1 Atypical Haemolytic Uraemic Syndrome (aHUS) Overview of Disease and Diagnosis MD Name Title, Institution

2 Chronic, progressive, risk of sudden death and vital organ damage 1-4 : 33-40% of patients die or progress to End Stage Renal Disease (ESRD) with the first clinical manifestation 2,3  10-15% mortality in the initial phase 3 –19% mortality after initial manifestation in patients with CFH mutation 3 65% of all patients die, require dialysis, or have permanent renal damage within the first year after diagnosis despite plasma exchange or plasma infusion (PE/PI) 2 Atypical Haemolytic Uraemic Syndrome (aHUS): A Genetic, Devastating and Life-Threatening Disease 1.Sallee M, et al. Nephrol Dial Transplant. 2010;25: Caprioli J et al Blood. 2006; 108: Noris M, et al. Clin J Am Soc Nephrol. 2010;10: Noris M, et al. N Engl J Med. 2009;361: Significant morbidity and mortality within 1 year Cumulative Fraction of CFH Patients Free of Events Follow-up After Initial Onset (Months) Modified from Caprioli et al, Data show patients with CFH mutations. CFH mutations=most common mutations. 70% of patients with CFH mutation (the most common mutation) died, required dialysis, or had permanent renal damage within 1 year 2

3 aHUS: Complement-Mediated Thrombotic Microangiopathy (TMA) Due to a genetic deficiency of complement regulators, aHUS is a permanent, ongoing disease of systemic, complement- mediated TMA 1,2 Defined by the clinical characteristics of TMA: –Decreased platelet count 1 –Evidence of microangiopathic haemolysis 3 –Evidence of organ impairment/damage (e.g. serum creatinine >ULN) 2,3 Coexisting diseases or conditions may unmask aHUS 4 Affects both adults and children 2 1. Noris M et al. N Engl J Med. 2009;361: ; 2. Noris M et al. Clin J Am Soc Nephrol 2010;5:1844–1859; 3. Desch K et al. JASN 2007;18: ; 4. Kavanagh D et al. British Medical Bulletin 2006; 77 and 78: 5–22.

4 The Role of Complement in aHUS

5 The Complement System: Always on, Strongly Amplified, Dependent on Natural Regulators The complement system is a vital component of the innate protective immune system 1 Complement is activated by three mechanisms (classical, alternative, and lectin) which allow the system to respond to inflammatory, infectious, ischaemic, necrotic insult, as well as foreign and self antigens Always ‘on’ to allow rapid immune response 1 –Rapid amplification leads to powerful and destructive immune reactions 2 –Natural inhibitors of complement keep amplification in check and prevent uncontrolled complement activation 2 1. Holers VM et al. Immunol Rev 2008;223:300316; 2. Zipfel PF et al. Curr Opin Nephrol Hypertens 2010;4: Holers VM et al. Immunol Rev 2008;223:300–316; 2. Zipfel PF et al. Curr Opin Nephrol Hypertens 2010;4:372–378.

6 Factors That Amplify Complement Activation Glovsky MM et al. Ann Allergy Asthma Immunol 2004;93:513–523; Rubio MT et al. Bone Marrow Transplant 2008;41(Suppl. 1):S220. Abstract P766; Mastellos D et al. Immunologic Res 2003;3:367–385; Mergenhagen STE et al. J Infect Dis 1973;128:S86; Chenoweth DE et al. N Engl J Med 1981;304:497–503; Giradi G. Am J Reprod Immunol 2008;59:183–192. InfectionSurgery AutoimmunePregnancy

