Paroxysmal Nocturnal Hemoglobinuria

Transcription

1 Paroxysmal Nocturnal Hemoglobinuria Jun Ho Jang, M.D., Ph.D. Professor, Division of Hematology-Oncology, Samsung Medical Center Sungkyunkwan University School of Medicine, Seoul, Korea

2 Contents 1. Disease Overview 2. Risk Factors of Thrombosis & Mortality 3. PNH Treatment 4. SolirisTreatment in Korea 2

3 PNH : Disease Overview 3

4 CONS HEM Q1 2011Gbl 4

5 Paroxysmal Nocturnal Hemoglobinuria It s not paroxysmal 1 Even in the absence of symptoms, destructive progression of hemolysis is ongoing It s not nocturnal 1 Hemolysis in PNH is subtle and constant, 24 hours a day Hemoglobinuria is a less commonly seen complication ¾ patients present without hemoglobinuria 2 1. Rother, R et al. Nature Biotechnology. 2007; 25,11: International PNH Interest Group. Blood. 2005;106: CONS HEM Q1 2011Gbl 5

6 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 surface 1,2 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.2002;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; 2005; p

7 PNH: Pathophysiology Anchored Protein (eg, CD59) Acquired Genetic Mutations of PIG-AGene Result in the Inability to Assemble the GPI Anchor GPI-Anchor Transmigration N-acetylglucosamine Phosphatidylinositol PIG-A Translation X Endoplasmic Reticulum Vesicle Formation

8 Voting: PNH의Pathophysiology에관여하는것은? 1.CD 34 2.CD 14 3.CD 59 4.CD 3 5.CD 10 CONS HEM Q1 2011Gbl 8

9 The Complement System Microorganisms Antigen-Antibody Constitutive/ Microorganisms Lectin Classical Alternative Proximal C3 C3b C3a Weak anaphylatoxin Microbial opsonization Immune complex clearance Terminal C5 C5b C5a C5b-9 Strong anaphylatoxin Terminal Complement Complex (TCC) Cause of Hemolysis in PNH Lysis of Neisseria Figueroa JE, et al. Clin Microbiol Rev. 1991;4: Walport. N Engl J Med. 2001;344:

10 Biologic Effects of Complement Activation 10

11 Absence of CD59 Allows Terminal Complement Complex Formation C9 CD55 C5b-8 CD59 C5b-8 CD59 C9 C9 Walport MJ, et al. N Engl J Med 2001;344:

12 Electron Micrograph of TCC (MAC) 12

13 Voting: PNH의Pathophysiology에관여하는것은? 1.Complement system 2.Coagulation system 3. Apoptosis 4. Phagocytosis 5. Immune mediated hemolysis CONS HEM Q1 2011Gbl 13

14 Historically Viewed as a Hemolytic Anemia 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 Complement Activation Intact RBC Reduced Free Hemoglobin Red Cell Mass Anemia 1. International PNH Interest Group. Blood. 2005;106: Brodsky R Paroxysmal Nocturnal Hemoglobinuria. In: Hematology -Basic Principles and Practices. 4th ed. R Hoffman; EJ Benz; S Shattilet al, eds. Philadelphia, PA: Elsevier Churchill Livingstone; 2005; RotherRP et al. JAMA. 2005;293: SocieG et al. Lancet. 1996;348: Hill A et al. Br J Haematol.2007;137:

15 Chronic Uncontrolled Complement Activation Leads to Devastating Consequences 1-8 Normal red blood cells are protected from complement attack by a shield of terminal complement inhibitors Complement Activation Without this protective complement inhibitor shield, PNH red blood cells are destroyed Thrombosis Renal Failure Pulmonary Hypertension Abdominal Pain Dyspnea Dysphagia Significant Impact on Survival Intact RBC Free Hemoglobin/Anemia Fatigue Hemoglobinuria Significant Impact on Morbidity NO Erectile Dysfunction 1. International PNH Interest Group. Blood. 2005;106: Brodsky R.Hematology -Basic Principles and Practices. 4th ed. 2005; RotherRP et al. JAMA. 2005;293: SocieG et al. Lancet. 1996;348: Hill A et al. Br J Haematol.2007;137: Lee JW et al. Hematologica. 2010;95(s2): Abstract #505 and Hill A et al. Br J Haematol. 2010; May;149(3): Hillmen P et al. Am J Hematol. 2010;85:

