Slide # 1

PNH: Complications and PNH: Complications and

LongLong--Term IssuesTerm Issues

Carlos M. de Castro, MD

Duke University Medical Center

October 2012

AA&MDSIF Conference

PNH: PNH: ComlicationsComlications and and

LongLong--Term IssuesTerm Issues

What happens to PNH patients?

What are the long-term complications of PNH and can they be

prevented?

– Thrombosis (blood clots)

– Renal failure

– Pulmonary Hypertension

– Development of aplastic anemia, myelodysplastic syndrome, or AML

Long term complications of therapy

What are some special situations for PNH patients?

– Pregnancy

– Surgery

– Vaccinations

What is PNH and what is the long term outlook?

Slide # 2

Paroxysmal Nocturnal Paroxysmal Nocturnal HemoglobinuriaHemoglobinuria::

Long term outcomesLong term outcomes

100100

8080

6060

4040

2020

00

00 55 1010 1515 2020 2525

Years After DiagnosisYears After Diagnosis

Pati

en

ts S

urv

ivin

g (

%)

Pati

en

ts S

urv

ivin

g (

%)

Actuarial Survival From the Time ofActuarial Survival From the Time of

Diagnosis in 80 Patients With PNH Diagnosis in 80 Patients With PNH (1)(1)

AgeAge-- and sexand sex--

matched controlsmatched controls

Patients with PNHPatients with PNH

(1) Hillmen P et al. NEJM 1995; 333:1253-8;

Paroxysmal Nocturnal Hemoglobinuria:Paroxysmal Nocturnal Hemoglobinuria:

Long term outcomesLong term outcomes

Kaplan-Meier Survival Curve of patients with PNH from Duke University (n=173). Average survival was 19.4 years.

Nishimura et al Medicine 83: 193-207, 2004.

PNH – What do patients die from?

Cause of death Duke Japan

Thrombosis 16 (42%) 3 (8%)

Abd site 8 1

Other site 7 0

Arterial 3 2

Hemorrhage 4 (10.5%) 9 (24%)

Severe Infection 14 (36.5%) 14 (36.8%)

MDS/AML 3 (8%) 6 (16%)

Renal failure 3 (8%) 7 (18%)

Other malignancy 2 (5%) 2 (5%)

Unknown 2 (5%) 0

Nishimura et al Medicine 83: 193-207, 2004.

Slide # 3

PNH & Thrombosis

8

PNH & Thrombosis – How do you know if you have a blood clot?

• Symptoms can be quite variable – intense pain, swelling,

shortness of breath, headaches.

• Diagnosis is based on laboratory tests and imaging

studies.

• Ultrasound

• MRI/MR(V or A).

• Blood clots can be life threatening. They require

immediate medical attention.

Thrombosis in PNH

• Recognized early as a problem

• Occurs in ~40% of European-descended populations

– less in East Asian populations

• Is the worst prognostic indicator

• Is the leading cause of death

• Once a thrombosis occurs, no clear evidence that any

anticoagulant will prevent further clots

Slide # 4

Relationship of PNH Clone Size and Relationship of PNH Clone Size and

Thromboembolic EventsThromboembolic Events

PNH Granulocyte Clone Size (%)

% T

E

Lee JW et al. Hematologica. 2010. 95 (s2): Abstract #505.

South Korean National Registry

Incidence of symptoms or complications of PNH

Correlation with clone size

International PNH Registry data – 524 patients

Urbano-Ispizua A, et al. EHA meeting 2010. Haematologica 95(s2): Abstract 1022

Mesenteric / splenic

18%

Hepatic / portal

16%

PE

7%

Cerebral

6%

Superficial

4%

Arterial / CVA

14%

Arterial / MI

2% DVT: leg

18%

DVT: other

15%

Thrombosis in PNH

CVA, cerebrovascular accident; DVT, deep vein thrombosis; MI, myocardial infarction

Slide # 5

Peculiarities of thrombosis in PNH

• Incidence may be much higher

– small, undetectable thromboses

– D-dimer data

• Once established, tends to recur and continue

– inexorable course of hepatic vein thrombosis

• Incidence lower in East Asian populations

– includes Mexican population

• Role of surgery and pregnancy in initiating thrombosis

• Other risk factors include prolonged immobility, oral contraceptives,

inherited thrombophilia.

