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(1)

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

(2)

Contents

1. Disease Overview

2. Risk Factors of Thrombosis & Mortality 3. PNH Treatment

4. Soliris Treatment in Korea

2

(3)

PNH : Disease Overview

(4)

4 CONS HEM Q1 2011Gbl

(5)

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.

(6)

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

(7)

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)

8 CONS HEM Q1 2011Gbl

Voting: PNH의

의의의 Pathophysiology에에에 관여하는에 관여하는관여하는관여하는 것것

것것은은은은?

1.CD 34

2.CD 14

3.CD 59

4.CD 3

5.CD 10

(9)

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

(10)

Biologic Effects of Complement Activation

10

(11)

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 +

(12)

Electron Micrograph of TCC (MAC)

12

(13)

CONS HEM Q1 2011Gbl

Voting: PNH의

의의의 Pathophysiology에에에 관여하는에 관여하는관여하는관여하는 것것

것것은은은은?

1.Complement system 2.Coagulation system 3. Apoptosis

4. Phagocytosis

5. Immune mediated hemolysis

(14)

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

(15)

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↓

(16)

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

(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

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.

(18)

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

(19)

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)

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

(21)

Risk Factors of Thrombosis and Mortality

in Korean Population

(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) 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

(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

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

(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:

• 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

(25)

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

2

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)

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

(27)

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

(28)

• 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

2

Multivariate 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

(29)

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

(30)

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

(31)

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)

32

PNH Treatment

(33)

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

3

(34)

Treatment : 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

(35)

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)

36

(37)

Treatment of PNH

Bone marrow (stem cell) transplant

Complement Inhibition therapy

: Eculizumab (Soliris®)

(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

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

(39)

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%

(40)

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

(41)

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)

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

(43)

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)

44

C O N S H E M Q 1

Voting: PNH의

의의의 신약인신약인신약인신약인 Eculizumab이이이이 block 하는하는하는하는 곳은

곳은곳은

곳은 complement system의의의의 어느어느어느 곳인가어느 곳인가곳인가?곳인가

1. Complement terminal complex 2. C3

3. C9

4. C5

5. C2

(45)

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

(46)

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

1

TRIUMPH – Soliris / Extension

1

SHEPHERD – Soliris

1

AEGIS

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

(47)

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

(48)

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;110:4123-4128

48

(49)

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

(50)

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

(51)

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

1

(52)

Never 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

(53)

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.

(54)

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

(55)

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.

(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;355:1233-43. 56

(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 2007.

(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 2007. 58

(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 2007.

(60)

60

C O N S H E M Q 1

Voting: PNH의

의의의 신약인신약인신약인신약인 Eculizumab 사용은사용은사용은사용은 어떤어떤어떤어떤

infection이

이이이 문제가문제가문제가 될문제가 될될 수될 수수 있어수 있어있어 사용있어 사용사용사용 전전전전

vaccination이

이이이 필요한가필요한가필요한가필요한가?

1. Pneumococcus 2. HIV

3. Meningococcus

4. Pseudomonas

5. Aspergillosis

(61)

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

(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 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

(63)

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

(64)

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

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