Transcript Slide 1

PNH
Jack Goldberg MD FACP
Clinical Professor of Medicine
University of Pennsylvania
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Historically Viewed as a Hemolytic Anemia
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
Complement
Activation
Intact RBC
Free Hemoglobin
Reduced
Red Cell Mass
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® is the First and Only
Approved Therapy for PNH
SOLIRIS® (eculizumab) [package insert]. Alexion Pharmaceuticals; 2009.
SOLIRIS® (eculizumab) Humanized
First in Class Anti - C5 Antibody
Human Framework Regions
• No mutations
• Germline
Hinge
Complementarity Determining Regions
(murine origin)
CH2
Rother R et al. Nat Biotech 2007;25:1256
CH3
Human IgG2 Heavy Chain
Constant Region 1 and Hinge
(Eliminates Fc receptor binding)
Human IgG4 Heavy Chain
Constant Regions 2 and 3
(Eliminates complement activation)
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SOLIRIS® Blocks Terminal Complement
SOLIRIS®
Terminal
Proximal
Complement Cascade
C3
C3a
• Terminal complement - C5a
and C5b-9 activity blocked
C3b
C5
C5b
• SOLIRIS® binds with high
affinity to C5
C5a
C5b-9
Cause of Hemolysis
in PNH
• Proximal functions of
complement remain intact
• Weak anaphylatoxin
• Immune complex clearance
• Microbial opsonization
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.
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SOLIRIS® PNH Clinical Studies
Pilot Study – NEJM. 2004
N = 11
Primary endpoint: reduction of hemolysis
TRIUMPH – NEJM. 2006
Pivotal Phase III, Double-Blind,
Placebo-Controlled Trial, N = 87
Long-Term Extension Trial
Hillmen Blood. 2007
Evaluated long-term safety,
efficacy and effect on
thrombosis; Placebo patients
switched to SOLIRIS®
N = 187
SHEPHERD – Blood. 2008
Broader patient population, including
those receiving minimal transfusions or
with thrombocytopenia, N = 97
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Dosing Schedule
Pretreatment
 2 weeks
before
induction
Neisseria
meningitidis
vaccination
Induction Phase
Maintenance Phase
→
1
2
3
4
5
6
7
8
9 and
every
2 weeks
thereafter
SOLIRIS®
dose, mg
600
600
600
600
900
X
900
X
900
Week
→
 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.
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86% Reduction in LDH:
Lactate Dehydrogenase (U/L)
TRIUMPH and SHEPHERD
3000
TRIUMPH – Placebo/Extension
TRIUMPH – SOLIRIS®/Extension
2500
SHEPHERD – SOLIRIS®
2000
1500
100% response after the
first dose
1000
500
0
0
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12
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Time, Weeks
TRIUMPH placebo patients switched to SOLIRIS® after week 26.
All TRIUMPH patients entered the long-term extension study.
P<0.001 at all measured time points.
Hillmen P et al. Blood. 2007;110(12):4123-8.
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73% Reduction in Mean Units Transfused
Across all Subgroups: TRIUMPH
Median Units Transfused
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16
14
Patients not on SOLIRIS® (n=44)
SOLIRIS® (n=43)
12
10
8
6
4
*
*
2
*
*
0
(n=87)
(n=30)
(n=35)
(n=22)
Overall
4-14
15-25
>25
Pre-treatment Transfusion Strata◘
• 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
*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.
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Patients Report Rapid and Sustained
Improvement Across Broad Range of Measures
Large
Impact
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0.8
Moderate
Impact
0.6
0.4
Small
Impact
EORTC
Functioning
*P<0.05.
◘P<0.001.
Brodsky R et al. Blood. 2006;108(11): Abstract 3770. Data on file. Alexion Pharmaceuticals.
Diarrhea
Nausea
Constipation
Insomnia*
Pain*
Dyspnea◘
Cognitive*
Role◘
Physical◘
Global Health◘
0
EORTC Fatigue◘
0.2
FACIT-Fatigue◘
Standard Effect Size (SES)
1.2
EORTC
Symptoms
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Thrombotic Events (#)
92% Reduction in Thrombotic Events
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30
25
20
15
10
5
0
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N=195
P=0.0001
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Pre-SOLIRIS® Treatment
SOLIRIS® Treatment

63% of patients received concomitant anticoagulants 1
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The effect of anticoagulant withdrawal was not studied 2
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Events observed in both venous and arterial sites 3
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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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-Fatigue Score
≥3 or more points denotes a clinically
significant improvement
11.5
Hemoglobin, g/dL
8
P<0.001
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11.0
4
10.5
2
Hgb Level
10.0
0
9.5
-2
9.0
-4
FACIT-Fatigue Score
Change from Baseline
FACIT-Fatigue Score
12.0
-6
8.5
0
2
4
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Time, Weeks
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24
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SOLIRIS® (n=43)
Patients not on SOLIRIS® (n=44)
SOLIRIS® Hgb
 In SHEPHERD, 78% patients reported a significant improvement in fatigue1
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.
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What Is The Long-Term Experience with SOLIRIS®?
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SOLIRIS® PNH Clinical Studies
Pilot Study – NEJM. 2004
N = 11
Primary endpoint: reduction of hemolysis
TRIUMPH – NEJM. 2006
Pivotal Phase III, Double-Blind,
Placebo-Controlled Trial, N = 87
Long-Term Extension Trial
Hillmen Blood. 2007
Evaluated long-term safety,
efficacy and effect on
thrombosis; Placebo patients
switched to SOLIRIS®
N = 187
SHEPHERD – Blood. 2008
Broader patient population, including
those receiving minimal transfusions or
with thrombocytopenia, N = 97
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86% Reduction in LDH Sustained Out Past 4 ½
Years: Long-Term Extension Results
*P<0.001
◘P=0.002
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Study Year
Patient (n)
187/149 173
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171
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 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.
Summary of Clinical Efficacy
In 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.
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Important Safety Information
About SOLIRIS®
All Patients Should Receive a
Medication Guide Before Starting
SOLIRIS® Treatment
Please See Full Prescribing Information for SOLIRIS®
Warning
WARNING: SERIOUS MENINGOCOCCAL INFECTION
 SOLIRIS® increases the risk of meningococcal infections.
Meningococcal infection may become rapidly lifethreatening 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.
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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 lifethreatening 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.
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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.
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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.
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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
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Thank You
Jack Goldberg M.D. FACP
Clinical Professor of Medicine
University of Pennsylvania