Jun Ho Jang, M.D., Ph.D.
Professor, Division of Hematology-Oncology, Samsung Medical Center
Sungkyunkwan University School of Medicine, Seoul, Korea
Paroxysmal Nocturnal Hemoglobinuria
Contents
1. Disease Overview
2. Risk Factors of Thrombosis & Mortality 3. PNH Treatment
4. Soliris Treatment in Korea
2
PNH : Disease Overview
4 CONS HEM Q1 2011Gbl
CONS HEM Q1 2011Gbl
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 ,11:1256-1264. 2. International PNH Interest Group. Blood. 2005;106:3699-3709.
CD55
The Defect in PNH
1. Adapted from: Johnson RJ et al. J Clin Pathol: Mol Pathol. 2002;55:145-152. 2. Brodsky R. Paroxysmal Nocturnal Hemoglobinuria. In: Hematology - Basic Principles and Practices. 4th ed. R Hoffman; EJ Benz; S Shattil et al, eds. Philadelphia, PA: Elsevier Churchill Livingstone; 2005; p. 419-427.
CD59 GPI-anchor
CD55
Prevents formation and augments instability of the C3 convertases, attenuating the
complement cascade CD59
Forms a defensive shield for RBCs from complement-mediated lysis
Inhibits the assembly of the membrane attack complex
6
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
Vesicle Formation
PIG-A Translation
Endoplasmic Reticulum Anchored Protein
(eg, CD59)
GPI-Anchor
Transmigration
PNH: Pathophysiology
Phosphatidylinositol
N-acetylglucosamine
X
Acquired Genetic Mutations of
PIG-A Gene Result in the Inability
to Assemble the GPI Anchor
8 CONS HEM Q1 2011Gbl
Voting: PNH의
의의의 Pathophysiology에에에 관여하는에 관여하는관여하는관여하는 것것것것은은은은?
1.CD 34
2.CD 14
3.CD 59
4.CD 3
5.CD 10
The Complement System
Lectin Classical Alternative
C3 C3a
C3b
C5 C5a
C5b
Weak anaphylatoxin Microbial opsonization
Immune complex clearance
Strong anaphylatoxin
Terminal Complement Complex (TCC) Cause of Hemolysis in PNH
Lysis of Neisseria
P ro x im a l T e rm in a l
Microorganisms Antigen-Antibody
Constitutive/
Microorganisms
Figueroa JE, et al. Clin Microbiol Rev. 1991;4:359-395.
Walport. N Engl J Med. 2001;344:1058-66.
C5b-9
Biologic Effects of Complement Activation
10
Absence of CD59 Allows
Terminal Complement Complex Formation
C5b-8 C5b-8
CD55
CD59
C9
C 9 C 9
CD59
Walport MJ, et al. N Engl J Med 2001;344:1058-1066 +
Electron Micrograph of TCC (MAC)
12
CONS HEM Q1 2011Gbl
Voting: PNH의
의의의 Pathophysiology에에에 관여하는에 관여하는관여하는관여하는 것것것것은은은은?
1.Complement system 2.Coagulation system 3. Apoptosis
4. Phagocytosis
5. Immune mediated hemolysis
Anemia
Reduced Red Cell Mass Free Hemoglobin 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
Intact RBC
Complement Activation
Historically Viewed as a Hemolytic Anemia
1. International PNH Interest Group. Blood. 2005;106:3699-3709. 2. Brodsky R Paroxysmal Nocturnal Hemoglobinuria. In: Hematology - Basic Principles
and Practices. 4th ed. R Hoffman; EJ Benz; S Shattil et al, eds. Philadelphia, PA: Elsevier Churchill Livingstone; 2005; 419-427. 3. Rother RP et al. JAMA. 2005;293:1653-1662. 4.
Socie G et al. Lancet. 1996;348:573-577. 5. Hill A et al. Br J Haematol. 2007;137:181-192.
14
Chronic Uncontrolled Complement Activation Leads to Devastating Consequences 1-8
Thrombosis
Fatigue Renal Failure
Abdominal Pain Dyspnea Dysphagia
Hemoglobinuria Erectile Dysfunction
Significant Impact on Survival
Significant Impact on Morbidity Pulmonary Hypertension
1. International PNH Interest Group. Blood. 2005;106:3699-3709. 2. Brodsky R. Hematology - Basic Principles and Practices. 4th ed. 2005;419-427.