Possible causes of thrombosis in PNH

Platelet activation by complement

Role for nitric oxide on platelets and endothelium

ADP release by hemolyzed RBC’s

Reduced expression of urokinase plasminogen activator

receptor

Increased circulating microparticles from lysed RBC’s

How to manage thrombosis in PNHHow to manage thrombosis in PNH

Role of Role of coumadincoumadin prophylaxis to prevent clots remains prophylaxis to prevent clots remains

controversial.controversial.

Patients presenting with an acute clot should undergo Patients presenting with an acute clot should undergo

treatment with a clottreatment with a clot--busting drug busting drug –– TPA, TPA, urokinaseurokinase

Patients should then be on anticoagulant therapy Patients should then be on anticoagulant therapy

((coumadincoumadin, , lovenoxlovenox, , etcetc). ).

Duration Duration -- Probably for their lifetime.Probably for their lifetime.

Patients with a thrombotic event should start Patients with a thrombotic event should start eculizumabeculizumab..

Whether one can stop anticoagulation once Whether one can stop anticoagulation once eculizumabeculizumab is is

started has not been well studied.started has not been well studied.

A bone marrow transplant can be considered.A bone marrow transplant can be considered. 15

Slide # 6

What is the impact of eculizumab

on thrombosis?

• Equalized patient-years

• 92% fewer thrombotic events post eculizumab vs pre eculizumab

39

3

0

10

20

30

40

50

Pre-eculizumab

treatment

Eculizumab

treatment

P=0.0001

Thro

mbo

tic e

ve

nts

(n)

Hillmen P et al. Blood 2007; 110: 4123-4128

Effect of eculizumab on thromboembolic

event rate: concomitant antithrombotics

• Pre-eculizumab event rate elevated despite use of antithrombotics

• 91% reduction in event rate with eculizumab

10.61

0.62

0

2

4

6

8

10

12

Pre-eculizumab

treatment

Eculizumab treatment

P<0.0000000001

Thro

mbo

sis

eve

nt

rate

(pe

r 1

00

pa

tie

nt-

ye

ars

)

(n=103)

Hillmen P et al. Blood 2007; 110: 4123-4128

Will Eculizumab affect survival by lowering

the incidence of thrombosis?

We certainly hope so.

Data from recent meetings is encouraging.

Please enroll in the International PNH registry.

Slide # 7

PNH – Renal Failure

Renal Damage in PNH: BackgroundRenal Damage in PNH: Background

Renal failure has been identified as Renal failure has been identified as

the cause of death in approximately the cause of death in approximately

8 8 –– 18% of PNH patients18% of PNH patients1,21,2

68% have a significant reduction in 68% have a significant reduction in

creatininecreatinine clearanceclearance33

64% of patients with PNH have 64% of patients with PNH have

chronic kidney diseasechronic kidney disease22

Historically underappreciated in PNHHistorically underappreciated in PNH

1. Nishimura JI, et al. Medicine. 2004;83:193-207. 2. Hillmen P et al. Am. J. Hematol. 2010; 85:553–559. 3. Rother RP, et al. JAMA. 2005;293:1653-1662

Renal Damage in PNH: BackgroundRenal Damage in PNH: Background

Chronic haemolysis and cellChronic haemolysis and cell--free plasma haemoglobin lead to free plasma haemoglobin lead to

several serious clinical sequelae in PNHseveral serious clinical sequelae in PNH11––33

Evidence of renal damage is highly prevalent in patients with Evidence of renal damage is highly prevalent in patients with

PNHPNH55––99

May be acute renal failure, which is frequently reversibleMay be acute renal failure, which is frequently reversible44