16 Thrombosis Chronic Kidney Disease Common Symptoms of PNH Common Signs and Symptoms in Patients with PNH PNH Symptom Incidence Rate (%) 41% Dysphagia1 47% Pulmonary Hypertension2 66% Dyspnea1 57% Abdominal Pain1 64% Chronic Renal Insufficiency3 47% Erectile dysfunction1 26% Hemoglobinuria4 40% Thrombosis5 89% Anemia6 96% Fatigue, Impaired QoL1 1. Meyers G et al. Blood. 2007;110(11):Abstract Hill A et al. Br. J. Hematol.2010; 149(3): HillmenP et al. Am. J. Hematol. 2010; 85: International PNH Interest Group. Blood.2005;106(12): HillmenP et al. N EnglJ Med. 1995;333: Nishimura J et al. Medicine. 2004;83(3): CONS HEM Q1 2011Gbl 16

17 Paroxysmal Nocturnal Hemoglobinuria: A Chronic, Systemic and Life-Threatening Disease Prevalence: 15.9 / million 1 Diagnosed at all Ages Median age early 30 s 3,4 Progressive disease 2-4 Uncontrolled complement activation underlies the morbidities and mortality Despite best supportive care 5 year mortality: 35% 2 Patients Surviving (%) Actuarial Survival From the Time of Diagnosis in 80 Patients With PNH Years After Diagnosis Age- and Gender- Matched Controls Patients with PNH 1. Hill A et al. Blood. 2006;108(11): 290a. Abstract Hillmen P et al. N Engl J Med. 1995;333: Nishimura JI, et al. Medicine. 2004;83: SociéG et al.lancet. 1996;348:

18 Prognosis of Patients with PNH Thrombosis and renal failure are leading cause of death 1-3 Prognosis of Asian Patients with PNH 4,5 Variety of clinical symptoms including; Thrombosis Impaired Renal Function Pulmonary hypertension Impaired QoL(abdominal pain, dyspnea, severe fatigue independent of anemia) Prognosis of Western Patients with PNH 6,7 Thrombosis Impaired Renal Function Evolution to 2nd disorder (i.e, AA/MDS, AML) Old age (Over 55 years) Thrombocytopenia at diagnosis 1. Hill A et al. Blood. 2006;108(11): 290a. Abstract Hillmen P et al. N EnglJ Med. 1995;333: Nishimura JI, et al. Medicine. 2004;83: Lee JW et al. Hematologica, 2010 abstract, 5.Lee JW et al. Hematologica 2010 abstract 6. Socié et al. Lancet. 1996;348: Nishimura et al. Medicine Volume 83,

19 Prevalence of Thrombosis Thromboembolism is a frequent and life threatening complication of PNH. 2-5 % of Thrombosis by region South Korea Japan Duke French UK (n=301) 1 (n=29) 2 (n=209) 3 (n=176) 3 (n=454) 4 (n=80) 5 18% 17% 6.2% 19.3% 28% 39% 1. Lee JW et al. Hematologica2009 abstract, #0505, 2.Kanakura et al. IntJ Hematol Nishimura et al. Medicine de LatourRP et al. Blood 2008; 112: Hillmen P, et al. N EnglJ Med 1995;33:

20 Voting: PNH 의 m/c cause of death 는? 1. Heart failure 2. Renal failure 3. Hepatic failure 4. Thrombosis 5. Bleeding 20 ONS HEM Q1

21 Risk Factors of Thrombosis and Mortality in Korean Population 21

22 Elevated Hemolysis(LDH 1.5 ULN) at diagnosis was associated with TE Demographics at Diagnosis Total (N=301) TE (n=54) Non-TE (n=247) P-value Age Median, range 37 (8~88) 38 (19~88) 36 (8~88) Gender Female,% Male,% History of bone marrow disorders % PNH granulocyte cl one size (n=195) Median, % Granulocyte>=50,% 49 (0-100) 48% 50 (1-100) 51% 49 (0-100) 47% WBC Median,x10 9 /L PLT Median,x10 9 /L Hemoglobin Median, g/dl Median LDH Fold at Diagnosis (ULN) Median, range LDH >=1 5,% 4.1 (0.2-36) (1-17) (0-36) < Lee JW et al. Hematologica 2010 abstract, #0505,