3. Rother RP et al. JAMA. 2005;293:1653-1662. 4. Socie G et al. Lancet. 1996;348:573-577. 5. Hill A et al. Br J Haematol. 2007;137:181-192. 6. Lee JW et al.
Hematologica. 2010;95(s2): Abstract #505 and 506. 7. Hill A et al. Br J Haematol. 2010; May;149(3):414-425. 8. Hillmen P et al. Am J Hematol. 2010;85:
553-559.
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
Intact RBC
Complement Activation
Free Hemoglobin/Anemia
NO↓
CONS HEM Q1 2011Gbl 16 Chronic Kidney Disease Common Symptoms of PNHCommon Symptoms of PNH
Thrombosis
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 PNH Symptom Incidence Rate (%)
1. Meyers G et al. Blood. 2007;110(11):Abstract 3683.3. 2. Hill A et al. Br. J. Hematol. 2010; 149(3): 414-425. 3. Hillmen P et al. Am. J. Hematol. 2010;
85:553–559. 4. International PNH Interest Group. Blood. 2005;106(12):3699-3709. 5. Hillmen P et al. N Engl J Med. 1995;333:1253-8. 6. Nishimura J et al. Medicine. 2004;83(3):193-207
Common Signs and Symptoms in Patients with PNH
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
Years After Diagnosis
P a ti e n ts S u rv iv in g ( % )
Actuarial Survival From the Time of Diagnosis in 80 Patients With PNH 2 100
80 60 40 20 0
0 5 10 15 20 25
Age- and Gender- Matched Controls
Patients with PNH
1. Hill A et al. Blood. 2006;108(11): 290a. Abstract 985. 2. Hillmen P et al. N Engl J Med. 1995;333:1253-1258. 3. Nishimura JI, et al. Medicine. 2004;83:193-
207. 4. Socié G et al. Lancet. 1996;348:573-577.
Prognosis of Patients with PNH
Prognosis of Western Patients with PNH 6 ,7 Prognosis of Western Patients with PNH 6 ,7 Prognosis of Asian P atients
with PNH 4,5
Prognosis of Asian P atients
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)
• 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 985. 2. Hillmen P et al. N Engl J Med. 1995;333:1253-1258. 3. Nishimura JI, et al. Medicine. 2004;83:193-207. 4. Lee JW et al.
Hematologica, 2010 abstract, 5.Lee JW et al. Hematologica 2010 abstract 6. Socié et al. Lancet. 1996;348:573-77. 7. Nishimura et al. Medicine Volume 83, 2004 18
Thrombosis and renal failure are leading cause of death 1-3
Prevalence of Thrombosis
Thromboembolism is a frequent and life threatening complication of PNH. 2-5
1. Lee JW et al. Hematologica 2009 abstract, #0505, 2.Kanakura et al. Int J Hematol 2011 3. Nishimura et al. Medicine 2004 4. de Latour RP et al. Blood 2008; 112: 3099-3106. 5. Hillmen P, et al. N Engl J Med 1995;33:1253–8.
% 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%
20
C O N S H E M Q 1
Voting: PNH의
의의의 m/c cause of death는는는는?1. Heart failure 2. Renal failure 3. Hepatic failure 4. Thrombosis
5. Bleeding
Risk Factors of Thrombosis and Mortality
in Korean Population
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) 0.425
Gender
Female, % Male,%
50 50
37 63
52
48 0.042
History of bone marrow
disorders % 47 47 47 0.981
PNH granulocyte cl one size (n=195)
Median, %
Granulocyte>=50,%
49 (0-100) 48%
50 (1-100) 51%
49 (0-100) 47%
0.189 0.621
WBC Median, x10
9/L 3.5 3.7 3.45 0.604
PLT Median, x10
9/L 100 98 94 0.481
Hemoglobin Median, g/dL 7.8 7.5 8 0.111
Median LDH Fold at Diagnosis (ULN)
Median, range LDH >=1·5× × ×,% ×
4.1 (0.2-36) 76.3
4.8 (1-17) 95.6
3.9 (0-36) 71.5
0.05
<0.001
1. Lee JW et al. Hematologica 2010 abstract, #0505, 0506 22
Thrombosis & Bone marrow failure
: About 50% of PNH patients with bone marrow failure have evidence of TE.