Associated with haemolysis and/or microvascular thrombosisAssociated with haemolysis and/or microvascular thrombosis2,42,4

Renal damage in PNH may be due to repetitive exposure of Renal damage in PNH may be due to repetitive exposure of

tissue to celltissue to cell--free haemoglobinfree haemoglobin99

1. Parker C et al. Blood 2005; 106:3699-709.; 2. Brodsky RA. Hematology: Basic Principles and Practice. Churchill Livingstone; 2005:419-27.; 3. Rother RP et al. JAMA 2005;293:1653-62.; 4. Clark DA et al. Blood 1981;57:83-9.; 5. Hill A et al. Presented at the 48th ASH Annual Meeting, Dec 9, 2006.; 6. Mulopulos GP

et al. Am J Roentgenol 1986;146:51-2.; 7. Rimola J et al. Br J Radiol 2004;77:953-6.; 8. Tanaka YO et al. J Comput Assist Tomogr 1993;17:749-53; 9. Nishimura J et al. Medicine 2004;83:193-207.

Slide # 8

0 5 10 30 40 20

100

90

80

70

60

50

40

30

20

0

10

Time to Major Clinical Kidney Event Time to Major Clinical Kidney Event

Prior to Prior to EculizumabEculizumab Treatment Treatment

Pro

bab

ilit

y (

%)

of

Main

tain

ing

No

rmal

Kid

ney F

un

cti

on

Time Since PNH Diagnosis (years)

n 195 103 60 21 4

Kaplan-Meier probability of patients progressing to an MCK event.

Hillmen P et al. Am. J. Hematol. 2010; 85:553–559.

Normal

tissue

on the right

Interstitial

scarring

on the left

Clark DA et al. Blood 1981; 57: 83-89

Renal pathology in PNH

Micrograph of a renal biopsy from a PNH patient,

indicative of vascular damage

Chronic Kidney Disease Staging Identifies Chronic Kidney Disease Staging Identifies

Both Function and DamageBoth Function and Damage

Stage GFR

(ml/minute/1.73 m2)

Objective Measure of Kidney Damage

Description Action*

1 ≥ 90 Evidence of proteinuria

Kidney damage with normal GFR

Diagnose and treat

Treat comorbid conditions;

Slow progression;

CVD risk reduction

2 60-89 Evidence of proteinuria

Kidney damage with mild decreased GFR

Estimate progression

3 30-59 No additional evidence necessary

Moderately decreased GFR

Evaluate and treat complications

4 15-29 No additional evidence necessary

Severely decreased GFR

Prep for kidney replacement therapy; Predialysis

5 < 15 (or dialysis) No additional evidence necessary

Kidney Failure Replacement (if uraemia present); Dialysis

Chronic Kidney Disease (CKD) Stages 1-5

*Includes actions from preceding stages. Levey AS et al. Ann Intern Med. 2003;129:137-147.

Slide # 9

64% of Patients Exhibit stage 164% of Patients Exhibit stage 1--5 CKD5 CKD

Among the 22 patients with minimal (0Among the 22 patients with minimal (0--1) transfusion history, 59% exhibited CKD 1) transfusion history, 59% exhibited CKD

Hillmen et al. Long term effect of the complement inhibitor eculizumab on kidney function in patients with paroxysmal nocturnal Hemoglobinuria. Am J Hematol 85:553-559, 2010.

Kidney Function

Stage 3 - 5 CKD

(n=40)

Stage 1 - 2 CKD

(n=84)

No CKD

(n=69)

20.5%

43.1%

35.4%

0

10

20

30

40

50

Pro

po

rtio

n o

f P

ati

en

ts (

%)

Renal Function with Eculizumab in Different

Baseline Populations – 12 Months

Hillmen et al. Long term effect of the complement inhibitor eculizumab on kidney function in patients with paroxysmal nocturnal

Hemoglobinuria. Am J Hematol 85:553-559, 2010.