23 Thrombosis & Bone marrow failure : About 50% of PNH patients with bone marrow failure have evidence of TE. History of TE by Bone Marrow Dysfunction OR = 0.993, 95% CI = (0.548, 1.800), P = % of reported TE PNH with underlying BMF 53% of reported TE Classical PNH No significant association between bone marrow failure and thromboembolism 1. Lee JW et al. Hematologica20010abstract, #

24 Multiple Thrombosis : Total 81 events were occurred in 54 patients. Following TE from 1 st TE occurred maximum 4 times. 81 TE occurred in 54 patients: 35.2% of reported over 1 episode of TE 1 event in 35 patients 2 events in 13 patients 3 events in 4 patients 4 events in 2 patients. 1. Lee JW et al. Hematologica2010 abstract, #

25 Multivariate analysis of risk factor affecting TE : Elevated hemolysis, impaired renal function and abdominal pain increase the risk of major thrombotic events Hemolysis (*LDH >=1 5 ) IRF or egfr<60 Abdominal pain Chest pain Dyspnea Hemoglobinuria Clone size P=0.013 P=0.006 P=0.027 P=0.054 P=0.187 P=0.934 P= Odds Ratio Impaired renal function (IRF) : History of renal failure or estimated glomerular filtration rate (egfr) < 60 min/ml/1.73 m 2 Hemolysiswas measured by LDH >= 1.5 x upper limit of normal (ULN) Fold above normal at Diagnosis 1. Lee JW et al. HAA 2012 abstract submission, 25

26 Clone size was not affecting the prevalence of TE No evidence of any association between clone size category and the risk of experiencing a TE (P = 0.843) The prevalence of TE TE (%) OR = % CI ( ) P=0.757 OR = % CI ( ) P= Clone size <20% Clone size 20-50% Clone size >50% 1. Lee JW et al. HAA 2012 abstract 26

27 Both Hemolysis and Symptoms are risk factors for TE : Patients with elevated hemolysis with clinical symptoms had greater risk of a TE than any of the individual factors alone Abdominal pain Hemolysis& Abdominal pain P=0.006 P=0.006 Chest pain 2.7 P=0.022 Hemolysis& Chest pain 19.0 P<0.001 Dyspnea 2.9 P=0.003 Hemolysis& Dyspnea 10.3 P=0.002 Hemoglobinuria 1.3 P=0.493 Hemolysis& Hemoglobinuria 10.3 P= Odds Ratio Hemolysiswas measured by LDH >= 1.5 x upper limit of normal (ULN) Fold above normal at Diagnosis 224 patients with LDH value at diagnosis was analyzed 1. Lee JW et al. Blood 2012 abstract #51478, 27

28 Multivariate analysis of risk factors affecting mortality : TE and IRFincrease the risk of mortality TE 6.85 P<0.001 *IRF or egfr<60 Hemolysis (*LDH >=1 5 ) Abdominal pain P=0.025 P=0.113 P=0.176 Dyspnea 1.13 P=0.771 Chest pain 0.76 P=0.625 Clone size 1.01 P=0.785 Hemoglobinuria 0.48 P= Odds Ratio Impaired renal function (IRF) : History of renal failure or estimated glomerular filtration rate (egfr) < 60 min/ml/1.73 m 2 Hemolysiswas measured by LDH >= 1.5 x upper limit of normal (ULN) Fold above normal at Diagnosis 1. Lee JW et al. HAA 2012 abstract, 28

29 Overall survival : Compared with the age-and gender-matched general Korean population, PNH patients had a mortality rate 3.9 fold higher than the general population Overall survival for PNH patients 100 Patients Surviving (%) SMR=3.89, 95% CI= (2.73, 5.05), p<0.001 Population age-sex controls Patients with PNH Year after PNH diagnosis The expected survival of an age and sex-matched control group is shown for comparison (Statistics Korea 2009) 29

