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PNH
Jack Goldberg MD FACP
Clinical Professor of Medicine University of Pennsylvania
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Anemia
Reduced Red Cell MassFree 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
ComplementActivation
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.
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SOLIRIS® (eculizumab)
SOLIRIS® is a Complement Inhibitor Indicated for the Treatment of Patients With
PNH to Reduce Hemolysis
SOLIRIS® (eculizumab) [package insert]. Alexion Pharmaceuticals; 2009.
SOLIRIS® is the First and Only Approved Therapy for PNH
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SOLIRIS® (eculizumab) Humanized First in Class Anti - C5 Antibody
Hinge
CH
3C
H2
Human IgG4 Heavy ChainConstant Regions 2 and 3
(Eliminates complement activation)
Complementarity Determining Regions(murine origin)
Human Framework Regions• No mutations• Germline
Human IgG2 Heavy ChainConstant Region 1 and Hinge
(Eliminates Fc receptor binding)
Rother R et al. Nat Biotech 2007;25:1256
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SOLIRIS® Blocks Terminal Complement
C3 C3a
C3b
C5
Pro
xim
alTe
rmin
al
Figueroa JE, Densen P. Clin Microbiol Rev. 1991;4(3):359-395.
Walport MJ. N Engl J Med. 2001;344(14):1058-66.
SOLIRIS® (eculizumab) [package insert]. Alexion Pharmaceuticals; 2009. Rother RP et al. Nature Biotech. 2007;25(11):1256-64.
C5b-9Cause of Hemolysis
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
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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. 2004N = 11
Primary endpoint: reduction of hemolysis
TRIUMPH – NEJM. 2006 Pivotal Phase III, Double-Blind, Placebo-Controlled Trial, N = 87
SHEPHERD – Blood. 2008Broader patient population, including
those receiving minimal transfusions or with thrombocytopenia, N = 97
SOLIRIS® PNH Clinical Studies
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Dosing Schedule
Pretreatment Induction Phase Maintenance Phase
2 weeks before
induction
Week→ 1 2 3 4 5 6 7 8
9 and every
2 weeks thereafter
Neisseria meningitidis vaccination
SOLIRIS®
dose, mg→
600 600 600 600 900 X 900 X 900
In clinical trials all patients received a meningococcal vaccination
SOLIRIS® should be administered via IV infusion over 35 minutes every 7 days during induction and every 14 days during maintenance
SOLIRIS® dose adjustment to every 12 days may be necessary for some patients to maintain LDH reduction
Concomitant medications allowed:– Steroids, immunosuppressant drugs, anti-clotting agents and hematinics1
SOLIRIS® (eculizumab) [package insert]. Alexion Pharmaceuticals; 2009.
1. Hillmen P et al. N Engl J Med. 2004;350(6):552-9. 40
86% Reduction in LDH:TRIUMPH and SHEPHERD
P<0.001 at all measured time points.
Hillmen P et al. Blood. 2007;110(12):4123-8.
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®
Lac
tate
Deh
ydro
gen
ase
(U
/L)
0
500
1000
1500
2000
2500
3000
Time, Weeks
0 4 8 12 16 20 24 28 32 36 40 44 48 52
100% response after the first dose
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73% Reduction in Mean Units Transfused Across all Subgroups: TRIUMPH
*P<0.001. ◘Transfusion data obtained during 12 months before treatment; values were normalized for a 6-month period
1. Hillmen P et al. N Engl J Med. 2006;355;1233-1243. 2. Schubert J. Br. J Haematol. 2008;142(2):263-72.
Patients not on SOLIRIS® (n=44)
SOLIRIS® (n=43)
*
**
*
(n=87) (n=30) (n=35) (n=22)0
2
4
6
8
10
12
14
16
Overall 4-14 15-25 >25
Pre-treatment Transfusion Strata◘
Med
ian
Un
its
Tran
sfu
sed
18
• 51% of SOLIRIS patients achieved transfusion independence vs 0% of patients not on SOLIRIS1
• Patients with concomitant bone marrow dysfunction may continue to require minimal transfusions
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Patients Report Rapid and Sustained Improvement Across Broad Range of Measures
*P<0.05.◘P<0.001.
Brodsky R et al. Blood. 2006;108(11): Abstract 3770. Data on file. Alexion Pharmaceuticals.
