Pathology in PNH 7

8 Incidence of Chronic Kidney Disease (CKD) in PNH Proportion of Patients (%) (n=4) (n=84) (n=69) Stage 3-5 CKD Stage 1-2 CKD No CKD 1. Hillmen P et al. Am J Hematol 21;85: Common Symptoms Have a Significant Impact on QoL Fatigue Headache 76 Dyspnea 66 Abdominal pain 59 Hemoglobinuria 55 Erectile Dysfunction 47 Dysphagia n= Patients (%) The majority of patients reported symptoms as moderate to very severe 59% of 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 because of PNH Weitz I et al. J Intern Med 212. Chronic Kidney Disease Common Symptoms of PNH Patients (%) Clone Size Does Not Correlate to Symptom Severity 1% 8% 6% 4% 2% International PNH Registry Gran Clone <1% Gran Clone 1 49% Gran Clone 5% % Abdominal Pain Shortness of Breath Chest Pain Clinical Symptoms Discolored Urine Fatigue 1. Urbano-Ispizua A et al. Hematologica 21;95(s2): Abstract

9 Chronic Kidney Disease Common Symptoms of PNH Impact of PNH on Quality of Life ~75% of Patients Reported Symptoms as Moderate to Very Severe 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 *Moderate to severe; N=29. Meyers G et al. Blood. 27;11 (11): Abstract Historical Management of PNH Transfusions Risk of iron overload Transient treatment of anemia Anticoagulants Risk of hemorrhage Ineffective in many patients 2 Red cell supplements ESAs may expand clones and elevate hemolysis Folic acid, iron, erythropoiesis stimulating agents Steroids/androgen hormones No controlled clinical trials AE s ESA = erythropoietin stimulating agents. 1. International PNH Interest Group. Blood. 25;16: Hillmen P et al. Blood. 27;11: PNH Bone Marrow Transplant BMT is the only potentially curative therapy for PNH 1, Indications for transplant include 1. uncontrollable hemolysis 2.thrombosis 3. Bone marrow failure state There is considerable morbidity and mortality associated with BMT for PNH. Patient selection and timing of transplant are important variables in making the decision. 1. Santarone S et al. Haematologica. 21;Jun;95(6): De Latour PF et al. Abstract #316. EBMT Bieri S et al. Bone Marrow Transplantation. 28; Fraser CJ et al. Blood. 26;18: Brodsky RA. Blood. 29;113:

10 PNH Bone Marrow Transplant In a recent retrospective study in France examining PNH patients 2 54% had GVHD In another study examining PNH patients (n=23) 1 5% chronic GVHD; 42% acute GVHD BMT has a significant impact on quality of life post transplant 3,4 Allogeneic BMT recommended for PNH patients with lifethreatening cytopenias or possibly the rare patient with disabling hemolysis or thrombosis not controlled with existing therapy 5 1. Santarone S et al. Haematologica. 21;Jun;95(6): De Latour PF et al. Abstract #316. EBMT Bieri S et al. Bone Marrow Transplantation. 28; Fraser CJ et al. Blood. 26;18: Brodsky RA. Blood. 29;113: BMT In PNH Study Year Pub (N) Age Median (range) Study Population Mortality GVHD Cause of Death Risk of Death or GVHD Santarone S et al. Hematologica + EBMT 28 abstract PNH patients; 23 42% overall n=1 of 2 evaluable N=11: infections n=4, agvhd n=1, (2-59) HLA matched patients (5%) cgvhd cgvhd n=2, multiorgan failure [34% at 6 mo. (22 identical n=2, EBV lymphoma n=1 (from abstract)] N=11 agvhd (42%) sib), 3 unmatched At least 42% De Latour et al. EBMT, Abstract # (23-38) N=83 (54%) 31% treated vs. BMF; 17% controls at N=69 (45%) PNH 5 years N=1 (54%) N=53 deaths 28 from infections 13 from GVHD At least 31% Ruggeri et al. EBMT, Abstract #O SAA 7 PNH 53% 2 years (projected) 28 +/- 6% agvhd N=14 of 44 at risk (32%) cgvhd NA At least ~28% de Latour et al. Blood % (n=22) NA NA 42% (death) de Latour et al. ASH abstract (23-36) N=75 (54%) ~3% at 5 yrs vs. BMF; 32.2% at 1 N=62 (45%)PNH years for controls (n=41; ) n=45 (32%) cgvhd n=35 (25%) agvhd N=39 (28%) Main causes: Infection (n=19) GvHD (n=9) Hemorrhage (n=4) At least 25% Witherspoon et al (19-42) Hemolytic PNH 43% < 6 months 5% N=6: GVHD n=2, infections n=2, other n=2 At least 43% 9 2 Non-Hemolytic 33% 44% N=3: infections n=2, other n=1 At least 33% (14-38) PNH Parker PNH Patients 44% (1 yr) NA NA 44% (death) Hegenbart et al Hemolytic PNH; 43% n=5 (71%) n=3: Infection n=1; GVHD n=1; At least 43% (25-49) 2 BMF Organ failure n=1 Saso et al % SAA 44% at 2 yr n=16 (34%) agvhd 19/48 (4%) died in HLA identical At least 33% (1-47) 21d engraftment; cohort n=13/39 cgvhd with GvHD (n=3) 9d engraftment August 12_1_21Gbl Considerations for Managing the PNH/AA Patient PNH PNH with hemolysis PNH Intermediate + hemolysis AA/PNH Moderate AA with hemolysis Moderate AA without hemolysis Severe AA without hemolysis Eculizumab? Prophylactic Anticoagulaion IST BMT De Latour RP, Amoura Z, and Socie G. La revue de medecine interne. 21;