30 RISK FACTORS OF MORTALITY Significant association between TE and Hemolysis, IRF, Abdominal pain regardless of clone size 100 Population age-sex controls 100 Population Age- sex controls Patient Surviving (%) By TE Patients without TE Patients with TE SMR=13.92, 95% CI= (8.23,19.61), P<0.001 Patients Surviving (%) By Abdominal pain No Abdominal Pain Abdominal pain SMR=4.92, 95% CI=(3.06, 6.77), P<0.001 Patients Surviving (%) By IRF Year after PNH diagnosis Population Age- sex controls Patients without IRF Patients with IRF SMR=7.81, 95% CI= (3.86, 11.77), P<0.001 Patients Surviving (%) Year after PNH diagnosis Population age-sex controls Patients with LDH <1.5 Patients with LDH >=1.5 By Hemolysis SMR=4.81, 95% CI= (3.03, 6.59), P< Year after PNH diagnosis Year after PNH diagnosis 30

31 Standard Mortality Ratio (SMR) according to risk factors : PNH is a life-threatening disease Standard mortality ratio (SMR) versus age- and gender-matched general population: Patient population SMR (95% CI) p value Total PNH patients (n=301) 3 89 ( ) <0 001 LDH <1 5 ULN (n=53) 1 17 ( ) LDH 1 5 ULN (n=171) 4 81 ( ) <0 001 No TE (n=247) 2 13 ( ) <0 001 TE (n=54) ( ) <0 001 No IRF (n=251) 3 06 ( ) <0 001 IRF (n=50) 7 81 ( ) <0 001 No abdominal pain (n=159) 2 87 ( ) <0 001 Abdominal pain (n=142) 4 92 ( ) <0 001 LDH 1 5 ULN + abdominal pain (n=92) 6 55 ( ) <0 001 No dyspnoea (n=189) 3 42 ( ) <0 001 Dyspnoea (n=112) 4 48 ( ) <0 001 LDH 1 5 ULN + dyspnoea (n=58) 5 58 ( ) <0 001 No chest pain (n=263) 3 82 ( ) <0 001 Chest pain (n=38) 4 29 ( ) <0 001 LDH 1 5 ULN + chest pain (n=24) 5 72 ( ) <

32 PNH Treatment 32

33 Historical Management of PNH Despite medical intervention with supportive care (78% of the patients use corticosteroids), patients continued to show disabling symptoms, progressive complications, and early mortality. Supportive Care do not impact progression or risk of severe morbidities and mortality 3 Korea 1 (n=301) Duke 2 (n=176) Japan 2 (n=209) Corticosteroid 77.4% 82.4% 46.9% Transfusions 59.1% 61.9% 40.2% IST including CSA 20.6% 25% 11.0% Anti-coagulation 14.6% 26.7% 4.3% BMT 12.3% 8.0% 1.9% 1. Lee JW et al. ASH Nishimura et al. Medicine Parker et al. Blood. 2005;106:

34 Treatment : TE vs. Non TE :55% of patients with TE received anticoagulation therapy. Overall treatment in Korean PNH patients [N=301,%] Corticosteroids (n=233) 77.4 TE n,(%) Non-TE n,(%) p-value 48(89) 185(75) P=0.018 RBC Transfusion (n=178) NSAIDs (n=66) IST (n=62) Anticoagulation (n=44) Opioids(n=39) BMT (n=37) (80) 135(55) P< (50) 39(16) P< (32) 45(18) P= (56) 14(6) P< (28) 24(10) P< (19) 27(11) P= Lee JW et al. Hematologica 2009 abstract, #0505,

35 Influence of anticoagulant treatment on TE : Currently available option for management of TE in PNH is unsatisfactory * Patients with anticoagulant use No. of patients had TE Prophylactic use had multiple TE Therapeutic use 5 of 16 (31%) patients received prophylactic anticoagulant use occurred TE events. 12 of 21 (57%) patients who received anticoagulant for treatment of TE had more than one episode of thrombosis during treatment of anticoagulant. * 37 patients who reported starting data of anticoagulant use was analyzed. 35

