paroxysmal nocturnal hemoglobinuria: a chronic, systemic...

1

Conf idential – For Internal Use Only 1

Jack Goldberg, MDJack Goldberg, MD

Clinical Clinical Professor of Professor of MedicineMedicine

ChiefChief, Division of Hematology and Medical , Division of Hematology and Medical

Oncology, Penn Presbyterian Medical CenterOncology, Penn Presbyterian Medical Center

Signs and Symptoms Signs and Symptoms

Predictive of Morbidities and Predictive of Morbidities and

Mortality in PNHMortality in PNH


Paroxysmal Nocturnal Hemoglobinuria:Paroxysmal Nocturnal Hemoglobinuria: A Chronic, Systemic and LifeA Chronic, Systemic and Life--Threatening DiseaseThreatening Disease

Prevalence: 15.9 / millionPrevalence: 15.9 / million11

Diagnosed at all AgesDiagnosed at all Ages

–– Median age early 30’sMedian age early 30’s3,43,4

Progressive diseaseProgressive disease22--44

–– Uncontrolled complement Uncontrolled complement

activation underlies the activation underlies the

morbidities and mortalitymorbidities and mortality

Despite best supportive careDespite best supportive care

–– 5 year mortality: 35%5 year mortality: 35%22

Years After Diagnosis

Pati

en

ts S

urv

ivin

g (

%)

Actuarial Survival From the Time ofActuarial Survival From the Time of

Diagnosis in 80 Patients With PNHDiagnosis in 80 Patients With PNH22

100100

8080

6060

4040

2020

00

00 55 1010 1515 2020 2525

AgeAge-- and Genderand Gender--

Matched ControlsMatched Controls

Patients with PNHPatients with PNH

1. Hill A et al1. Hill A et al. . BloodBlood. 2006;108(11. 2006;108(11):290a):290a. Abstract 985.. Abstract 985. 2. Hillmen P et al. 2. Hillmen P et al. N N EnglEngl J MedJ Med. . 1995;333:12531995;333:1253--12581258. . 3. 3. Nishimura JI, et al. Nishimura JI, et al. MedicineMedicine. .

2004;83:1932004;83:193--207207. . 4. 4. SociéSocié G et al.G et al. LancetLancet. . 1996;348:5731996;348:573--577577. .


Paroxysmal Nocturnal Paroxysmal Nocturnal HemoglobinuriaHemoglobinuria

It’s not It’s not paroxysmalparoxysmal11

–– Even in the absence of symptoms, destructive Even in the absence of symptoms, destructive

progression of hemolysis is ongoing progression of hemolysis is ongoing

It’s not It’s not nocturnalnocturnal11

–– Hemolysis in PNH is subtle and constant, Hemolysis in PNH is subtle and constant,

24 hours a day24 hours a day

HemoglobinuriaHemoglobinuria is a less commonly seen is a less commonly seen

complicationcomplication

–– ¾ patients present without hemoglobinuria¾ patients present without hemoglobinuria2

1. 1. RotherRother, R et al, R et al. . Nature Nature BiotechnologyBiotechnology. 2007;25,11:1256. 2007;25,11:1256--1264. 1264. 22. . International PNH Interest Group. International PNH Interest Group. Blood. Blood. 2005;106:36992005;106:3699--3709.3709.

2


CD55

The Defect in PNHThe Defect in PNH PNH is an acquired hemolytic disorder characterized by the PNH is an acquired hemolytic disorder characterized by the somatic mutation somatic mutation of the PIG A gene of the PIG A gene which prevents all which prevents all GPI GPI

anchored proteins from binding to anchored proteins from binding to the cell surfacethe cell surface11

1. McKeage K. Drugs. 2011;71(17):2327-2345. 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;419-427.

CD59

GPI-anchor

CD55CD55

Prevents formation and augments Prevents formation and augments instability of the C3 instability of the C3 convertasesconvertases, , attenuating the complement cascade attenuating the complement cascade

CD59CD59

Forms a defensive shield for Forms a defensive shield for RBCsRBCs from complementfrom complement--mediated mediated lysislysis

Inhibits the assembly of the Inhibits the assembly of the membrane attack complexmembrane attack complex

5 Conf idential – For Internal Use Only 5

PNH is a Disease of Chronic Complement PNH is a Disease of Chronic Complement DysregulationDysregulation