History of TE by Bone Marrow Dysfunction
47%
of reported TE PNH with underlying
BMF
53%
of reported TE Classical PNH
OR = 0.993, 95% CI = (0.548, 1.800), P = 0.981
No significant association between bone marrow failure and
thromboembolism
1. Lee JW et al. Hematologica 20010abstract, #0505
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:
• 1 event in 35 patients
• 2 events in 13 patients
• 3 events in 4 patients
• 4 events in 2 patients.
35.2%
of reported over 1 episode of TE
1. Lee JW et al. Hematologica 2010 abstract, #0505
24
7.00 2.88
2.19 2.22 1.57 1.03 1.00
0 1 2 3 4 5 6 7 8 9
Hemolysis (*LDH >=1·5 ) IRF or eGFR <60
Abdominal pain Chest pain
Dyspnea Hemoglobinuria
P=0.013
Odds Ratio
P=0.006
P=0.934 P=0.027 P=0.054 P=0.187
Clone size P=0.859
Multivariate analysis of risk factor affecting TE
: Elevated hemolysis, impaired renal function and
abdominal pain increase the risk of major thrombotic events
• Hemolysis was measured by LDH >= 1.5 x upper limit of normal (ULN) Fold above normal at Diagnosis
• Impaired renal function (IRF) : History of renal failure or estimated glomerular filtration rate (eGFR) < 60 min/ml/1.73 m
225
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)
16
19 20
0 5 10 15 20 25
Clone size <20% Clone size 20-50% Clone size >50%
T E ( % )
The prevalence of TE
OR =1.179
95% CI (0.416 – 3.340) P=0.757
OR =1.320
95% CI (0.509 – 3.427) P=0.568
1. Lee JW et al. HAA 2012 abstract 26
2.8
2.7
2.9
1.3
17.8
19.0
10.3
10.3
0 5 10 15 20
Hemolysis & Abdominal pain
Hemolysis & Chest pain
Hemolysis & Dyspnea
Hemolysis & Hemoglobinuria
Odds Ratio
P=0.006
P<0.001
P=0.025 P=0.002
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
• Hemolysis was 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
Abdominal pain
Chest pain
Dyspnea
Hemoglobinuria P=0.493
P=0.003
P=0.022
P=0.006
• Hemolysis was measured by LDH >= 1.5 x upper limit of normal (ULN) Fold above normal at Diagnosis
• Impaired renal function (IRF) : History of renal failure or estimated glomerular filtration rate (eGFR) < 60 min/ml/1.73 m
2Multivariate analysis of risk factors affecting mortality : TE and IRF increase the risk of mortality
6.85 3.07
5.61 1.80
1.13 0.76
1.01 0.48
0 1 2 3 4 5 6 7 8 9
Hemolysis (*LDH >=1·5 )
*IRF or eGFR <60
Abdominal pain
Chest pain Dyspnea
Hemoglobinuria
P<0.001
Odds Ratio
P=0.025
P=0.785 P=0.176 P=0.771 P=0.625 Clone size
P=0.104 TE
P=0.113
1. Lee JW et al. HAA 2012 abstract , 28
Overall survival for PNH patients
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
The expected survival of an age and sex-matched control group is shown for comparison (Statistics Korea 2009)
SMR=3.89, 95% CI= (2.73, 5.05), p<0.001 100
80
60
40
20
0 5 10 15 20 25 30
Patients with PNH Population age-sex controls
P a ti e n ts S u rv iv in g ( % )
Year after PNH diagnosis
29
Year after PNH diagnosis
SMR=4.92, 95% CI=(3.06, 6.77), P<0.001
P a ti e n ts S u rv iv in g ( % )
Population Age- sex controls 100
80 60 40 20
0 5 10 15 20 25 30
Abdominal pain No Abdominal Pain
Year after PNH diagnosis
P a ti e n t S u rv iv in g ( % )
100 80 60 40 20
0 5 10 15 20 25 30
Population age-sex controls Patients without TE
Patients with TE
SMR=13.92, 95% CI= (8.23,19.61), P<0.001
Year after PNH diagnosis
P a ti e n ts S u rv iv in g ( % )
100 80 60 40 20