58.1

23.4

76.9

35.2

71.4

20.5

6.7 5.2 2.6

0

10

20

30

40

50

60

70

80

90

Segment of PNH Population

Pro

po

rtio

n o

f P

ati

en

ts (%

)

P<0.001 P=0.02 P<0.001

No Change Improvement Worsening

Overall

(n=179)

Stage 1 – 2

(n=77)

Stage 3 - 5

(n=39)

How to manage renal complicationsHow to manage renal complications

Stay well hydratedStay well hydrated

Control other conditions which may affect the kidneys Control other conditions which may affect the kidneys

(hypertension, diabetes)(hypertension, diabetes)

Avoid drugs which may cause renal problems (Avoid drugs which may cause renal problems (egeg. Non. Non--

steroidal medications such as ibuprofen)steroidal medications such as ibuprofen)

Monitor kidney function at least once per year.Monitor kidney function at least once per year.

Block hemolysisBlock hemolysis

27

Slide # 10

Renal Function in PNH: Conclusions

Changes in renal function are common in PNH (65% of PNH patients;

6.6-fold more common than in the general population)1

Severe CKD is observed in 21% of PNH patients and appears to be

under-diagnosed in this patient population

21% of patients with CKD prior to eculizumab were no longer classified

with CKD during eculizumab treatment

Administration of eculizumab to patients with more mild baseline kidney

disease was associated with the greatest likelihood of improvement and

prevention of worsening in kidney function

Long-term eculizumab treatment resulted in a significant improvement

and prevention of worsening in CKD at all initial stages of renal disease

PNH & Pulmonary Hypertension

Hemolysis-associated pulmonary

hypertension

An important complication in hereditary hemolytic anemias

such as thalassemia, stomatocytosis, and spherocytosis

A common morbidity in sickle cell disease

Linked to intravascular hemolysis, leading to the term

‘hemolysis-associated pulmonary hypertension’ (PHT)

An independent risk factor for death in sickle cell disease

Gladwin MT et al. N Engl J Med 2004; 350: 886-895

Slide # 11

Brain natriuretic peptide

Elevated levels of BNP:

– released from stretched right heart chambers

– reflect cardiac chamber volume and pressure overload

– indicate increased PHT and right ventricular dysfunction

In patients with hemolytic syndrome, NT-proBNP >160 pg/mL:1

– is a highly positive predictive value for diagnosis of PHT

– is an independent predictor of mortality

TRIUMPH study: 47% of PNH patients had baseline levels of

NT-proBNP >160 pg/mL2

Suggestive of PHT

1Machado RF et al. JAMA 2006; 296: 310-318; 2Hillmen P et al. N Engl J Med 2006; 355: 1233-1243 BNP, brain natriuretic peptide

Change in BNP during eculizumab

treatment

PHT with NT-proBNP ≥160 pg/mL1

Eculizumab vs placebo (P<0.001)

50% reduction

14% increase

Baseline Baseline Week 26 Week 26

52.5

39.4

26.3

43.8

0

10

20

30

40

50

60

Placebo Eculizumab

Treatment group: TRIUMPH (n=73)

Pro

po

rtio

n o

f p

ati

en

ts

wit

h e

vid

en

ce o

f P

HT

Hill A et al. British J Haematol 149: 414-425, 2010

Pulmonary Hypertension - Summary

PHT is a serious and life-threatening complication of hemolytic

disorders

PHT and PNH symptoms are common in patients with hemolytic PNH

PHT may be under-diagnosed clinically in patients with PNH

Hemoglobinemia, NO consumption, and disruption of vasomotor tone

contribute to PHT in patients with PNH

Eculizumab treatment significantly reduces PHT, as measured by BNP,

and PHT-related symptoms in patients with PNH

Eculizumab treatment dramatically reduces hemolysis,

hemoglobinemia, and NO consumption in patients with PNH

Slide # 12

PNH – development of AA or MDS

Sir John V. Dacie (1911 - 2005)

Lewis SM, Dacie JV. The aplastic anemia-paroxysmal nocturnal

hemoglobinuria syndrome. Br J Haematol 13:236, 1967.