Leading to Leading to HemolysisHemolysis and Progressive Morbidities and Mortality and Progressive Morbidities and Mortality

Thrombosis

FatigueFatigue

Renal Failure

Abdominal Pain

Dyspnea

DysphagiaDysphagia

HemoglobinuriaHemoglobinuria

Erectile DysfunctionErectile Dysfunction

Significant

Impact on Survival

Significant

Impact on Morbidity

Pulmonary Hypertension

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. 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 Normal red blood cells are

protected from complement protected from complement

attack by a shield of terminal attack by a shield of terminal

complement inhibitorscomplement inhibitors

Without this protective Without this protective

complement inhibitor complement inhibitor

shield, PNH red blood shield, PNH red blood

cells are destroyedcells are destroyed

Intact RBCIntact RBC

ComplementComplement

ActivationActivation

Free Hemoglobin/Free Hemoglobin/AnemiaAnemia

NO↓NO↓


Is the leading cause of deathIs the leading cause of death22

–– Accounts for 40Accounts for 40--67% of deaths67% of deaths11

–– First thrombotic event can be fatalFirst thrombotic event can be fatal1,31,3

–– First TE increases risk for death 5 to 10First TE increases risk for death 5 to 10--foldfold11

Up to 44% of patients experience clinical thrombotic eventsUp to 44% of patients experience clinical thrombotic events11

Occurs in typical and atypical sitesOccurs in typical and atypical sites44

Is not adequately managed with anticoagulationIs not adequately managed with anticoagulation11

All patients with PNH are at risk for thrombosisAll patients with PNH are at risk for thrombosis11

Thrombosis in PNHThrombosis in PNH11

1. Hillmen et al. Blood. 2007;110:4123-4128. 2. International PNH Group et al. Blood. 2005;106(12):3699-3709. 3. Audebert HJ et al. J Neurol. 2005;252:1379-

1386. 4. Lee JW et al. Hematologica 2010;95(s2): Abstract #506.

Chronic Kidney DiseaseChronic Kidney Disease Common Symptoms of PNHCommon Symptoms of PNH ThrombosisThrombosis ThrombosisThrombosis

3


Mechanisms for Thrombosis in PNHMechanisms for Thrombosis in PNH

Multifactorial pathogenesis of thrombosis in PNH:Multifactorial pathogenesis of thrombosis in PNH:

HemolysisHemolysis

–– Reduced nitric oxideReduced nitric oxide11--33

•• Platelet Platelet hyperreactivityhyperreactivity

•• HypercoagulabilityHypercoagulability

–– Prothrombotic membranesProthrombotic membranes22

Impaired fibrinolysisImpaired fibrinolysis1,31,3

Excessive platelet activation from CD59 deficiencyExcessive platelet activation from CD59 deficiency1,31,3

Complement C5a also contributes to increased thrombotic riskComplement C5a also contributes to increased thrombotic risk1,41,4

–– Tissue factor initiated coagulationTissue factor initiated coagulation1,2,41,2,4

1. Hill A et al. Br J Haematol. 2007;137:181-192. 2. Weitz I. Thrombosis Research. 2010;125:S106-S107. 3. Helley D et al. Hematologica. 2010;95(4):574-581.

4. Markiew ski MM et al. Trends Immunology. 2007;28(4):184-192.



6.99

0

2

4

6

8

10

South Korean

Od

ds

Ra

tio

Thrombosis is Associated With Thrombosis is Associated With

Risk of Early MortalityRisk of Early Mortality

TE was a strong predictor of mortality (OR 6.99; 95% CI 3.2TE was a strong predictor of mortality (OR 6.99; 95% CI 3.2--15.2; 15.2; PP<0.0001) <0.0001) in a South Korean PNH registryin a South Korean PNH registry

21% of TE patients presented with a TE prior to PNH diagnosis21% of TE patients presented with a TE prior to PNH diagnosis

TE was an independent prognostic factor related to poor survival (HR 15.4; TE was an independent prognostic factor related to poor survival (HR 15.4; 95% CI 9.395% CI 9.3--25.4; 25.4; PP<0.001) in a large cohort of French PNH patients <0.001) in a large cohort of French PNH patients

TE increases risk of death 7-15 fold over patients with no TE

(N=286) (n=415)

1. Lee JW et al. Hematologica. 2010;95(s2): Abstract #505. 2. de Latour RP et al. Blood. 2008;112(8):3099-3106.

15.40

0

2

4

6

8

10

12

14

16

18

French

Hazard

Rati

o



Thrombosis Thrombosis CCan Occur Regardless of an Occur Regardless of

Clone Clone SSizeize

19%

37%

44%

0%

10%

20%

30%

40%

50%

<20% 20-50 >50

PNH Granulocyte Clone Size (%)

% T

E

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

(n=43)

South Korean National Registry.