0 5 10 15 20 25 30
Patients without IRF
Patients with IRF Population Age- sex controls
SMR=7.81, 95% CI= (3.86, 11.77), P<0.001
Year after PNH diagnosis
SMR=4.81, 95% CI= (3.03, 6.59), P<0.001
P a ti e n ts S u rv iv in g ( % )
Population age-sex controls 100
80 60 40 20
0 5 10 15 20 25 30
Patients with LDH >=1.5 Patients with LDH <1.5
RISK FACTORS OF MORTALITY
Significant association between TE and Hemolysis, IRF, Abdominal pain regardless of clone size
By TE By Abdominal pain
By IRF By Hemolysis
30
Patient population
Standard mortality ratio (SMR) versus age- and gender-matched general population:
SMR (95% CI) p value
Total PNH patients (n=301) 3·89 (2·73–5·05) <0·001
LDH <1·5×ULN (n=53) 1·17 (0·00–2·79) 0·824
LDH ≥1·5 ×ULN (n=171) 4·81 (3·03–6·59) <0·001
No TE (n=247) 2·13 (1·19–3·06) <0·001
TE (n=54) 13·92 (8·23–19·61) <0·001
No IRF (n=251) 3·06 (1·93–4·20) <0·001
IRF (n=50) 7·81 (3·86–11·77) <0·001
No abdominal pain (n=159) 2·87 (1·46–4·28) <0·001
Abdominal pain (n=142) 4·92 (3·06–6·77) <0·001
LDH ≥1·5 ×ULN + abdominal pain (n=92) 6·55 (3·60–9·49) <0·001
No dyspnoea (n=189) 3·42 (1·95–4·88) <0·001
Dyspnoea (n=112) 4·48 (2·61–6·35) <0·001
LDH ≥1·5 ×ULN + dyspnoea (n=58) 5·58 (2·85–8·32) <0·001
No chest pain (n=263) 3·82 (2·57–5·06) <0·001
Chest pain (n=38) 4·29 (1·11–7·47) <0·001
LDH ≥1·5×ULN + chest pain (n=24) 5·72 (0·71–10·73) <0·001
Standard Mortality Ratio (SMR) according to risk
factors : PNH is a life-threatening disease
32
PNH Treatment
Historical Management of PNH
Korea
1(n=301)
Duke
2(n=176)
Japan
2(n=209) 77.4%
Corticosteroid 82.4% 46.9%
59.1%
Transfusions 61.9% 40.2%
20.6%
IST including CSA 25% 11.0%
14.6%
Anti-coagulation 26.7% 4.3%
12.3%
BMT 8.0% 1.9%
1. Lee JW et al. ASH 2010 2. Nishimura et al. Medicine 2004 3. Parker et al. Blood. 2005;106:3699-3709
• 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
3Treatment : TE vs. Non TE
: 55% of patients with TE received anticoagulation therapy.
1. Lee JW et al. Hematologica 2009 abstract, #0505,0506 34
77.4 59.1
21.9 20.6 14.6 13.0 12.3 [N=301,%]
Anticoagulation (n=44) NSAIDs (n=66) Corticosteroids (n=233)
IST (n=62) RBC Transfusion (n=178)
Opioids (n=39) BMT (n=37)
TE n,(%)
Non-TE
n,(%) p-value
48(89) 185(75) P=0.018
43(80) 135(55) P<0.001 27(50) 39(16) P<0.001
17(32) 45(18) P=0.036
30(56) 14(6) P<0.001
15(28) 24(10) P<0.001
10(19) 27(11) P=0.142
Overall treatment in Korean PNH patients
21 16
0 5 10 15 20 25
Influence of anticoagulant treatment on TE
: Currently available option for management of TE in PNH is unsatisfactory
• 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.
Therapeutic use Prophylactic use
* 37 patients who reported starting data of anticoagulant use was analyzed.
* Patients with anticoagulant use
5 had TE
12 had multiple TE
N o . o f p a ti e n ts
36
Treatment of PNH
•
Bone marrow (stem cell) transplant
•
Complement Inhibition therapy
: Eculizumab (Soliris®)
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
Allogeneic BMT recommended for PNH patients with life-threatening
cytopenias or possibly the patients with disabling hemolysis or thrombosis not controlled with existing therapy 5
1. Santarone S et al. Haematologica. 2010;Jun;95(6):983-8. 2. de Latour PF et al. Abstract #316. EBMT 2009. 3. Bieri S et al. Bone Marrow Transplantation.