36 36

37 Treatment of PNH Bone marrow (stem cell) transplant Complement Inhibition therapy : Eculizumab(Soliris ) 37

38 Bone Marrow Transplant BMT is the only potentially curative therapy for PNH. BMT is associated with significant morbidity and mortality In Italian study (n=23) 1 50% chronic GVHD; 42% acute GVHD, 10 yr-dfs 57% In French study 2 54% had GVHD BMT has a significant impact on quality of life post transplant 3,4 AllogeneicBMT recommended for PNH patients with life-threatening cytopeniasor possibly the patients with disabling hemolysisor thrombosis not controlled with existing therapy 5 1. Santarone S et al. Haematologica. 2010;Jun;95(6): de Latour PF et al. Abstract #316. EBMT Bieri S et al. Bone Marrow Transplantation. 2008; Fraser CJ et al. Blood. 2006;108: Brodsky RA. Blood. 2009;113:

39 OS of BMT in PNH (IBMTR) * N=57 ( ) * Median age: 28 (10-47) * MSD (n=48, 84%) * SAA (32%) * GVHD prophylaxis: CsA+MTx(58%) * Conditioning: Bu/Cy or TBI/Cy (74%) TNI/Cy (19%) Cy alone (5%) * 2-year survival : 56% Saso R et al, BJH 1999;104:

40 Patients Survival with SCT: Patients with RIST had a better survival than those with conventional conditioning. Korean BMT data Overall Survival Survival with Conditioning Regimen Reduced intensity (n=18) Patients Surviving (%) Total Patients with SCT (N=39) Patients Surviving (%) P=0.023 Conventional (n=20) Month after SCT Month after SCT Jang JH et al, APBMT

41 Korean BMT data Survival with evidence of TE with SCT: Previous history of thrombosis confers worse outcomes of survival in patients undergoing all-sct for PNH. Survival in SCT patients with TE vs. Non-TE 1 Survival in TE patients with transplanted vs. non-transplanted patients Patients Surviving (%) Patients without TE (n=25) p=0.082 Patients with TE (n=14) (n=24 ) (n=24 ) HR=10.0 (95%CI, ), p= Month after SCT 1. Jang JH et al, APBMT De Latouret al. Haematologica, Epub Matching between transplanted and nontransplanted patients in case of thrombotic events. Survival analysis in 24 matched pairs of transplanted (bold line) versus non-transplanted patients (thin line) is represented in panel A

42 SOLIRIS (eculizumab) Humanized First in Class Anti -C5 Antibody Human Framework Regions No mutations Germline Hinge Complementarity Determining Regions (murine origin) CH2 Human IgG 2 Heavy Chain Constant Region 1 and Hinge (Eliminates Fc receptor binding) CH3 Human IgG 4 Heavy Chain Constant Regions 2 and 3 (Eliminates complement activation) Rother R et al. Nat Biotech 2007;25:

43 SOLIRIS Blocks Terminal Complement 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 Haemolysis 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. 2001;344(14): SOLIRIS SmPC: SOLIRIS (eculizumab) summary of product characteristics. Alexion Europe SAS Rother RP et al. Nature Biotech. 2007;25(11):

44 Voting: PNH의신약인 Eculizumab이 block 하는곳은 complement system의어느곳인가? 1. Complement terminal complex 2. C3 3. C9 4. C5 5. C2 ONS HEM Q1 44

45 SOLIRIS PNH Clinical Studies Pilot Study NEJM N = 11 Primary endpoint: reduction of haemolysis TRIUMPH NEJM Pivotal Phase III, Double-Blind, Placebo-Controlled Trial, N = 87 Long-Term Extension Trial Hillmen Blood Evaluated long-term safety, efficacy and effect on thrombosis; Placebo patients switched to SOLIRIS N = 187 SHEPHERD Blood Broader patient population, including those receiving minimal transfusions or with thrombocytopenia, N = 97 AEGIS N = 29 Primary endpoint: reduction of hemolysis AEGIS Extension N = 27 Evaluated long-term safety and efficacy 45

46 Reduction in Hemolysis as Measured by LDH Results observed in all patients, across all subgroups 3000 Lactate Dehydrogenase(U/L) * TRIUMPH Placebo/ Extension 1 TRIUMPH Soliris/ Extension 1 SHEPHERD Soliris 1 AEGIS 2 0 Dashed line represents the upper limit of the normal range( U/L) Time, Weeks *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. 1. Hillmen P et al. Blood. 2007;110(12): Kanakura Y et al. Int J Hematol. 2011;93:

47 86% Reduction in LDH Sustained Out Past 4½ Years: Long-Term Extension Results 2500 Lactate Dehydrogenase, U/L * * * * * * *P<0.001 P= Patient (n) Study Year 187/ patients who participated in the pilot study demonstrated sustained reduction in LDH out past 5 years Patients followed for up to 54 months 1. Socié G et al. Blood. 2007;110(11): Abstract SOLIRIS SmPC: SOLIRIS (eculizumab) summary of product characteristics. AlexionEurope SAS

48 Reduction in Thrombotic events was observed During SOLIRIS Non of TE was reported during Soliris treatment in AEGIS P<0.001 Thrombotic events Pre-SOLIRIS treatment SOLIRIS treatment Pre-SOLIRIS treatment SOLIRIS treatment AEGIS (N=29) 0 Multinational SOLIRIS (N=195) 3 1. Kanakura Y et al. Int J Hematol. 2011;93: Hillmen P, et al, Blood. 2007;110:

49 SolirisReduced Thrombosis in Patients Treated with Anticoagulants 1 Thrombosis Event Rate (TE per 100 patient-years) P< (n=91) Pre-SOLIRIS Treatment SOLIRIS Treatment *excludes patients on antiplatelet agents 94% reduction in event rate with SOLIRIS 1. Hillmen P, et al. Blood. 2007;110:

50 Renal Function with SOLIRIS in Different Baseline Populations 18 Months Proportion of Patients (%) Overall (n=166) P< Stage 1 2 (n=73) P< P=0.05 Stage 3-5 (n=35) 5.7 Segment of PNH Population No Change Improvement Worsening Hillmen P et al. Am. J. Hematol. 2010; 85:

51 TRIUMPH Demonstrated that Improvement in Fatigue Occurred Independent of Hemoglobin Response 12.0 P< or more points denotes a clinically significant improvement FACIT-Fatigue Score 6 Hemoglobin, g/dl Hgb Level FACIT-Fatigue Score Change from Baseline FACIT-Fatigue Score Time, Weeks -6 Soliris (n=43) Patients not on Soliris (n=44) Soliris Hgb In SHEPHERD, 78% patients reported a significant improvement in fatigue 1 FACIT = Functional Assessment of Chronic Illness Therapy. 1. Adapted from: Hillmen P et al. NEJM. 2006;355: Brodsky R et al. Blood Rev. 2008;22: Hill A et al. Haematologica. 2008;93 (Suppl 1):359. Abstract Brodsky R et al. Blood. 2008;111:

52 Never Transfused PNH Patients Experienced Significant Clinical Benefit with SOLIRIS Measure LDH (median U/L) (n=27) TE events (b) (n=36) TE Event-Free survival at 3 years (n = 36) Impaired Quality of Life (n = 11) Pre-SOLIRIS Treatment During SOLIRIS Treatment (a) P-value 1, < NA 68% 100% % 0% NA (a) Period of SOLIRIS treatment:1.2year (median n=41) (b) TE events reported as present or absent prior and during SOLIRIS treatment. In AEGIS, never transfused PNH patients experienced reduced hemolysis(ldh), improvement in fatigue and dyspneaand no TE events. 1. HillmenP, et al, N EnglJ Med. 2006;355: Brodsky RA, stal. Blood. 2008; 111: Kanakura Y et al. Int J Hematol. 2011;93:

53 Solirishas a Major Impact on Survival in PNH Cumulative Surviving (%) % (76/79) patient survival There was no difference in mortality between patients on Solirisand the normal population (P=0.46) During Soliris treatment N=79 P=0.46 Age-and gender-matched healthy UK population Time (years) Kelly RJ et al. Blood. 2011;117:

54 Improved Overall Survival in Patients Treated With Soliris 100 Cumulative Surviving (%) Five-year survival rate for patients treated with Soliriswas significantly better than PNH patients pre-soliris* (95% vs 66.8%) During Soliris treatment, N=79 Untreated, n=30 X²=6.46 P= Time (years) *Pre-Solirispatients were treated with supportive care and for disease complications. Derived by the log-rank test of the Kaplan-Meier method. Kelly RJ et al. Blood. 2011;117: Median age at diagnosis was 37 years (range: 12 years to 79 years); median age at initiation of Soliriswas 46 years (range: 14 to 84 years). Mean treatment period with Soliriswas 39 months (range: 1 to 98 months). 54