11 Eculizumab ( Soliris) Complement Cascade SOLIRIS Proximal C3 C3b C3a SOLIRIS binds with high affinity to C5 Terminal complement C5a and C5b 9 activity blocked Terminal C5 C5b C5a C5b-9 Cause of Hemolysis in PNH Proximal functions of complement remain intact Weak anaphylatoxin Immune complex clearance Microbial opsonization 1. Figueroa JE, Densen P. Clin Microbiol Rev. 1991;4(3): Walport MJ. N Engl J Med. 21;344(14): SOLIRIS (eculizumab) [package insert]. Alexion Pharmaceuticals; Rother RP et al. Nature Biotech. 27;25(11): Eculizumab Clinical Trials in PNH Pilot Study NEJM. 24 N = 11 Primary endpoint: reduction of hemolysis TRIUMPH NEJM. 26 Pivotal Phase III, Double-Blind, Placebo-Controlled Trial, N = 87 SHEPHERD Blood. 28 Broader patient population, including those receiving minimal transfusions or with thrombocytopenia, N = 97 Long-Term Extension Trial Hillmen Blood. 27 Evaluated long-term safety, efficacy and effect on thrombosis; Placebo patients switched to SOLIRIS N = 187 Dosing Schedule Pretreatment Induction Phase Maintenance Phase 2 weeks before induction Week and every 2 weeks thereafter Neisseria meningitidis vaccination SOLIRIS dose, mg X 9 X 9 In clinical trials all patients received a meningococcal vaccination 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 Concomitant medications allowed Steroids, immunosuppressant drugs, anti clotting agents and hematinics 1 SOLIRIS (eculizumab) [package insert]. Alexion Pharmaceuticals; Hillmen P et al. N Engl J Med. 24;35(6):

12 TRIUMPH and SHEPHERD: Response Lactate Dehydrogenase (U/L) % response after the first dose Time, Weeks TRIUMPH Placebo/Extension TRIUMPH SOLIRIS /Extension SHEPHERD SOLIRIS TRIUMPH placebo patients switched to SOLIRIS after week 26. All TRIUMPH patients entered the long-term extension study. P<.1 at all measured time points. Hillmen P et al. Blood. 27;11(12): Reduction in Transfusion :TRIUMPH Trial Median Units Transfused Patients not on SOLIRIS (n=44) SOLIRIS (n=43) * * * (n=87) * (n=3) (n=35) (n=22) Overall >25 Pre treatment Transfusion Strata 51% of SOLIRIS patients achieved transfusion independence vs % of patients not on SOLIRIS 1 Patients with concomitant bone marrow dysfunction may continue to require minimal transfusions *P<.1. 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. 26;355; Schubert J. Br. J Haematol. 28;142(2): Improvement of QOL Measures 1.2 Standard Effect Size (SES) Large Impact Moderate Impact Small Impact *P<.5. P<.1. FACIT Fatigue EORTC Fatigue Global Health Physical Role Cognitive* Dyspnea Pain* EORTC Functioning Insomnia* Constipation Nausea Diarrhea EORTC Symptoms 1. Brodsky R et al. Blood. 26;18(11): Abstract Data on file. Alexion Pharmaceuticals. 12

13 Eculizumab therapy and Thrombotic Events Thrombotic Events (#) Pre SOLIRIS Treatment N=195 P=.1 3 SOLIRIS Treatment 63% of patients received concomitant anticoagulants 1 The effect of anticoagulant withdrawal was not studied 2 Events observed in both venous and arterial sites 3 PI: There were fewer thrombotic events with SOLIRIS treatment than during the same period of time prior to treatment. 1. Brodsky R et al. Blood. 28;111(4): SOLIRIS (eculizumab) [package insert]. Alexion Pharmaceuticals; Hillmen P, et al. Blood. 27;11: Who should be receiving anticoagulation? The frequency of thrombotic events while on eculizumab was not a primary endpoint of the studies published on eculizumab in PNH. The actual risk of thrombosis in PNH patients on eculizumab has not been prospectively studied. This issue should addressed in an individualized fashion, dependent on type of thrombosis, severity, concomitant risk factors, presence of other hypercoagulable states etc.. Safety: Warnings and Precautions The effect of withdrawal of anticoagulant therapy during SOLIRIS treatment has not been established. Therefore, treatment with SOLIRIS should not alter anticoagulant management Patients who discontinue SOLIRIS must be monitored closely for signs of serious hemolysis If serious hemolysis occurs after SOLIRIS discontinuation, consider the following procedures/treatments: blood transfusion (packed RBCs), or exchange transfusion if the PNH RBCs are >5% of the total RBCs by flow cytometry; anticoagulation; corticosteroids; or reinstitution of SOLIRIS In clinical trials, 16 of 196 PNH patients discontinued SOLIRIS treatment; no serious hemolysis was observed SOLIRIS (eculizumab) [package insert]. Alexion Pharmaceuticals;