4


Common Clinical Symptoms are Common Clinical Symptoms are

Predictive of ThrombosisPredictive of Thrombosis

Lee JW et al. Hematologica. 2010;95(s2): Abstract #505 and 506.

Abdominal Pain Chest Pain Dyspnea Hemoglobinuria0

0.5

1

1.5

2

2.5

3

3.5

4

Od

ds

Ra

tio

Symptoms Predictive of TE in PNH Patients

South Korean National Registry.

(P=0.0004) (P=0.002) (P=0.015) (P=0.046)



Thrombosis in PNH ConclusionsThrombosis in PNH Conclusions

40-67% mortality in PNH results from thrombosis1

– Thrombosis is the leading cause of death in PNH2

– First TE increases risk for death 5 to 10-fold1

DVT or PE most common clinical presentation1

Arterial thromboses are also common1

Anticoagulant therapy may not be adequate to control thrombosis in PNH1

– Anticoagulant therapy also associated with higher risk of fatal hemorrhage in PNH4

Clinical thrombosis evident in PNH patients:1

– Minimal hemolysis

– No transfusion history

– Smaller clone size3

1. Hillmen P et al. Blood. 2007;110:12:4123-4128. 2. International PNH Group et al. Blood. 2005;106(12):3699-3709. 3. Lee JW et al. Hematologica.

2010;95(s2): Abstract #506. 4. Hall C et al. Blood. 2003;102:3587-3591.


12 Conf idential – For Internal Use Only

Chronic Chronic hemolysishemolysis and celland cell--free plasma hemoglobin lead to chronic free plasma hemoglobin lead to chronic

kidney disease in PNHkidney disease in PNH11--44

Repetitive exposure of tissue to cellRepetitive exposure of tissue to cell--free hemoglobin may lead to renal free hemoglobin may lead to renal

damage in PNHdamage in PNH3,43,4

80% of PNH patients (median age of 31.5 years) had MRI evidence of 80% of PNH patients (median age of 31.5 years) had MRI evidence of

significant renal hemosiderosissignificant renal hemosiderosis1,51,5

–– Marked Marked hemosiderinhemosiderin deposits in the proximal renal tubule are a deposits in the proximal renal tubule are a

common feature in all autopsy and biopsy reports dealing with PNHcommon feature in all autopsy and biopsy reports dealing with PNH

–– Demonstrable by MRI even when no overt Demonstrable by MRI even when no overt hemoglobinuriahemoglobinuria

is seenis seen

Autopsy and biopsy often show interstitial nephritis and fibrosisAutopsy and biopsy often show interstitial nephritis and fibrosis3,43,4

Kidney Pathology in PNHKidney Pathology in PNH

1. Brodsky R. 1. Brodsky R. Hematology: Basic Principles and PracticeHematology: Basic Principles and Practice. Churchill Livingstone; 2005:419. Churchill Livingstone; 2005:419--427. 2. 427. 2. RotherRother R et al. R et al. JAMAJAMA. 2005;293:1653. 2005;293:1653--1662. 3. Clark DA et al. 1662. 3. Clark DA et al.

BloodBlood. 1981;57(1):83. 1981;57(1):83--89. 4. 89. 4. HillmenHillmen P et al. P et al. Am J Am J HematolHematol. 2010; 85:553. 2010; 85:553--559559.. 5. Hill A et al. 5. Hill A et al. BloodBlood. 2006;108:Abstract 979. . 2006;108:Abstract 979.