Moderate Impact
Small Impact
Large Impact
Sta
nd
ard
Eff
ect
Siz
e (S
ES
)
EORTCFunctioning
EORTC Symptoms
FAC
IT-F
atig
ue◘
EO
RT
C F
atig
ue◘
Glo
bal
Hea
lth
◘
Ph
ysic
al◘
Ro
le◘
Co
gn
itiv
e*
Dys
pn
ea◘
Pai
n*
Inso
mn
ia*
Co
nst
ipat
ion
Nau
sea
Dia
rrh
ea
0
0.2
0.4
0.6
0.8
1
1.2
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92% Reduction in Thrombotic Events
63% of patients received concomitant anticoagulants1
The effect of anticoagulant withdrawal was not studied2
Events observed in both venous and arterial sites3
PI: There were fewer thrombotic events with SOLIRIS® treatment than during the same period of time prior to treatment.
1.Brodsky R et al. Blood. 2008;111(4):1840-47. 2.SOLIRIS® (eculizumab) [package insert]. Alexion Pharmaceuticals; 2009.
3.Hillmen P, et al. Blood. 2007;110:4123-4128.
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3
05
1015202530354045
Pre-SOLIRIS® Treatment SOLIRIS® Treatment
Th
rom
bo
tic
Eve
nts
(#)
P=0.0001
N=195
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Is the Primary Cause of Fatigue in PNH Anemia or Hemolysis?
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TRIUMPH Demonstrated that Improvement in Fatigue Occurred Independent of Hemoglobin
Response
FACIT = Functional Assessment of Chronic Illness Therapy
Adapted from: Hillmen P et al. NEJM. 2006;355:1233-43. Brodsky R et al. Blood Rev. 2008; 22: 65-74. Hill A et al. Haematologica. 2008; 93 (Suppl 1): 359. Abstract 0904.
1. 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
Hem
og
lob
in,
g/d
L
8.5
Ch
ang
e fr
om
Bas
elin
e FA
CIT
-Fat
igu
e S
core
-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)
SOLIRIS® HgbPatients not on SOLIRIS® (n=44)
In SHEPHERD, 78% patients reported a significant improvement in fatigue1
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What Is The Long-Term Experience with SOLIRIS®?
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SOLIRIS® PNH Clinical Studies
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. 2004N = 11
Primary endpoint: reduction of hemolysis
TRIUMPH – NEJM. 2006 Pivotal Phase III, Double-Blind, Placebo-Controlled Trial, N = 87
SHEPHERD – Blood. 2008Broader patient population, including
those receiving minimal transfusions or with thrombocytopenia, N = 97
Patient (n)
187/149 173 171 171 68 21 10
86% Reduction in LDH Sustained Out Past 4 ½Years: 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
Socié G et al. Blood. 2007;110(11): Abstract 3672. SOLIRIS® (eculizumab) [package insert]. Alexion Pharmaceuticals; 2009.
Study Year
*P<0.001P=0.002
* * * *
◘
◘
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Summary of Clinical EfficacyIn clinical trials, SOLIRIS® significantly reduced hemolysis1 the underlying cause of morbidity and mortality in PNH
86% sustained reduction in hemolysis as measured by LDH2
Fewer thrombotic events were observed with SOLIRIS in clinical trials1,3
– The majority of patients (63%) received concomitant anticoagulant therapy1
– The effect of anticoagulant withdrawal during SOLIRIS treatment has not been studied1
78% clinically meaningful improvement in fatigue– Fatigue in PNH impacted by hemolysis – Significant improvement noted in pain and dyspnea along with a
broad range of QoL measures4
73% reduction in need for transfusions across all patient populations2
1. SOLIRIS® (eculizumab) [package insert]. Alexion Pharmaceuticals; 2009. 2. Hillmen P et al. N Engl J Med. 2006;355:1233-43.
3. Hillmen P et al. Blood. 2007;110(12):4123-8. 4. Socie G et al. Blood. 2007;110(11)::Abstract 3672.
Important Safety Information About SOLIRIS®
All Patients Should Receive a Medication Guide Before Starting
SOLIRIS® Treatment
Please See Full Prescribing Information for SOLIRIS®
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Warning
WARNING: SERIOUS MENINGOCOCCAL INFECTION
SOLIRIS® increases the risk of meningococcal infections. Meningococcal infection may become rapidly life-threatening or fatal if not recognized 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® (eculizumab) [package insert]. Alexion Pharmaceuticals; 2009. 52
Safety: Contraindications
SOLIRIS® is contraindicated for patients with unresolved serious Neisseria meningitidis infection or who are not currently vaccinated against Neisseria meningitidis
SOLIRIS® (eculizumab) [package insert]. Alexion Pharmaceuticals; 2009.