2008;42 819-827. 4. Fraser CJ et al. Blood. 2006;108:2867-2873. 5. Brodsky RA. Blood. 2009;113:6522-6527. 38
OS of BMT in PNH (IBMTR)
Saso R et al, BJH 1999;104:392-396
* N=57 (1978-1995)
* 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%
Overall Survival
100
80
60
40
20
0
20 40 60 80
P a ti e n ts S u rv iv in g ( % )
Month after SCT
0 100 120 140
Reduced intensity (n=18)
Conventional (n=20) P=0.023
Survival with Conditioning Regimen
Patients Survival with SCT:
Patients with RIST had a better survival than those with conventional conditioning.
100
80
60
40
20
0
P a ti e n ts S u rv iv in g ( % )
Month after SCT
Total Patients with SCT (N=39)
20 40 60 80
0 100 120 140
Jang JH et al, APBMT 2012
Korean BMT data
40
Survival with evidence of TE with SCT:
Previous history of thrombosis confers worse outcomes of survival in patients undergoing all-SCT for PNH.
Korean BMT data
Survival in SCT patients with TE vs. Non-TE 1 100
80
60
40
20
0
20 40 60 80
P a ti e n ts S u rv iv in g ( % )
Month after SCT
0 100 120 140
Patients without TE (n=25)
Patients with TE (n=14)
p=0.082
1. Jang JH et al, APBMT 2012 2. De Latour et al. Haematologica, Epub. 2012 -41-
Matching between transplanted and non- transplanted 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.
(n=24 )
(n=24 )
HR=10.0 (95%CI, 1.3 – 78.1), p=0.007 Survival in TE patients with transplanted vs.
non-transplanted patients 2
41
42
SOLIRIS ® (eculizumab) Humanized First in Class Anti - C5 Antibody
Hinge
C H 3 C H 2
Human IgG 4 Heavy Chain Constant Regions 2 and 3 (Eliminates complement activation)
Complementarity Determining Regions (murine origin)
Human Framework Regions
• No mutations
• Germline
Human IgG 2 Heavy Chain Constant Region 1 and Hinge (Eliminates Fc receptor binding)
Rother R et al. Nat Biotech 2007;25:1256
SOLIRIS ® Blocks Terminal Complement
C3 C3a
C3b C5
P ro x im a l Te rm in a l
1. Figueroa JE, Densen P. Clin Microbiol Rev. 1991;4(3):359-395. 2. Walport MJ. N Engl J Med. 2001;344(14):1058-66. 3. SOLIRIS® SmPC: SOLIRIS®(eculizumab) summary of product characteristics. Alexion Europe SAS 2007. 4. Rother RP et al. Nature Biotech. 2007;25(11):1256-64.
C5b-9
Cause of Haemolysis in PNH
C5a C5b
SOLIRIS ®
• Proximal functions of
complement remain intact
• Weak anaphylatoxin
• Immune complex clearance
• Microbial opsonization
• Terminal complement - C5a and C5b-9 activity blocked
• SOLIRIS ® binds with high affinity to C5
Complement Cascade
44
C O N S H E M Q 1
Voting: PNH의
의의의 신약인신약인신약인신약인 Eculizumab이이이이 block 하는하는하는하는 곳은곳은곳은
곳은 complement system의의의의 어느어느어느 곳인가어느 곳인가곳인가?곳인가
1. Complement terminal complex 2. C3
3. C9
4. C5
5. C2
Long-Term Extension Trial Hillmen Blood. 2007
Evaluated long-term safety, efficacy and effect on thrombosis; Placebo
patients switched to SOLIRIS ® N = 187
Pilot Study – NEJM. 2004
N = 11
Primary endpoint: reduction of haemolysis
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
SOLIRIS ® PNH Clinical Studies
AEGIS N = 29
Primary endpoint: reduction of hemolysis
AEGIS Extension N = 27
Evaluated long-term
safety and efficacy
Time, Weeks
La ct a te D e h y d ro g e n a se (U /L )
0 4 8 12 16 20 24 28 32 36 40 44 48 52
0 500 1000 1500 2000 2500 3000
Reduction in Hemolysis as Measured by LDH
Results observed in all patients, across all subgroups
TRIUMPH – Placebo / Extension
1TRIUMPH – Soliris / Extension
1SHEPHERD – Soliris
1AEGIS
2*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):4123-4128. 2. Kanakura Y et al. Int J Hematol. 2011;93:36-46.