Chronic Kidney DiseaseChronic Kidney Disease Chronic Kidney DiseaseChronic Kidney Disease Common Symptoms of PNHCommon Symptoms of PNH ThrombosisThrombosis

5


Kidney failure is the cause of 8Kidney failure is the cause of 8--18% of PNH18% of PNH--related related deathsdeaths11

Kidney disease in PNH is caused by hemolysisKidney disease in PNH is caused by hemolysis22

64% of patients with PNH exhibit chronic kidney disease 64% of patients with PNH exhibit chronic kidney disease

at any one timeat any one time33

Late stage renal impairment in PNH is predictive of Late stage renal impairment in PNH is predictive of

mortalitymortality44

Kidney disease is underappreciated in PNHKidney disease is underappreciated in PNH33

Kidney Disease in PNH ConclusionsKidney Disease in PNH Conclusions

1. Nishimura JI et al. 1. Nishimura JI et al. MedicineMedicine. 2004;83:193. 2004;83:193--207. 207. 2. Clark DA et al. 2. Clark DA et al. Blood.Blood. 1981 Jan;57(1):831981 Jan;57(1):83--89. 3. 89. 3. HillmenHillmen P et al. P et al. Am J Am J HematolHematol. 2010;85:553. 2010;85:553--559559. .

44. . Kim JSKim JS et al. et al. HematologicaHematologica. 2011;96(S2): Abstract #271. 2011;96(S2): Abstract #271..

Chronic Kidney DiseaseChronic Kidney Disease Chronic Kidney DiseaseChronic Kidney Disease Common Symptoms of PNHCommon Symptoms of PNH ThrombosisThrombosis


Common Symptoms Have a Significant Impact Common Symptoms Have a Significant Impact

on Quality of Lifeon Quality of Life

57

66

4147

96

0

20

40

60

80

100

Abdominal Pain

Shortness of Breath*

Dysphagia Erectile Dyfunction

Fatigue

% o

f P

ati

en

ts

*Moderate to severe; N=29. Meyers G et al. Blood. 2007;110(11): Abstract 3683.

~75% of Patients Reported Symptoms as Moderate to Very Severe~75% of Patients Reported Symptoms as Moderate to Very Severe

Chronic Kidney DiseaseChronic Kidney Disease Common Symptoms of PNHCommon Symptoms of PNH Common Symptoms of PNHCommon Symptoms of PNH ThrombosisThrombosis

59% patients were transfusion59% patients were transfusion--free for at least 12 months or had never been transfusedfree for at least 12 months or had never been transfused

76% were forced to modify their daily activities to manage their PNH76% were forced to modify their daily activities to manage their PNH

17% were unemployed due to PNH 17% were unemployed due to PNH


Soliris is the First and Only Soliris is the First and Only

Approved Therapy for PNHApproved Therapy for PNH

Soliris is a Complement Inhibitor Soliris is a Complement Inhibitor

Indicated for the Treatment of Patients With Indicated for the Treatment of Patients With

PNH to Reduce HemolysisPNH to Reduce Hemolysis

SolirisSoliris®® (eculizumab)(eculizumab)

SolirisSoliris®® ((eculizumabeculizumab) [package insert]. ) [package insert]. AlexionAlexion Pharmaceuticals; 2011.Pharmaceuticals; 2011.

6


Soliris Humanized Soliris Humanized

First in Class Anti First in Class Anti -- C5 AntibodyC5 Antibody

Rother R et al. Rother R et al. Nat BiotechNat Biotech. 2007;25:1256.. 2007;25:1256.

Hinge Hinge

CH

3

CH

2

Human IgGHuman IgG44 Heavy ChainHeavy Chain Constant Regions 2 and 3Constant Regions 2 and 3

(Eliminates complement activation)(Eliminates complement activation)

Complementarity Determining RegionsComplementarity Determining Regions

(murine origin)(murine origin)

Human Framework RegionsHuman Framework Regions No mutationsNo mutations GermlineGermline

Human IgGHuman IgG22 Heavy ChainHeavy Chain Constant Region 1 and HingeConstant Region 1 and Hinge

(Eliminates Fc receptor binding)(Eliminates Fc receptor binding)