William Dameshek 1900-1962

Dameshek W. Riddle:What do aplastic anemia, paroxysmal nocturnal hemoglobinuria

(PNH), and “hypoplastic” leukemia have in common? Blood 30:251, 1967

Slide # 13

PNH – Aplastic anemia and MDS/leukemia

A fairly sizable proportion of patients with aplastic anemia

may later develop PNH (20-40%).

Patients with PNH may often have bone marrow failure and

some will develop aplastic anemia.

Patients with PNH may develop myelodysplastic syndrome

and or acute myelogenous leukemia (<5%).

Patients with MDS may have a small PNH clone present

and these patients may respond better to

immunosuppressive therapy with ATG and/or cyclosporine.

Models of pathogenesis

Norma l Aplastic PNH MDS

Marrow Anemia_________________________

Immune Assault

Immune Assault

PNH (hemolysis)

PNH (hypoplasia)

Stromal cell Dysregulation, Immune

Assault

Treatment of AA or MDS/AMLTreatment of AA or MDS/AML

Aplastic anemia when severe enough is treated with either Aplastic anemia when severe enough is treated with either

immunosuppressive therapy (ATG, cyclosporine) or with a immunosuppressive therapy (ATG, cyclosporine) or with a

stem cell transplant.stem cell transplant.

MyelodysplasticMyelodysplastic syndrome has multiple different therapies syndrome has multiple different therapies

depending on the severity.depending on the severity.

AML is treated with chemotherapy and/or stem cell AML is treated with chemotherapy and/or stem cell

transplant.transplant.

39

Slide # 14

Complications of PNH Therapy

Complications of PNH Therapy

Eculizumab

– Neisseria infection

– Cost and convenience

– Extravascular hemolysis

ATG/Cyclosporine

– Hospitalization

– Anaphylactic reactions

– Serum sickness

– Immunosuppression / Infection

Bone marrow transplantation

– Allogeneic bone marrow transplant

– Prolonged hospitalization

– Up to 44% mortality at 2 yrs with HLA-matched

sibling donor

– Acute GVHD in 34%; chronic GVHD in 33%

– GVHD-free survival in 14% of patients

Serious Adverse Events:

Clinical Trial Experience

Meningococcal infections are the most important adverse

events that may be experienced by patients receiving

Eculizumab

In PNH clinical studies, 2 patients experienced

meningococcal sepsis

– Both patients had received a meningococcal vaccine

In clinical studies among patients without PNH,

meningococcal meningitis occurred

in 1 unvaccinated patient

Slide # 15

Special Situations in PNHSpecial Situations in PNH

43

Special Situations in PNHSpecial Situations in PNH

Vaccinations

– May activate complement

– Role for Eculizumab

Surgery

– May activate complement

– May lead to thrombosis

– Role for Eculizumab

Pregnancy

PNH and surgeryPNH and surgery

Slide # 16

PNH and Pregnancy

PNH is a known hypercoagulable state

Pregnancy is a hypercoagulable state

High estrogen levels

Compression of abdominal and pelvic veins by the enlarging uterus

PNH and Pregnancy

23 women: 19 with PNH, 4 with AA/PNH

38 pregnancies

11 miscarriages

Pregnancy: 6 hemolysis, 6 hemorrhage Labor: 5 hemolysis, 3 hemorrhage 1 thrombosis, 1 sepsis

No maternal deaths

Uncomplicated in one-third of pregnancies

De Gramond et al., Lancet 1987;1:868

Women with PNH Effects on Pregnancy (N=33)

Thrombosis: 5 women

2 with previous clots (Budd-Chiari syndrome, pulmonary embolus)

1 during pregnancy (phlebitis)

2 post-partum (hepatic, intracranial)

Hemolysis: 24 pregnancies (73%)

20 required PRBC transfusions

Thrombocytopenia: 9 cases

Obstetrical complications: 4 women

Hypertension, pre-eclampsia, eclampsia

Ray et al., Haemostasis 2000;30:103-117

Slide # 17

Women with PNH Effects on Infants

Perinatal outcomes of 33 pregnancies

45% of the babies were pre-term

Average birthweight 2800g

Three infant deaths

Two had hemolytic disease of the newborn, not related to PNH

No infant thrombosis

Ray et al., Haemostasis 2000;30:103-117

50

27 pregnancies in 22 PNH patients from 10 different medical centers.