*
Dashed line represents the upper limit of the normal range (103 – 223 U/L)
46
86% Reduction in LDH Sustained Out Past 4½ Years: Long-Term Extension Results
10 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 3672. 2. SOLIRIS® SmPC: SOLIRIS®(eculizumab) summary of product characteristics. Alexion Europe SAS 2007.
Patient (n)
187/149 173 171 171 68 21 10 0
500 1000 1500 2000 2500
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5
L a c ta te D e h y d ro g e n a s e , U /L
Study Year
*
* * * * *
*P<0.001
†
P=0.002
†
39
3 0
10 20 30 40
5
0 0
10 20 30 40
Reduction in Thrombotic events was observed During SOLIRIS
Non of TE was reported during Soliris treatment in AEGIS
T h ro m b o ti c e v e n ts Pre-SOLIRIS
®treatment SOLIRIS
®treatment
AEGIS (N=29)
Multinational SOLIRIS ® (N=195)
P<0.001
Pre-SOLIRIS
®treatment SOLIRIS
®treatment
1.Kanakura Y et al. Int J Hematol. 2011;93:36-46.
2.
Hillmen P, et al, Blood. 2007;110:4123-412848
Soliris Reduced Thrombosis in Patients Treated with Anticoagulants 1
94% reduction in event rate with SOLIRIS
11.54
0.72 0
2 4 6 8 10 12
Pre-SOLIRIS™ Treatment SOLIRIS Treatment T h ro m b o s is E v e n t R a te (T E p e r 1 0 0 p a ti e n t- y e a rs )
(n=91) P<0.001
*excludes patients on antiplatelet agents
Renal Function with SOLIRIS ® in Different Baseline Populations – 18 Months
60.2
30.1
71.4
34.3
67.1
22.9
5.4 2.7 5.7
0 10 20 30 40 50 60 70 80
Segment of PNH Population
P ro p o rt io n o f P a ti e n ts ( % )
P<0.001 P<0.001 P=0.05
Overall (n=166)
Stage 1 – 2 (n=73)
Stage 3 - 5 (n=35)
Hillmen P et al. Am. J. Hematol. 2010; 85:553–559
No Change Improvement Worsening
50
TRIUMPH Demonstrated that Improvement in Fatigue Occurred Independent of Hemoglobin Response
FACIT = Functional Assessment of Chronic Illness Therapy.
1. Adapted from: Hillmen P et al. NEJM. 2006;355:1233-1243. 2. Brodsky R et al. Blood Rev. 2008;22:65-74. 3. Hill A et al. Haematologica. 2008;93 (Suppl 1):359. Abstract 0904. 4. Brodsky R et al. Blood. 2008;111:1840-1847.
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Time, Weeks 9.0
9.5 10.0 10.5 11.0 11.5 12.0
H e m o g lo b in , g /d L
8.5
C h a n g e f ro m B a s e li n e F A C IT -F a ti g u e S c o re -6
-4 -2 0 2 4 6 8 FACIT-Fatigue Score
FACIT-Fatigue Score Hgb Level P<0.001
≥3 or more points denotes a clinically significant improvement
Soliris (n=43) Patients not on Soliris (n=44) Soliris Hgb
In SHEPHERD, 78% patients reported a significant improvement in fatigue
1Never Transfused PNH Patients Experienced Significant Clinical Benefit with SOLIRIS ®
Measure Pre-SOLIRIS ®
Treatment
During SOLIRIS ®
Treatment (a) P-value LDH (median U/L)
(n=27) 1,603 380 < 0.001
TE events (b)
(n=36) 11 0 NA
TE Event-Free survival at 3 years
(n = 36) 68% 100% 0.01
Impaired Quality of Life
(n = 11) 91% 0% NA
In AEGIS, never transfused PNH patients experienced reduced hemolysis (LDH), improvement in fatigue and dyspnea and no TE events.
1. Hillmen P, et al, N Engl J Med. 2006;355:1233-1243 2. Brodsky RA, st al. Blood. 2008; 111: 2840-1847 3. Kanakura Y et al. Int J Hematol. 2011;93:36-46.