Soliris Blocks Terminal ComplementSoliris Blocks Terminal Complement1,21,2

C5C5

Pro

xim

al

Term

inal

1. Soliris® (eculizumab) [package insert; 2011. 2. Rother RP et al. Nature Biotech. 2007;25(11):1256-1264.

3. Walport MJ. N Engl J Med. 2001;344(14):1058-1066. 4. Figueroa JE, Densen P. Clin Microbiol Rev. 1991;4(3):359-395.

C5aC5a

Soliris Soliris

Proximal functions of

complement remain intact1,2

• Weak anaphylatoxin2,4

• Immune complex clearance2

• Microbial opsonization2

Terminal complement - C5a

and C5b-9 activity blocked1,2

Soliris binds with high affinity

to C51,2

Complement CascadeComplement Cascade2,32,3

C5bC5b--99 C5bC5b

C3C3 C3aC3a

C3bC3b


LongLong--TermTerm Extension Trial Extension Trial HillmenHillmen BloodBlood. 2007. 2007

Evaluated long-term safety, efficacy and

effect on thrombosis; Placebo patients

switched to Soliris

N = 187

Pilot Pilot StudyStudy –– HillmenHillmen et al. NEJMet al. NEJM, 2004, 2004 N = 11N = 11

TRIUMPHTRIUMPH –– HillmenHillmen et al. NEJM, et al. NEJM, 2006 2006 Pivotal Phase III, DoublePivotal Phase III, Double--Blind, PlaceboBlind, Placebo--Controlled Controlled

Trial, N = 87Trial, N = 87

SHEPHERDSHEPHERD –– Brodsky Brodsky et al.et al. BloodBlood. 2008. 2008 Broader patient population, including those receiving Broader patient population, including those receiving

minimal transfusions or with thrombocytopenia, minimal transfusions or with thrombocytopenia,

N = 97N = 97

SolirisSoliris Experience in PNH Clinical Trials Experience in PNH Clinical Trials

195 Patients 195 Patients With With

>250 >250 Patient Patient Years of Years of

SolirisSoliris ExposureExposure

7


Time, Weeks

0 4 8 12 16 20 24 28 32 36 40 44 48 52

86% Reduction in LDH:86% Reduction in LDH:

TRIUMPH and SHEPHERDTRIUMPH and SHEPHERD

PP<0.001 at all measured time points.<0.001 at all measured time points. Hillmen P et al. Hillmen P et al. BloodBlood. 2007;110(12):. 2007;110(12):41234123--41284128..

TRIUMPH placebo patients switched to Soliris after Week 26

All TRIUMPH patients entered the long-term extension study

TRIUMPH – Placebo/Extension

TRIUMPH – Soliris/Extension

SHEPHERD – Soliris

Lacta

te D

eh

yd

rog

en

ase (U

/L)

0

500

1000

1500

2000

2500

3000

100% response after the

first dose


92% Reduction in Thrombotic Events92% Reduction in Thrombotic Events

63% of patients received concomitant anticoagulants63% of patients received concomitant anticoagulants11

The effect of anticoagulant withdrawal was not studiedThe effect of anticoagulant withdrawal was not studied22

Events observed in both venous and arterial sitesEvents observed in both venous and arterial sites33

There were fewer thrombotic events with There were fewer thrombotic events with SolirisSoliris treatment than treatment than during the same period of time prior to treatmentduring the same period of time prior to treatment22

1. Brodsky R et al. 1. Brodsky R et al. BloodBlood. 2008;111(4):1840. 2008;111(4):1840--1847. 2. 1847. 2. SolirisSoliris®® ((eculizumabeculizumab) [package insert]. ) [package insert]. AlexionAlexion Pharmaceuticals; 2011. 3. Pharmaceuticals; 2011. 3. HillmenHillmen P, et al. P, et al. BloodBlood. .

2007;110:41232007;110:4123--4128. 4128.

39

3

0

5

10

15

20

25

30

35

40

45

Pre-Soliris Treatment Soliris Treatment

Th

rom

bo

tic E

vents

(#)

P=0.0001

N=195


Soliris Treatment Results in Soliris Treatment Results in

Large and Clinically Meaningful Improvements in Large and Clinically Meaningful Improvements in

PatientPatient--Reported OutcomesReported Outcomes

1. Brodsky R et al. 1. Brodsky R et al. BloodBlood. 2006;108(11): Abstract 3770. 2. Data on f ile. . 2006;108(11): Abstract 3770. 2. Data on f ile. AlexionAlexion Pharmaceuticals.Pharmaceuticals.