55 Consistent Result between Asian and Western studies. In clinical trials, Solirissignificantly reduced hemolysisthe underlying cause of morbidity and mortality in PNH Asian 8 (%) Western 1-7 (%) Reduction in Thrombotic events 100% 92% Reduction in Hemolysis (measured by LDH) Reduction in Mean Number of Units Transfused Either improved or maintained CKD stages Reduction of Pulmonary Hypertension 87% 86% 71% 73% 97% 92% - 50% 8 year Survival Rate - 96% 1. Soliris (eculizumab) Summary of Product Characteristics. Alexion Europe SAS; Kelly RJ et al. Blood. 2011;117: Hillmen P et al. Blood. 2007;110(12): Hillmen P et al. Am J Hematol. 2010;85: Hill A et al. Br J Haematol. 2010; May;149(3): SocieG et al. 55 Blood. 2007;110(11):Abstract Hillmen P et al. N Engl J Med. 2006;355: Kanakura Y et al. Int J Hematol. 2011;93:36-46.

56 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 10 (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) 0 Sinusitis 3 (7) 0 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) Hillmen P et al. The Complement Inhibitor Eculizumab in Paroxysmal Nocturnal Haemoglobinuria. NEJM. 2006;355:

57 Warning WARNING: SERIOUS MENINGOCOCCAL INFECTION SOLIRIS increases the risk of meningococcal infections. Meningococcal infection may become rapidly life-threatening or fatal if not recognised 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 SmPC: SOLIRIS (eculizumab) summary of product characteristics. Alexion Europe SAS

58 Patient Safety Card Patients should be informed that they will be provided with a Patient Safety Card Patients should carry the card with them at all times The card describes symptoms, which if experienced, should prompt the patient to seek immediate medical attention Instruct patients to show the card to all health care providers involved in their care SOLIRIS SmPC: SOLIRIS (eculizumab) summary of product characteristics. Alexion Europe SAS

59 Conclusions Safety The most commonly reported adverse reactions of SOLIRIS are headache, dizziness, nausea and pyrexia each occurring in 5% or more Patients must be vaccinated against Neisseria meningitidis at least 2 weeks prior to starting SOLIRIS SOLIRIS SmPC: SOLIRIS (eculizumab) summary of product characteristics. Alexion Europe SAS

60 Voting: PNH의신약인 Eculizumab 사용은어떤 infection이문제가될수있어사용전 vaccination이필요한가? 1. Pneumococcus 2. HIV 3. Meningococcus 4. Pseudomonas 5. Aspergillosis ONS HEM Q1 60

61 Solirisin Korean PNH Patients Key Result: Efficacy of Soliris 1) 85% Reduction in the degree of hemolysis 2) Reduction in transfusion requirement 3) Improvement of clinical symptoms: The FACIT-Fatigue scores improved by a median of 8 points during the first 24 weeks of Soliristherapy. Kim JS et al. Korean J Hematol Dec;45(4):

62 SUMMARY Elevated hemolysis(ldh 1.5 ULN) at diagnosis and impaired renal function (IRF)increases the risk of thrombosis, and mortality among patients with PNH. The size of the PNH clone did not correlate with risk of thrombosis, and mortality. This highlights that clone size should just play a role in confirming diagnosis of PNH. The combination of elevated hemolysisand one or more of the clinical symptoms poses a much greater risk of a TE than any of the individual factors alone. 62

63 SUMMARY LDH, TE, IRF, Abd. pain, Chest pain and dyspneain PNH have a significantly increased mortality rate over the age and gender matched general population. Solirishas become the therapeutic gold-standard for hemolytic PNH patients and led to a major improvement in survival The decision to recommend the treatment option of PNH must take into account factors related both to PNH and to comorbid conditions. We are emphasizing the importance of patient selection in case of allo-sct. 63

64 Proposed guideline for PNH Management Risk factors of TE & Mortality Finding an evidence of TE LDH Fold 1.5 ; Hemolysis Full Clinical Assessment is critical Monitoring Renal function (Cr or egfr) PNH diagnosis confirmed via Flow cytometry; Clone size 10% Regardless clone size Asking Clinical Symptoms If experienced abdominal pain or Chest pain or Dyspnea Effective PNH treatment option is required in high risk patients 64