14 Chronic Kidney Disease Common Symptoms of PNH Renal Function change with eculizumab At 6 Months Proportion of Patients (%) Overall (n=189) P< Stage 1 2 (n=81) P< P=.5 Stage 3 5 (n=4) 5. Segment of PNH Population No Change Improvement Worsening Hillmen P et al. Am. J. Hematol. 21; 85: Eculizumab has a Major Impact on Survival in PNH Survival is comparable to age and sex matched control population 96% (76/79) patient survival. There was no difference in mortality between patients on eculizumab and the normal population (P=.46) 2 patients over 7 years of age had worse survival (P=.42). No patients under the age of 5 years died Kelly R et al. Blood. 21;116(21) Abstract # Warning WARNING: SERIOUS MENINGOCOCCAL INFECTION SOLIRIS increases the risk of meningococcal infections. Meningococcal infection may become rapidly lifethreatening or fatal if not recognized and treated early. Vaccinate patients with a meningococcal vaccine at least 2 weeks prior to receiving the first dose of SOLIRIS Revaccinate according to current medical guidelines for vaccine use Monitor patients for early signs of meningococcal infections, evaluate immediately if infection is suspected, and treat with antibiotics if necessary SOLIRIS (eculizumab) [package insert]. Alexion Pharmaceuticals;

15 Serious Adverse Events: Clinical Trial Experience Meningococcal infections are the most important adverse events that may be experienced by patients receiving SOLIRIS In clinical studies, 2 out of 196 patients developed serious meningococcal infections while receiving treatment with SOLIRIS Both patients had been vaccinated In clinical studies among non PNH patients, meningococcal meningitis occurred in one patient, who was unvaccinated In post marketing experience, cases of serious or fatal meningococcal infections have been reported SOLIRIS (eculizumab) [package insert]. Alexion Pharmaceuticals; 29. Adverse Reactions Reported in 5% of SOLIRIS Treated Patients in TRIUMPH Patients, n (%) Reaction SOLIRIS (n=43) Placebo (n=44) Headache 19 (44) 12 (27) Nasopharyngitis 1 (23) 8 (18) Back pain 8 (19) 4 (9) Nausea 7 (16) 5 (11) Fatigue 5 (12) 1 (2) Cough 5 (12) 4 (9) Herpes simplex virus infections 3 (7) Sinusitis 3 (7) Respiratory tract infection 3 (7) 1 (2) Constipation 3 (7) 2 (5) Myalgia 3 (7) 1 (2) Pain in extremity 3 (7) 1 (2) Influenza-like illness 2 (5) 1 (2) SOLIRIS (eculizumab) [package insert]. Alexion Pharmaceuticals; 29. PNH Registry Overview The PNH Registry is an ongoing global, observational, non interventional study collecting safety, effectiveness, clinical characteristic and quality of life data on patients with PNH irrespective of clone size or treatment. The PNH Registry has been established in order to describe the real world outcomes of PNH, capturing a wide range of patients from all over the world. 15

16 PNH Registry Data Collection Physician Reported Data Data collected at study enrollment and every six months thereafter Data entry minimally includes: demographics, medical history, PNH diagnosis, flow cytometry results, symptoms, and clinical outcomes All necessary information can be gathered from patient medical records Patient Reported Outcomes Patients complete questionnaires at study enrollment and every six months thereafter EORTC QLQ 3* FACIT F fatigue scale* Overall health status Symptom frequency and bother Healthcare utilization Work Status *validated quality of life instruments in other disease states PNH Registry: Future Research Topics PNH and Thrombotic Events PNH and Renal Dysfunction PNH in the Pediatric Setting Association of Clinical & Patient Characteristics with PNH Treatment Evolution of PNH Clones Survival / Mortality Correlation of PNH with Laboratory Markers PNH: Conclusions PNH is a rare and life threatening disease Delays in diagnosis range from 1 to more than 1 years 1 high risk patients should be identified and tested for PNH 2 Reliable testing and reporting procedures matter 2 Granulocyte analysis in all cases PNH testing on RBCs alone is not adequate Adding quantitative results to report forms is essential and kidney disease can result in significant morbidity/mortality With the advent of treatment options for PNH, there is a compelling reason to identify patients 3 1. Hillmen P et al. N Engl J Med. 1995;333: Borowitz MJ et al. for International Clinical Cytometry Society. Part B Clin Cytometry. 21;78B: Brodsky R et al. Blood. 28;111(4):