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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
Conf idential – For Internal Use Only 2
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. .
Conf idential – For Internal Use Only 3
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
Conf idential – For Internal Use Only 4
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↓
6 Conf idential – For Internal Use Only 6
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
7 Conf idential – For Internal Use Only 7
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.
Chronic Kidney DiseaseChronic Kidney Disease Common Symptoms of PNHCommon Symptoms of PNH ThrombosisThrombosis ThrombosisThrombosis
8 Conf idential – For Internal Use Only 8
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
Chronic Kidney DiseaseChronic Kidney Disease Common Symptoms of PNHCommon Symptoms of PNH ThrombosisThrombosis ThrombosisThrombosis
9 Conf idential – For Internal Use Only 9
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.
Chronic Kidney DiseaseChronic Kidney Disease Common Symptoms of PNHCommon Symptoms of PNH ThrombosisThrombosis ThrombosisThrombosis
4
10 Conf idential – For Internal Use Only 10
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)
Chronic Kidney DiseaseChronic Kidney Disease Common Symptoms of PNHCommon Symptoms of PNH ThrombosisThrombosis ThrombosisThrombosis
11 Conf idential – For Internal Use Only 11
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.
Chronic Kidney DiseaseChronic Kidney Disease Common Symptoms of PNHCommon Symptoms of PNH ThrombosisThrombosis ThrombosisThrombosis
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
13 Conf idential – For Internal Use Only
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
14 Conf idential – For Internal Use Only
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
Conf idential – For Internal Use Only 15
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
16 Conf idential – For Internal Use Only
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)
17 Conf idential – For Internal Use Only
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
Conf idential – For Internal Use Only 18
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
Conf idential – For Internal Use Only 19
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
Conf idential – For Internal Use Only 20
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
Conf idential – For Internal Use Only 21
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
Conf idential – For Internal Use Only 22
Uncontrolled
Complement
Activation
Increased Increased
MortalityMortality
Increased Increased
MortalityMortality
TETE
RenalRenal
GastrointestinalGastrointestinal PulmonaryPulmonary
CardiacCardiac
HepaticHepatic
TETE
RenalRenal
GastrointestinalGastrointestinal PulmonaryPulmonary
CardiacCardiac
HepaticHepatic
End Organ Damage Hemolysis
ComplicationsComplications
Associated Associated
With ElevatedWith Elevated HemolysisHemolysis
(LDH)(LDH)
ComplicationsComplications
Associated Associated
With ElevatedWith Elevated HemolysisHemolysis
(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
??
Conf idential – For Internal Use Only 23
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
Conf idential – For Internal Use Only 24
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
Conf idential – For Internal Use Only 25
SolirisSoliris has a Major Impact on has a Major Impact on
Survival in PNHSurvival in PNH
Kelly RJ et al. Blood. 2011;117:6786-6792.
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
Conf idential – For Internal Use Only 26
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
Kelly RJ et al. Blood. 2011;117:6786-6792.
Conf idential – For Internal Use Only 27
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
Conf idential – For Internal Use Only 28
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
GastrointestinalGastrointestinal PulmonaryPulmonary
CardiacCardiac
HepaticHepatic
ThrombosisThrombosis RenalRenal
GastrointestinalGastrointestinal PulmonaryPulmonary
CardiacCardiac
HepaticHepatic
End Organ Damage Hemolysis
ComplicationsComplications
Associated Associated
With ElevatedWith Elevated HemolysisHemolysis
(LDH)(LDH)
ComplicationsComplications
Associated Associated
With ElevatedWith Elevated HemolysisHemolysis
(LDH)(LDH)
Poor Outcomes
Decreased
Mortality
Decreased
Mortality
Conf idential – For Internal Use Only 29
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