Moderate Moderate

Clinical Clinical

ImpactImpact

Small Small

Clinical Clinical

ImpactImpact

Large Large

Clinical Clinical

ImpactImpact

Sta

nd

ard

Eff

ect

Siz

e (

SE

S)

Sta

nd

ard

Eff

ect

Siz

e (

SE

S)

Dyspnea*Dyspnea*

00

0.20.2

0.40.4

0.60.6

0.80.8

11

1.21.2

EORTC Fatigue*EORTC Fatigue* FACITFACIT--Fatigue*Fatigue* PainPain††

((PP=0.002)=0.002) ((PP<0.001)<0.001) ((PP<0.001)<0.001) ((PP<0.001)<0.001)

1.13 1.12

0.69 0.65

8


Uncontrolled

Complement

Activation

Increased Increased

MortalityMortality

Increased Increased

MortalityMortality

TETE

RenalRenal

GastrointestinalGastrointestinal PulmonaryPulmonary

CardiacCardiac

HepaticHepatic

TETE

RenalRenal


CardiacCardiac

HepaticHepatic

End Organ Damage Hemolysis

ComplicationsComplications

Associated Associated

With ElevatedWith Elevated HemolysisHemolysis

(LDH)(LDH)




(LDH)(LDH)

Poor Outcomes

What is the Impact of LongWhat is the Impact of Long--term term SolirisSoliris

Treatment on Clinical Outcomes and Survival?Treatment on Clinical Outcomes and Survival?

Decreased Decreased

MortalityMortality

??

Decreased Decreased

MortalityMortality

??


LongLong--term Treatment With term Treatment With SolirisSoliris in in

Paroxysmal Paroxysmal Nocturnal Nocturnal HemoglobinuriaHemoglobinuria: :

Sustained Sustained Efficacy and Improved SurvivalEfficacy and Improved Survival

79 consecutive patients 79 consecutive patients

with PNHwith PNH

–– Treated with Treated with SolirisSoliris

between May 2002 between May 2002

and July 2010and July 2010

Mortality and disease Mortality and disease

symptoms were evaluatedsymptoms were evaluated


Paroxysmal Nocturnal Paroxysmal Nocturnal HemoglobinuriaHemoglobinuria:: A Chronic, Systemic and LifeA Chronic, Systemic and Life--Threatening DiseaseThreatening Disease

100100

8080

6060

4040

2020

00

00 55 1010 1515 2020 2525

Years After Diagnosis

Pati

en

ts S

urv

ivin

g (

%)

Pre-Eculizumab from time of Diagnosis in 80 Patients With PNH1

AgeAge-- and sexand sex--

matched controlsmatched controls

Patients with PNHPatients with PNH

96% (76/79) patient survival

There was no difference in mortality between patients

on eculizumab and the healthy population (P=0.46)

2 patients over 70 years of age had worse survival

(P=0.0042). No patients under the age of 50 years died

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

Improved Overall Survival in Improved Overall Survival in

Patients Treated With Patients Treated With SolirisSoliris

Cu

mu

lati

ve

Su

rviv

ing

(%

)

Time (years)

100100

8080

6060

4040

2020

00

00 11 22 66 77 99 44 55 88 33

N=79

Age- and gender-matched

healthy UK population

Soliris treated

P<0.46

9


SolirisSoliris has a Major Impact on has a Major Impact on

Survival in PNHSurvival in PNH


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 gender-matched healthy UK population

Soliris treated

P<0.46


Time (years)Time (years)

Improved Overall Survival in Patients Improved Overall Survival in Patients

Treated With Treated With SolirisSoliris

Cu

mu

lati

ve S

urv

ivin

g (

%)

Soliris n = 79

Untreated n = 30

11 22 33 44 55 66 77 88 99

2020

4040

6060

8080

100

00



Summary of Clinical EfficacySummary of Clinical Efficacy

In clinical trials, Soliris significantly reduced hemolysisIn clinical trials, Soliris significantly reduced hemolysis11 the underlying the underlying

cause of cause of morbitiesmorbities in PNHin PNH

86% sustained reduction in hemolysis as measured by LDH86% sustained reduction in hemolysis as measured by LDH22

Fewer thrombotic events were observed with Soliris in clinical trialsFewer thrombotic events were observed with Soliris in clinical trials1,31,3