7AnaphylaxisInflammationThrombosis Consequences Cell destruction InflammationThrombosis Consequences C5a Potent anaphylatoxin Chemotaxis Pro-inflammatory leucocyte activation Endothelial activation Pro-thrombotic C5b-9 Membrane attack complex Cell lysis Pro-inflammatory Platelet activation leucocyte activation Endothelial activation Pro-thrombotic C5b C6 C7 C8 C9 1. Zipfel PF et al. Vaccine 2008;26(Suppl 8):I67–74; 2. Figueroa JE, Densen P. Clin Microbiol Rev 1991;4:359–395; 3. Walport MJ. N Engl J Med 2001;344:1058–1066; 4. Rother RP et al. Nat Biotechnol 2007;25:1256–1264; 5. Meyers G et al. Blood 2007;110:abs 3683; 6. Hill A et al. Br J Haematol 2010;149:414–425; 7. Hillmen P et al. Am J Hematol. 2010;85:553–559; 8. Parker C et al. Blood 2005;106:3699–3709; 9. Hillmen P et al. N Engl J Med 1995;333:1253–1258; 10. Nishimura J et al. Medicine (Baltimore) 2004;83:193–207; 11. Caprioli J et al. Blood 2006;108: 1267–1279; 12. Noris M et al. Clin J Am Soc Nephrol 2010;5:1844–1859; 13. George JN. Blood 2010;116:4060–4069; 14. Loirat C et al. Pediatr Nephrol 2008;23:1957–1972; 15. Ståhl AL et al. Blood 2008;111:5307–5315; 16. Hosler GA et al. Arch Pathol Lab Med 2003;127;834–839; 17. Ariceta G et al. Pediatr Nephrol. 2009;24:687–696. Chronic Uncontrolled Complement Activation Leads to Devastating Consequences in aHUS − − Proximal Terminal Lectin Pathway Classical Pathway Alternative Pathway C3a Weak anaphylatoxin C3 + H 2 O: always active (chronic) Amplification + 7 iC3b

8 Ongoing Research in the Field of Complement Inhibitors Most genetic mutations have been discovered in the past 20 years 1 30–50% of patients with aHUS have no identifiable genetic mutation 2 1. Timeline adapted from: Le Quintrec M et al. Semin Thromb Hemost 2010;36:641–665; 2. Noris M et al. Clin J Am Soc Nephrol 2010;5:1844–1859. Link with low C3 Homozygous CFH deficiency CFI mutations C3 mutations Link with RCA – CFH mutations (SCR20) Thrombomodulin mutations Hybrid (CFH-CFHRI) Heterozygous CFH deficiency Association with low CFH MCP mutations Anti-FH auto-antibodies Homozygous MCP deficiency CFB mutations  CFHR1/  CFHR3 deletion

9 Endothelial cells: - Activation - Swelling and disruption Platelets: - Activation - Aggregation leucocytes: - Activation Platelet consumption Mechanical haemolysis Blood clotting Vessel occlusion Inflammation ischaemia Systemic multi-organ complications Clinical consequences: Red cells: -haemolysis Modified by Zipfel and Jokiranta from Desch et al. JASN 2007;18:2457–6240; Licht C et al. Blood :4538–4545; Noris M et al. NEJM 2009;361:1676–687; Stahl A et al. Blood 2008;111:5307–5315; Morigi et al. J Immunol 2011 Uncontrolled complement activation on cells Chronic Uncontrolled Complement Activation Leads to Endothelial and End Organ Damage

10 Renal More than 50% of patients progress to ESRD 7 Elevated creatinine Proteinuria 2 Oedema, 3 malignant hypertension 4 Decreased eGFR 5 CNS Up to 48% of patients experience neurological symptoms 2 Confusion 6 Stroke 6 Encephalopathy 4 Seizure 2 Cardiovascular Up to 43% of patients experience cardiovascular symptoms 2 Myocardial infarction 8 Hypertension 9 Diffuse vasculopathy 5 Peripheral gangrene 10 Gastrointestinal Up to 30% of patients present with diarrhoea 11 Colitis 6 Nausea/Vomiting 12 Pancreatitis 12 Abdominal pain 6 Gastroenteritis 2 Liver necrosis 2 Blood Thrombocytopenia 7 Decreased haptoglobin 7 Elevated LDH 7 Decreased haemoglobin 7 Schistocytes 7 Pulmonary Dyspnoea 8 Pulmonary haemorrhage 13 Pulmonary oedema 8 1. Ariceta G et al. European Paediatric Study Group for HUS. Pediatr Nephrol 2009;24:687–696; 2. Neuhaus TJ et al. Arch Dis Child 1997;76:518– Ståhl A-L et al. Blood 2008;111:5307– Noris M et al. Clin J Am Soc Nephrol 2010;5:1844–1859; 5. Loirat C et al. Pediatr Nephrol 2008;23:1957–1972; 6. Ohanian M et al. Clin Pharmacol 2011;3:5–12 ; 7. Caprioli J et al. Blood 2006;108:1267–1279; 8. Sallée M et al. Nephrol Dial Transplant 2010;25:2028–2032; 9.Kavanagh D et al. Med Bull 2006;77–78:5–22; 10. Malina M et al. Pediatr Nephrol 2011;26:1678; 11. Zuber J et al. Nat Rev Nephrol 2011;7:23–35; 12. Dragon-Durey M-A et al. J Am Soc Nephrol 2010;21:2180–2187; 13.Sellier-Leclerc A-L al; French Society of Pediatric Nephrology. J Am Soc Nephrol 2007;18: ; 14. Larakeb A et al. Pediatr Nephrol 2007;22:1967–1970. Systemic, Complement-mediated TMA Affects Multiple Vital Organs and Tissues Visual Ocular occlusion 14