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Safety: Warnings and Precautions
SOLIRIS® therapy increases the risk of meningococcal infections. Meningococcal infection may become rapidly life-threatening or fatal if not recognized and treated early
All patients must be vaccinated against Neisseria meningitidis ≥ 2 weeks prior to receiving SOLIRIS®
Use caution when administering SOLIRIS® to patients with any systemic infection
Other infections: SOLIRIS blocks terminal complement; therefore patients may have increased susceptibility to infections, especially with encapsulated bacteria– Use caution when administering SOLIRIS to patients
with any systemic infection
SOLIRIS® (eculizumab) [package insert]. Alexion Pharmaceuticals; 2009. 54
Safety: Warnings and Precautions (cont)
The effect of withdrawal of anticoagulant therapy during SOLIRIS® treatment has not been established. Therefore, treatment with SOLIRIS® should not alter anticoagulant management
Patients who discontinue SOLIRIS® must be monitored closely for signs of serious hemolysis– If serious hemolysis occurs after SOLIRIS discontinuation, consider
the following procedures/treatments: blood transfusion (packed RBCs), or exchange transfusion if the PNH RBCs are >50% of the total RBCs by flow cytometry; anticoagulation; corticosteroids; or reinstitution of SOLIRIS
– In clinical trials, 16 of 196 PNH patients discontinued SOLIRIS®
treatment; no serious hemolysis was observed
SOLIRIS® (eculizumab) [package insert]. Alexion Pharmaceuticals; 2009.
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Safety: Warnings and Precautions (cont)
LDH levels may be used to monitor hemolysis– SOLIRIS® dose adjustment to every 12 days may be
necessary for some patients to maintain LDH reduction
Infusion reactions may occur– In clinical trials, no patients experienced infusion
reactions that required discontinuation– SOLIRIS® treatment should be interrupted in all patients
experiencing severe infusion reactions and appropriate medical therapy administered
SOLIRIS® (eculizumab) [package insert]. Alexion Pharmaceuticals; 2009. 56
Serious Adverse Events:Clinical Trial Experience
Meningococcal infections are the most important adverse events that may be experienced by patients receiving SOLIRIS®
In clinical studies, 2 out of 196 patients developed serious meningococcal infections while receiving treatment with SOLIRIS– Both patients had been vaccinated
In clinical studies among non-PNH patients, meningococcal meningitis occurred in one patient, who was unvaccinated
In post-marketing experience, cases of serious or fatal meningococcal infections have been reported
SOLIRIS® (eculizumab) [package insert]. Alexion Pharmaceuticals; 2009.
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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)
SOLIRIS® (eculizumab) [package insert]. Alexion Pharmaceuticals; 2009. 58
Patient Counseling
Prior to treatment, patients should be informed and fully understand:– The risks and benefits of SOLIRIS®, in particular the risk
of meningococcal infection– Meningococcal vaccine does not prevent all
meningococcal infections– They are required to receive a meningococcal vaccination
at least 2 weeks prior to receiving the first dose of SOLIRIS®, if they have not previously been vaccinated
– There is a potential for serious hemolysis when SOLIRIS®
is discontinued and that they will be monitored by their healthcare professional for at least 8 weeks following SOLIRIS® discontinuation
SOLIRIS® (eculizumab) [package insert]. Alexion Pharmaceuticals; 2009.
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SOLIRIS® OneSource Program
OneSource provides education, assistance with access and treatment support for people living with paroxysmal nocturnal hemoglobinuria (PNH) and their caregivers.
It is staffed by Alexion Nurse Case Managers, who are registered nurses with healthcare and insurance experience.
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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® (eculizumab) [package insert]. Alexion Pharmaceuticals; 2009.
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Global, observational, non-interventional study to collect real world safety, effectiveness and QoL data– Open to all physicians treating patients with
PNH regardless of therapy
Objectives:– Database for publications to enhance understanding of disease and
improve outcomes– Promote evidence-based medicine
Current enrollment:– Over 500 patients enrolled – Participation in 14 countries, including the United States, Argentina,
Denmark, Netherlands, Belgium, Australia, France, New Zealand, Germany, and Taiwan
Enrollment information: (800) 913-4893 or www.pnhsource.com
Thank You
Jack Goldberg M.D. FACP
Clinical Professor of Medicine
University of Pennsylvania
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