–– The majority of patients (63%) received concomitant anticoagulant The majority of patients (63%) received concomitant anticoagulant

therapytherapy11

–– The effect of anticoagulant withdrawal during Soliris treatment has not The effect of anticoagulant withdrawal during Soliris treatment has not

been studiedbeen studied11

78% clinically meaningful improvement in fatigue78% clinically meaningful improvement in fatigue

–– Fatigue in PNH impacted by hemolysis Fatigue in PNH impacted by hemolysis

–– Significant improvement noted in pain and dyspnea along with Significant improvement noted in pain and dyspnea along with

a broad range of QoL measuresa broad range of QoL measures44

73% reduction in need for transfusions across all patient populations73% reduction in need for transfusions across all patient populations22

1. Soliris1. Soliris®® (eculizumab) [package insert]. Alexion Pharmaceuticals; 2011. 2. Hillmen P et al. (eculizumab) [package insert]. Alexion Pharmaceuticals; 2011. 2. Hillmen P et al. N Engl J MedN Engl J Med. 2006;355:1233. 2006;355:1233--1243. 3. Hillmen P et al. 1243. 3. Hillmen P et al. BloodBlood. .

2007;110(12):41232007;110(12):4123--4128. 4. Socie G et al. 4128. 4. Socie G et al. BloodBlood. 2007;110(11):Abstract 3672. . 2007;110(11):Abstract 3672.

10


Sustained Complement Inhibition Leads to Reduced Sustained Complement Inhibition Leads to Reduced HemolysisHemolysis, Thrombosis and Improvements in Survival, Thrombosis and Improvements in Survival

Reduction in LDH (P<0.0001)

100% response rate in pivotal clinical trial programs (As measured by reduction in LDH)

4 fold improvement in CKD over placebo (P<0.04)

Soliris appears to normalize survival in patients with PNH

Significant reduction in abdominal pain

Improvement in dyspnea, dysphagia, fatigue, hemoglobinuria

SolirisSoliris SolirisSoliris

1. Hillmen P et al. Blood. 2007;110(12):4123-4128. 2. Brodsky R et al. Blood. 2010;116(21): Abstract #4237. 3. Hill A et al. Blood. 2004;104:772: Abstract #2823. 4. Data on fi le. Alexion Pharmaceuticals, Inc. 5. Hillmen et al. N Engl J Med. 2004;350 552. 6. Brodsky et al. Blood. 2008;111:1840-1847. 7. Hillmen et al. Blood. 2007;110:4123-4128.

8. Hill A et al. Br J Haematol . 2010; May;149(3):414-425. 9. Hillmen P et al. Am J Hematol. 2010;85:553-559. 10. Hill et al. Blood. 2008;112: Abstract A486.

92% (P<0.0001) reduction in TE

Uncontrolled

Complement

Activation

Increased Increased

MortalityMortality

Increased Increased

MortalityMortality

ThrombosisThrombosis RenalRenal


CardiacCardiac

HepaticHepatic

ThrombosisThrombosis RenalRenal


CardiacCardiac

HepaticHepatic

End Organ Damage Hemolysis




(LDH)(LDH)




(LDH)(LDH)

Poor Outcomes

Decreased

Mortality

Decreased

Mortality


Global, observational, nonGlobal, observational, non--interventional study to collect real world interventional study to collect real world

safety, effectiveness and QoL datasafety, effectiveness and QoL data

Open to all physicians treating patients with PNH regardless of therapyOpen to all physicians treating patients with PNH regardless of therapy

ObjectivesObjectives

Database for publications to enhance understanding of disease and Database for publications to enhance understanding of disease and

improve outcomesimprove outcomes

Promote evidencePromote evidence--based medicinebased medicine

Current enrollmentCurrent enrollment

Over 1200 patients enrolled Over 1200 patients enrolled

Participation in 21 countries, including Participation in 21 countries, including Argentina, Australia, Belgium,

Canada, Denmark, Finland, France, Germany, Netherlands, New

Zealand, Russia, South Korea, Spain, Sweden, Switzerland, Taiwan,

United Kingdom, United States

Enrollment information: www.pnhsource.comEnrollment information: www.pnhsource.com

paroxysmal nocturnal hemoglobinuria: a chronic, systemic...

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