PNH and Pregnancy Summary

Pregnancy is possible for women with PNH, with or without aplastic anemia, but is potentially hazardous for mother and infant.

Pregnancy leads to complications in up to 50% of women: worse cytopenia, transfusion dependency, thrombosis, and the need for anticoagulation or immunosuppressants

Pregnancy for women with PNH is risky, and should be planned carefully with an experienced hematologist and high-risk OB.

There is emerging data on the use of Eculizumab in pregnancy.

Slide # 18

Special situations for patients with PNH

Surgery – Singer A et al. Successful Liver Transplantation for Budd-Chiari Syndrome

in a Patient with Paroxysmal Nocturnal Hemoglobinuria Treated with the

Anti-Complement Antibody Eculizumab. Liver Transplant 15: 540-543, 2009.

Pregnancy – Kelly R, et al. The management of pregnancy in paroxysmal nocturnal

haemoglobinuria on long term eculizumab. Br J Haematol 149: 446-450,

2010.

– Danilov AV, et al. Managing a pregnant patient with paroxysmal nocturnal

hemoglobinuria in the era of eculizumab. Leukemia Research 34: 566-571,

2010.

Clinical Impact of Extravascular Haemolysis

Consequences

Increased LDH

Anemia

Fatigue?

Complement-mediated Intravascular Haemolysis

PNH RBC Survival

No Eculizumab Treatment

Eculizumab Treatment

PNH RBC

C3b Deposition, Possible Extravascular

Haemolysis

1. Hill, A et al. Haematologica. 2010; 95:567-573. 2. Risitano, AM. Blood. 2009;113:4094-4100. 3. Hillmen P et al. N Engl J Med. 1995;333:1253-1258.

Consequences

Increased LDH

Anemia

Hemoglobinuria

Nitrous Oxide Squelching

Fatigue

Does Does EculizumabEculizumab improve survival?improve survival?

Slide # 19

PNH PNH –– What do patients die from?What do patients die from?

Cause of death Duke Japan

Thrombosis 16 (42%) 3 (8%)

Abd site 8 1

Other site 7 0

Arterial 3 2

Hemorrhage 4 (10.5%) 9 (24%)

Severe Infection 14 (36.5%) 14 (36.8%)

MDS/AML 3 (8%) 6 (16%)

Renal failure 3 (8%) 7 (18%)

Other malignancy 2 (5%) 2 (5%)

Unknown 2 (5%) 0

Nishimura et al Medicine 83: 193-207, 2004.

PNH Survival PNH Survival –– PrePre--eculizumabeculizumab

100100

8080

6060

4040

2020

00

00 55 1010 1515 2020 2525

Years After Diagnosis

Pati

en

ts S

urv

ivin

g (%

)

Actuarial Survival From the Time of

Diagnosis in 80 Patients With PNH2

AgeAge-- and genderand gender--

matched controlsmatched controls

Patients with PNHPatients with PNH

De Latour RP et al., Blood, 2008;112:3099-3106.