11 aHUS: More than a Renal Disease Presence of aHUS Complications by System¹ 1. Langman C et al. Systemic Multi-Organ Complications in Atypical haemolytic uraemic Syndrome (aHUS): Retrospective Study in a Medical Practice Setting. Poster 0490 presented at EHA SystemSigns/Symptoms Number (%) of Patients with Complication RenalKidney impairment30 (100%) CardiovascularThrombi (various locations), cardiac arrest, cardiomyopathy 14 (47%) GastrointestinalDiarrhoea, vomiting, pancreatitis, splenic vein occlusion 11 (37%) NeurologicSeizure, acute disseminated encephalomyelitis, stroke, transient ischaemic attacks, facial paralysis, headache 6 (20%) aHUS complications in >1 system19 (63%) 11 (37%) of the 30 aHUS patients experienced thrombi beyond the kidney Retrospective chart review of 30 paediatric, adoloescent and adult aHUS patients who received eculizumab treatment between 2007 and 2009 outside of controlled clinical trial setting. Data corresponding to the time period prior to the first dose of eculizumab are described.

12 PE/PI –No prospective controlled trials demonstrating efficacy of PE/PI in aHUS 3 –Complications reported in children (55%) and adults (15%) 1 –26% of patients experienced major complications from PE, including death, systemic infection, thrombosis, and pulmonary haemorrhage (Source: Oklahoma TTP-HUS Registry) 2 Dialysis –Does not protect patients from serious, extra renal morbidities, including thrombocytopenia, haemolysis, cerebral ischaemic events, ocular damage, peripheral gangrene, vascular stenoses and arterial steno-occlusive lesions 3–10 Kidney Transplant 1 Liver-Kidney Transplant – Anecdotal reports; high risk of morbidity and mortality 1,3,13,14 Antihypertensives 11,12 Packed Red Blood Cell Transfusions 11,12 1. Zuber J et al. Nat Rev Nephrol 2012;8:643–657; 2. Nguyen L et al. Transfusion 2009;49:392–394; 3. Loirat C et al. Semin Thromb Hemost 2010;36:673– 681; 4. Neuhaus TJ et al. Arch Dis Child 1997;76:518–521; 5. Malina M et al. Pediatr Nephrol 2011;26:1678; 6. Larekeb A et al. Pediatr Nephrol 2007;22:1967–1970; 7. Remuzzi G et al. Am J Transplant 2005;5:1146–1150; 8. Vergouwen MDI et al. AJNR Am J Neuroradiol 2008;29:e34; 9. Bresin E et al. International Registry of Recurrent and Familial HUS/TTP. Clin J Am Soc Nephrol 2006;1:88–99; 10. Davin JC et al. Am J Kidney Dis 2010;55:708–711; 11. Ariceta G et al. Pediatr Nephrol 2009;24:687–696; 12. Waters AM et al. Pediatr Nephrol 2011;26:41–57; 13.. Nester C, et al. Clin J Am Soc Nephrol 2011; 14. Saland JM et al. J Am Soc Nephrol 2009;20:940–949. Historical Care Options Fail to Address Underlying Chronic Uncontrolled Complement Activation