(a) Period of SOLIRIS®treatment:1.2year (median、n=41) (b) TE events reported as present or absent prior and during SOLIRIS®treatment.
52
Soliris has a Major Impact on Survival in PNH
96% (76/79) patient survival
There was no difference in mortality between patients on Soliris and the normal population (P=0.46)
N=79 P=0.46
During Soliris treatment Age- and gender-matched healthy UK population
C u m u la ti v e S u rv iv in g ( % )
100
80
60
40
20
0
Time (years)
0 1 2 3 4 5 6 7 8 9
Kelly RJ et al. Blood. 2011;117:6786-6792.
Improved Overall Survival in Patients Treated With Soliris
*Pre-Soliris patients 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;117:6786-6792.
C u m u la ti v e S u rv iv in g ( % )
100
80
60
40
20
0
Time (years)
0 1 2 3 4 5 6 7 8 9
During Soliris treatment, N=79 Untreated, n=30
X²=6.46 P=0.01 ‡
Five-year survival rate for patients treated with Soliris was significantly better than PNH patients pre-Soliris* (95% vs 66.8%)
Median age at diagnosis was 37 years (range: 12 years to
79 years); median age at initiation of Soliris was 46 years (range:
14 to 84 years). Mean treatment period with Soliris was 39 months (range: 1 to 98 months).
54
Consistent Result between Asian and Western studies.
55
Asian 8 (%) Western 1-7 (%) In clinical trials, Soliris significantly reduced hemolysis the underlying cause of morbidity and mortality in PNH
Reduction in Thrombotic events 100% 92%
Reduction in Hemolysis
(measured by LDH) 87% 86%
Reduction in Mean Number
of Units Transfused 71% 73%
Either improved or maintained
CKD stages 97% 92%
Reduction of Pulmonary
Hypertension - 50%
8 year Survival Rate - 96%
1. Soliris® (eculizumab) Summary of Product Characteristics. Alexion Europe SAS; 2012. 2. Kelly RJ et al. Blood. 2011;117:6786-6792. 3. Hillmen P et al.
Blood. 2007;110(12):4123-4128. 4. Hillmen P et al. Am J Hematol. 2010;85:553-559. 5. Hill A et al. Br J Haematol. 2010; May;149(3):414-425. 6. Socie G et al.
Blood. 2007;110(11):Abstract 3672. 7. Hillmen P et al. N Engl J Med. 2006;355:1233-1243. 8. Kanakura Y et al. Int J Hematol. 2011;93:36-46.
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;355:1233-43. 56
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 2007.
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 2007. 58
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 2007.
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C O N S H E M Q 1
Voting: PNH의
의의의 신약인신약인신약인신약인 Eculizumab 사용은사용은사용은사용은 어떤어떤어떤어떤infection이
이이이 문제가문제가문제가 될문제가 될될 수될 수수 있어수 있어있어 사용있어 사용사용사용 전전전전vaccination이
이이이 필요한가필요한가필요한가필요한가?1. Pneumococcus 2. HIV
3. Meningococcus
4. Pseudomonas
5. Aspergillosis
Key Result: Efficacy of Soliris
1) 85% Reduction in the degree of hemolysis 2) Reduction in transfusion requirement
Soliris in Korean PNH Patients
3) Improvement of clinical symptoms: The FACIT-Fatigue scores improved by a median of 8 points during the first 24 weeks of Soliris therapy.
Kim JS et al. Korean J Hematol. 2010 Dec;45(4):269-74
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 hemolysis and one or more of the clinical symptoms poses a much greater risk of a TE than any of the individual factors alone.
62
SUMMARY
LDH, TE, IRF, Abd. pain, Chest pain and dyspnea in PNH have a significantly increased mortality rate over the age and gender matched general population.
• Soliris has 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
Proposed guideline for PNH Management
LDH Fold ≥1.5 ; Hemolysis
PNH diagnosis confirmed via Flow cytometry ; Clone size ≥10%
Finding an evidence of TE
Effective PNH treatment option is required in high risk patients
Asking Clinical Symptoms
If experienced abdominal pain or Chest pain or Dyspnea Monitoring Renal function
(Cr or eGFR)
Full Clinical Assessment is critical
R is k fa ct o rs o f T E & M o rt a li ty
Regardless clone size
64