Mortality Rates in PNH: Mortality Rates in PNH:

Data from French Patients Data from French Patients

n 454 211 120 58 22 11 2 1

11

88

66

44

22

00

00 55 1010 2525 3030 4040 1515 2020 3535

Time after diagnosis (years)

O/N* 10-year Survival Rate (SE)

96/454 0.75 (0.03)

Su

rviv

al

Slide # 20

LongLong--term Treatment With term Treatment With EculizumabEculizumab in PNH: in PNH:

Sustained Efficacy and Improved SurvivalSustained Efficacy and Improved Survival

79 consecutive patients with PNH, 79 consecutive patients with PNH,

between May 2002 and July 2010between May 2002 and July 2010

Mortality and disease symptoms were Mortality and disease symptoms were

evaluatedevaluated

Kelly RJ et al. Blood. 117:6786-6792, June 2011

Thrombotic EventsThrombotic Events

Patients (n) 79

Pre-treatment

Thrombotic events (n) 34

Proportion occurring on anticoagulation (%) 47

Patient years (n) 608

Thrombotic event rate (n per 100 patient years)

5.60

Eculizumab Treatment

Thrombotic events (n) 2

Patient years (n) 260

Thrombotic event rate

(n per 100 patient years)

0.8

(P<0.001)

Kelly RJ et al. Blood. 117:6786-6792, June 2011

Eculizumab Has a Major Impact on Survival in PNHEculizumab Has a Major Impact on Survival in PNH

• 96% (76/79) patient survival

• There was no difference in mortality between patients on eculizumab

and the normal population (P=0.46)

Survival is comparable to age and genderSurvival is comparable to age and gender--matched control population out to 8 yearsmatched control population out to 8 years

Cu

mu

lati

ve s

urv

ivin

g (

%)

Time (years)

100100

8080

6060

4040

2020

00

00 11 22 66 77 99 44 55 88 33

n = 79

Age- and sex-matched normal population

Eculizumab treated

Kelly RJ et al. Blood. 117:6786-6792, June 2011

Slide # 21

Mortality in Patients on EculizumabMortality in Patients on Eculizumab

3 Patients Died in the 8 Year Study Period3 Patients Died in the 8 Year Study Period

1.1. 55 year old man died from 55 year old man died from metastaticmetastatic caecalcaecal carcinoma carcinoma

which was diagnosed prior to which was diagnosed prior to eculizumabeculizumab treatmenttreatment

2.2. 76 year old woman died from pneumonia following a long 76 year old woman died from pneumonia following a long

history of recurrent bronchopneumonia prior to starting history of recurrent bronchopneumonia prior to starting

eculizumabeculizumab

3.3. 79 year old man with a preceding history of 79 year old man with a preceding history of ischaemicischaemic

heart disease died from congestive cardiac failureheart disease died from congestive cardiac failure

Kelly RJ et al. Blood. 117:6786-6792, June 2011.

Improved Overall Survival in Patients Improved Overall Survival in Patients

Treated With Treated With EculizumabEculizumab

Time (years)Time (years)

Cu

mu

lati

ve S

urv

ivin

g (%

)

11 22 33 44 55 66 77 88 99

2020

4040

6060

8080

100

00

Kelly RJ et al. Blood. 117:6786-6792, June 2011.

On Eculizumab, n=79

Pre-eculizumab, n=30

Overall survival was 97.6% (95%CI 93.7Overall survival was 97.6% (95%CI 93.7--99.1) at 3 years and was maintained 99.1) at 3 years and was maintained

through 5.5 years of ongoing through 5.5 years of ongoing eculizumabeculizumab treatment (N=195)treatment (N=195)

Patient Survival in the Patient Survival in the EculizumabEculizumab Study PopulationStudy Population

Brodsky R et al. Blood. 2010;116(21) Abstract #4237.

Slide # 22

Where are we going?Where are we going?

Improve current therapyImprove current therapy

–– Oral Oral eculizumabeculizumab

–– Increase treatment intervalsIncrease treatment intervals

Find other ways to inhibit complementFind other ways to inhibit complement

Understand how PNH cells take over the bone marrow Understand how PNH cells take over the bone marrow so we can reverse this process (Restore normal stem so we can reverse this process (Restore normal stem cells)cells)

Gene therapyGene therapy

Stem cell transplantsStem cell transplants

Thank you. Any questions?