13 Factors defining PE/PI failure after 5 daily plasma exchanges: Platelet count and LDH are not normalized 1, Serum creatinine is not reduced by at least 25% 1 If TMA occurs in plasma dependent patients with detectable ADAMTS13 activity when withdrawing PE/PI, consider an alternative therapy Zuber J et al. Nat Rev Nephrol Nov;8(11): Assessing PE/PI Failure: Recommendations from French study group for aHUS

14 Affected ProteinOutcome of Kidney Transplantation 1 Factor H% of Patients with ongoing TMA: 80–90% CFHR1, R3% of Patients with ongoing TMA: 20% MCP% of Patients with ongoing TMA: 15–20% Factor I% of Patients with ongoing TMA: 70–80% Factor BOngoing TMA in 1 published case C3% of Patients with ongoing TMA: 40–50% THBDOngoing TMA in 1 published case Kidney Transplant Does Not Address the Cause of aHUS 1. Noris M et al. N Engl J Med 2009;361:1676–1687; 2. Bresin E et al. International Registry of Recurrent and Familial HUS/TTP. Clin J Am Soc Nephrol 2006;1:88–99.

15 Liver-Kidney Transplant Procedure associated with a high risk of morbidity and mortality 1 Newly available alternative therapeutic options reduce the indications for combined liver-kidney transplant 1 Very few successful cases worldwide 2 Complex procedure performed at limited centres with expertise 2 Patients dependent on life-long immunosuppression with multiple drug treatments 3 1. Zuber J, et al. Transplant Rev 2013; 2. Zuber J et al. Nat Rev Nephrol 2011;7:23– Nester C, et al. Clin J Am Soc Nephrol 2011; 6(6):

16 aHUS: Early Diagnosis is Critical to Improve Patient Outcomes

17 Challenges in Diagnosing aHUS Clinical presentation can be similar to other systemic TMAs 1–4 Historical treatment did not require differential diagnosis between aHUS, TTP, and STEC-HUS – historically grouped as TTP/HUS 4,5 aHUS is a rare disease, leading to lack of clinical suspicion 6 Advancements in treatment options warrant early diagnosis and intervention 1. George et al. Blood 2010;116:4060–4069; 2. Noris M et al. N Engl J Med 2009;361:1676–1687; 3. Zipfel PF et al. Curr Opin Nephrol Hypertens 2010;19:372–378; 4. Bianchi et al. Blood 2002;100:710–713; 5. Loirat C et al. Semin Thromb Hemost 2010;36:673–681; 6. Ariceta G et al.; European Paediatric Study Group for HUS. Pediatr Nephrol 2009;24:687–696.

18 Patients May Experience aHUS as a Single Disease or with Other Coexisting Diseases or Conditions In the International Registry of Recurrent and Familial HUS/TTP, 25% (47/191) of patients diagnosed with aHUS and no known affected family members had coexisting diseases: Comorbid Diseases aHUS Patients with Comorbid Disease, n (%) Malignancy and chemotherapy 1 (2) Malignant hypertension 14 (30) Post-transplant HUS* and calcineurin inhibitors 11 (23) Pregnancy-related HUS 10 (21) Systemic disease  Scleroderma  Systemic Lupus Erythematosus (SLE) 3 (6) Glomerulopathy † 8 (17) Total 47 (100) *Primary cause of nephropathy unknown in 6 /11 pts (3 w/mutations): 2 IgA nephropathy, 1 diabetes mellitus nephropathy, 1 membranoproliferative glomerulonephritis, 1 reflux nephropathy. † Glomerulopathy: membranoproliferative glomerulonephritis, nephrotic syndrome, mesangioproliferative glomerulonephritis, membranous glomerulonephritis. Noris M et al. Clin J Am Soc Nephrol. 2010;5:

19 TTPaHUSSTEC-HUS Severe Deficiency (≤5%) of ADAMTS13 Activity Genetic, Complement Mediated Shiga-toxin Induced Severely deficient (<5%) or no ADAMTS13 activity leaves von Willebrand Factor (vWF) multimers uncleaved Genetic defects in activators and/or inhibitors lead to chronic uncontrolled activation of the complement system Certain bacteria, notably E. coli produce toxins that cause uncontrolled complement activation and direct cell damage Sources: Caprioli J et al. Blood 2006;108:1267–1279; Ariceta G et al. European Paediatric Study Group for HUS. Pediatr Nephrol 2009;24:687–696; 3. Sadler JE et al. Hematology Am Soc Hematol Educ Program 2004:407–423; Zheng XL. Blood 2010;115:1475–1476; Moake JL. N Engl J Med 2002;347:589–600; Ruggenenti P et al. Kidney Int 2001;60:831–846; Sadler JE. Blood 2008;112:11–18; Hirt-Minkowski P et al. Nephron Clin Pract 2010;114:c219–c235; Loirat C et al. Pediatr Nephrol 2008;23:1957–1972; Bitzan M et al. Semin Thromb Hemost 2010;36:594–610; Tsai HM. J Am Soc Nephrol 2003;14:1072–1081; Mayer SA, Aledort LM. Mt Sinai J Med 2005;72:166–175. TMAs Often Share Similar Clinical Presentations But Differ in the Underlying Cause

20 Tests for Differential Diagnosis 1. Zuber J et al. Nat Rev Nephrol 2012 Nov;8:643–657 Recommended in patients with TMA to differentiate aHUS from severe ADAMTS13 deficiency 1 Recommended in patients with TMA and history/presence of GI symptoms to differentiate aHUS from STEC-HUS 1 While waiting for ADAMTS13 results: 1 Platelet count of >30 x 10 9 /L Serum creatinine level of >150–200 μmol/L almost eliminates a diagnosis of severe ADAMTS13 deficiency

21 Tests for Differential Diagnosis *Genetic testing encompasses evaluation for genetic mutation, deletions, polymorphisms and antibody testing. 1. Zuber J et al. Nat Rev Nephrol 2011;7:23–35; 2. Noris M et al. Clin J Am Soc Nephrol 2010;5:1844–1859; 3. Loirat C et al. Pediatr Nephrol 2008;23:1957–1972; 4. Tsai H-M. Kidney Int 2006;70:16–23; 5. Benz K et al. Curr Opin Nephrol Hypertens 2010;19:242–247 Complement mutation analysis is not indicated for aHUS diagnosis or initial treatment 1*Complement mutation analysis is not indicated for aHUS diagnosis or initial treatment 1* Results generally take weeks to months – therefore, does not impact initial clinical management 1 Genetic mutation cannot be identified in 30–50% of patients with aHUS 2-5 The majority of aHUS patients have normal levels of complement 2The majority of aHUS patients have normal levels of complement 2 Serum C3 – normal in many aHUS patients Complement Factor H (CFH) protein levels – normal in 87% of aHUS patients with CFH mutation

22 No Difference in Severity of Disease for Patients With an Identified Mutation Compared With Those With No Identifiable Mutation Consequences No Identifiable Mutation Identifiable Mutation % of patients that died, required dialysis, or had permanent renal damage within the first year after diagnosis 65%63% % of patients that died or required dialysis long term51%57% ESRD = end stage renal disease. Caprioli J et al. Blood 2006;108:1267–1272.

23 aHUS is a Clinical Diagnosis Supported by Appropriate Exclusion of Other TMAs

24 aHUS: Complement-Mediated Thrombotic Microangiopathy (TMA) Signs and symptoms of complement-mediated TMA 1,2 Decreased platelet count 1 Evidence of microangiopathic haemolysis 1 Evidence of organ impairment/damage (eg. serum creatinine >ULN) 2,3 Differentiate from other TMA diseases 1,2 ADAMTS13 Activity >5% → excludes severe ADAMTS13 deficiency (congenital or acquired TTP) 4,5,6,7 Absence of positive STEC test → excludes STEC as sole cause of TMA 8 No requirement for identified complement gene mutation Genetic mutation cannot be identified in 30%-50% of patients with aHUS 5 1. Davin et al. Am J Kid Dis. 2010;55(4): Noris et al. JASN. 2005;16(5): Dragon-Durey et al. J Am Soc Nephrol. 2010;21(12): Sellier-Leclerc AL, JASN. 2007;18: Noris M, et al. Clin J Am Soc Nephrol. 2010;5: Tsai H-M. Int J Hematol. 2010;91: Lamelle et al. Haematologica. 2008;93(2): Barbot et al. Brit J Haem. 2001;113(3):649.

