soliris® (eculizumab) 2.pdf · soliris® (eculizumab) soliris® is a complement inhibitor...
TRANSCRIPT
7/14/2014
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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 Chain
Constant Regions 2 and 3
(Eliminates complement activation)
Complementarity Determining Regions
(murine origin)
Human Framework Regions
• No mutations
• Germline
Human IgG2 Heavy Chain
Constant 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
al
Term
inal
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. 2007Evaluated 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. 6
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®
Lacta
te D
eh
yd
rog
en
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 T
ran
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 (
SE
S)
EORTC
FunctioningEORTC
Symptoms
FA
CIT
-Fati
gu
e◘
EO
RT
C F
ati
gu
e◘
Glo
bal
Healt
h◘
Ph
ysic
al◘
Ro
le◘
Co
gn
itiv
e*
Dysp
nea◘
Pain
*
Inso
mn
ia*
Co
nsti
pati
on
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
0
5
10
15
20
25
30
35
40
45
Pre-SOLIRIS® Treatment SOLIRIS® Treatment
Th
rom
bo
tic
Ev
en
ts (
#)
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
an
ge f
rom
Baselin
e
FA
CIT
-Fati
gu
e S
co
re
-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® Hgb
Patients 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. 2007Evaluated 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
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Patient (n)
187/149 173 171 171 68 21 10
86% Reduction in LDH Sustained Out Past 4 ½
Years: 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<0.001
P=0.002
* * * *
◘
◘
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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.
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. 18
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.
7/14/2014
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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. 20
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. 22
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. 24
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.
7/14/2014
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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