25 Plus One or More of the Following: Differential Diagnosis for TMAs: aHUS, TTP and STEC-HUS Evaluate ADAMTS13 activity and Shiga-toxin/EHEC* test 8,13–15 Renal Impairment 2,9,10 Elevated creatinine 10 and/or Decreased eGFR 2,10 and/or Elevated blood pressure 11 and/or Abnormal urinalysis 9 Neurological Symptoms 4-7 Confusion 4,5 and/or Seizures 6,8 and/or Other cerebral abnormalities 5 Gastrointestinal Symptoms 2,6,12 diarrhoea +/– blood 12 and/or Nausea/vomiting 6 and/or Abdominal pain 6 and/or Gastroenteritis 2,12 Microangiopathic haemolysis 2,3 Schistocytes 2,3 and/or Elevated LDH 2 and/or Decreased haptoglobin 2 and/or Decreased haemoglobin 2 AND v This pathway is intended as educational information for healthcare providers. It does not replace a healthcare professional’s judgment or clinical diagnosis. * Shiga-toxin/EHEC test is warranted with history/presence of GI symptoms. 1. Data on file. Alexion Pharmaceuticals, Inc.; 2. Caprioli et al. Blood 2006;108:1267-7; 3. Noris M et al. NEJM 2009;361:1676–1687; 4. Neuhaus et al. Arch Dis Chilid 1997;76:518–521; 5. Noris M et al. JASN 2005;16:1177–1183; 6. Dragon-Durey et al. J Am Soc Nephrol 2010;21:2180–2187; 7. Davin et al. Am J Kid Dis 2010;55:708–777; 8. Bianchi et al. Blood 2002;110:710–713; 9. Al-Akash et al. Pediatr Nephrol 2011;26:613–619; 10. Sellier-Leclerc AL. JASN 2007;18:2392–2400; 11. Benz et al. Curr Opin Nephrol Hypertens 2010;19:242–247; 12. Noris M et al. Clin J Am Soc Nephrol 2010;5:1844–1859; 13. Tsai H-M. Int J Hematol 2010;91:1–19; 14. Barbot et al. Br J Haematol 2001;113:649; 15. Bitzan M. Semin Thromb Hemost 2010;36:594–610.

26 *Adult patients Table Adapted from Coppo P et al. PLoS ONE 5(4): e doi: /journal.pone Zuber J et al. Nat Rev Nephrol 2012 Nov;8:643–657 Patient Characteristics* ADAMTS13 Deficiency group n=160 (standard deviation) ADAMTS13 Detectable group n=54 (standard deviation) P-Value Platelet count, ×10 9 /L17.4 (14.2)66.6 (49.3)< Creatinine level, µmol/L114 (68.4)454 (326)< Patient Characteristics* Adjusted Odds Ratio 95% CIP-Value Platelet count ≤30×10 9 /L9.13.4–24.2<0.001 Creatinine level ≤200 µmol/L (2.26 mg/dL) –62.5<0.001 While Waiting for ADAMTS13 results, a Platelet Count >30 x 10 9 /L or Serum Creatinine >150–200 µmol/L Almost Eliminates a Diagnosis of Severe ADAMTS13 Deficiency (TTP) 1

27 Plus One or More of the Following: Differential Diagnosis for TMAs: aHUS, TTP and STEC-HUS >5% ADAMTS13 Activity 12 ≤5% ADAMTS13 Activity 8,13,14 Shiga-toxin/EHEC Positive 14 Evaluate ADAMTS13 activity and Shiga-toxin/EHEC* test 8,13–15 Renal Impairment 2,9,10 Elevated creatinine 10 and/or Decreased eGFR 2,10 and/or Elevated blood pressure 11 and/or Abnormal urinalysis 9 Neurological Symptoms 4-7 Confusion 4,5 and/or Seizures 6,8 and/or Other cerebral abnormalities 5 Gastrointestinal Symptoms 2,6,12 Diarrhoea +/– blood 12 and/or Nausea/vomiting 6 and/or Abdominal pain 6 and/or Gastroenteritis 2,12 Microangiopathic haemolysis 2,3 Schistocytes 2,3 and/or Elevated LDH 2 and/or Decreased haptoglobin 2 and/or Decreased haemoglobin 2 AND v This pathway is intended as educational information for healthcare providers. It does not replace a healthcare professional’s judgment or clinical diagnosis. * Shiga-toxin/EHEC test is warranted with history/presence of GI symptoms. 1. Data on file. Alexion Pharmaceuticals, Inc.; 2. Caprioli et al. Blood 2006;108:1267-7; 3. Noris M et al. NEJM 2009;361:1676–1687; 4. Neuhaus et al. Arch Dis Chilid 1997;76:518–521; 5. Noris M et al. JASN 2005;16:1177–1183; 6. Dragon-Durey et al. J Am Soc Nephrol 2010;21:2180–2187; 7. Davin et al. Am J Kid Dis 2010;55:708–777; 8. Bianchi et al. Blood 2002;110:710–713; 9. Al-Akash et al. Pediatr Nephrol 2011;26:613–619; 10. Sellier-Leclerc AL. JASN 2007;18:2392–2400; 11. Benz et al. Curr Opin Nephrol Hypertens 2010;19:242–247; 12. Noris M et al. Clin J Am Soc Nephrol 2010;5:1844–1859; 13. Tsai H-M. Int J Hematol 2010;91:1–19; 14. Barbot et al. Br J Haematol 2001;113:649; 15. Bitzan M. Semin Thromb Hemost 2010;36:594–610; 16. Zuber J et al. Nat Rev Nephrol 2012 Nov;8:643–657. While waiting for ADAMTS13 results, a platelet count >30 x 10 9 /L or serum creatinine >150–200 µmol/L almost eliminates a diagnosis of severe ADAMTS13 deficiency (TTP) 16

28 aHUS Registry Registry Observational, non-interventional, multinational Patients with a diagnosis of aHUS, regardless of treatment, will be eligible for enrollment after providing written, informed consent Inclusion Criteria Male or female patients of any age, including minors, who have been diagnosed with aHUS Diagnosis of aHUS includes: –Clinical diagnosis of aHUS –Patients with or without an identified complement regulatory factor genetic abnormality or anti-complement factor antibody –ADAMTS13 >5% (if performed) Exclusion Criteria Patients with haemolytic uraemic syndrome (HUS) due to Shiga toxin are excluded

29 Summary aHUS causes sudden and progressive damage 1,2 aHUS is a chronic, genetic, life-threatening condition 3–5 aHUS has a systemic impact 3 –63% of aHUS patients have at least 1 complication outside of the kidney, including neurologic, cardiovascular, and gastrointestinal systems 6 aHUS affects both adults and children 1 –Approximately half of patients are adults High clinical suspicion of aHUS is required in all patients presenting with TMA 3 Advancements in treatment options warrant early diagnosis and intervention 1. Noris M et al. Clin J Am Soc Nephrol 2010;5:1844–1859; 2. Caprioli J et al. Blood 2006;108:1267–1279; 3. Loirat C. Pediatr Nephrol 2008;23:1957–1972; 4. Fang CJ et al. Br J Haematol 2008;143:336–348; 5. Hirt-Minkowski P et al. Nephron Clin Pract 2010;114:c219–c235; 6. Langman C. Presented at the 17th Congress of the European Hematology Association; June 14–17, 2012; Amsterdam, The Netherlands. Abstract 0490.

30 Questions © 2013 Alexion Pharmaceuticals Australasia Pty Limited. All rights reserved. Alexion Pharmaceuticals Australasia Pty Limited. ACN Suite 401, Level 4, Building A. 20 Rodborough Road Frenchs Forest NSW Sep AU/SaHUS/13/0007