Paroxysmal Nocturnal Hemoglobinuria
PNH
Jamile M Shammo, MD, FASCP, FACP
Associate Professor of Medicine and Pathology
Rush University Medical Center
Chicago
1
Outline
• How frequent is PNH?
• How does it happen?
• What are the symptoms and risks?
• How is it diagnosed?
• How is it treated?
2
PNH : Epidemiology
•
An estimated 4,000 – 6,000 patients in U.S.1
•
Median age of diagnosis is early 30’s2,3,4
•
5 year mortality: 35%2
1Hill,
et al. Blood. 2006;108:972.
et al. Br J Haematol. 2004;126:133-138.
3Socie, et al. Lancet. 1996;348:573-577.
4Nishimura, et al. Medicine. 2004;83:193–207.
2Moyo,
3
Paroxysmal Nocturnal Hemoglobinuria:
Actuarial Survival From the Time of
Diagnosis in 80 Patients With PNH1
Patients Surviving (%)
100
80
Age- and sexmatched controls
60
40
Patients with PNH
20
0
0
5
10
15
20
25
Years After Diagnosis
The expected survival of an age- and sex-matched control group is shown for comparison
(Hillmen et al 1995). In a patient population where ½ the patients have <30% clone, 1 in 7
patients died by 5 years (de Latour et al. Blood. 2008; 112: 3099-3106)
1. Hill A et al. Blood. 2006;108(11): 290a. Abstract 985 2. Hillmen, et al. N Engl J Med. 1995;333:1253-1258.
3. Nishimura JI, et al. Medicine. 2004;83:193-207. 4. Socié G et al. Lancet. 1996;348:573-77. 5. Hill A et al. Br J Haematol. 2007;137:181-92.
44
Paroxysmal Nocturnal Hemoglobinuria
How does it happen?
•
This is an acquired mutation of a gene (PIG-A) on the
X chromosome important in making protein anchors
(GPI).
• GPI protein anchors on the surface of all blood cells
•
•
protecting the red cells from destruction by a
component of the immune system known as
complement.
When the anchor and it’s associated proteins are
missing, red cells become susceptible to destruction
by the complement system.
Complement system is designed to attack bacteria, it
kills them by poking holes in the membrane-what is
called the Membrane Attack Complex (MAC)
5
PNH
•
PNH red cells are deficient in all GPI anchored
protein, but 2 are important in protecting red cells
from destruction: CD55 (DAF) and CD59 (MIRL).
• Without these proteins, red cells don’t have their
normal protection against the complement system.
•
In PNH, there is uncontrolled, complement mediated
hemolysis (destruction of red cells).
•
This happens all the time, and is accelerated when
there is an event that activates the complement
system.
6
The Defect in PNH
GPI-anchor & membrane
proteins
PROTEIN
Asp
NORMAL
C=O
NH
CH
2
CH
2
O
PNH
O=P=O
O
( 1-2)
( 1-6)
( 1-4)
O
N
O-P=O
O CH
CH NH
2
2
2
O
O-P-O
CH
O
2
CH
O
CH O
2
C=O
C=O
77
The Complement System
Microorganisms
Terminal Proximal
Lectin
Antigen-Antibody
Classical
C3
Constitutive/
Microorganisms
Alternative
C3a
Microbial opsonization
Immune complex clearance
C3b
C5
C5b
Weak anaphylatoxin
C5a
C5b-9
Figueroa JE, et al. Clin Microbiol Rev. 1991;4:359-395.
Walport. N Engl J Med. 2001;344:1058-66.
Strong anaphylatoxin
Terminal Complement Complex (TCC)
Cause of Hemolysis in PNH
Lysis of Neisseria
8
Absence of CD59 Allows
Terminal Complement Complex Formation
C9
CD55
C5b-8
CD59
C5b-8
CD59
C9
C9
Walport MJ, et al. N Engl J Med 2001;344:1058-1066
+9
PNH is a Progressive Disease of
Chronic
Hemolysis
Normal red blood cells
Without this protective
are protected from
complement attack by
a shield of terminal
complement inhibitors
complement inhibitor
shield, PNH red blood
cells are destroyed
Thrombosis
Renal Failure
Significant
Impact on
Survival
Pulmonary Hypertension
Abdominal Pain
Complement
Activation
Dyspnea
Dysphagia
Intact RBC
Fatigue
Significant
Impact on
Morbidity
Free Hemoglobin
Hemoglobinuria
Anemia
Erectile Dysfunction
International PNH Interest Group. Blood. 2005;106:3699-3709; 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; p. 419-427; Rother RP et al. JAMA. 2005;293:1653-1662; Socie G
et al. Lancet. 1996;348:573-577; Hill A et al. Br J Haematol. 2007;137:181-92.
10
10
Paroxysmal Nocturnal Hemoglobinuria
•
•
•
It’s not just paroxysmal
– Even in the absence of symptoms,
destructive progression of hemolysis is
ongoing
It’s not always nocturnal
– Hemolysis in PNH is subtle and constant,
24 hours a day
Hemoglobinuria is the hallmark of this disease,
however:
– ¾ patients present without hemoglobinuria1
1. International PNH Interest Group. Blood. 2005;106:3699-3709.
11
PNH Symptoms
Clinical signs or symptoms
Thrombosis
Anemia
Bone marrow failure
Fatigue, impaired QOL
Hemoglobinuria
Abdominal Pain
Dysphagia
Erectile Dysfunction
Chronic Renal Insufficiency
(GFR<60/ml/min)
Incidence Rate (%)
40%1
89%7
10-45%2-5
96%6
26%7
57%6
41%6
47%6
30%8
Average delay to diagnosis > 3 years; may be > 10 years1
1. Hillmen, et al. N Engl J Med. 1995;333:1253-1258. 2. Johnson & Hillmen. J Clin Path: Mol Pathol. 2002;55:145-152.
3. Wang, et al. Blood. 2002;100:3897-3902. 4. Iwanga, et al. Brit J Haem. 1998;102:465-474. 5. Maciejewski, et al. Brit J Haem. 2001;115:1015-1022. 6.
Meyers G et al. Abstract submitted to ASH 2007 for fatigue. 7. Rosse. Paroxysmal nocturnal hemoglobinuria In: R Hoffman; EJ Benz; SJ Shattil et al., eds.
Hematology: Basic Principles and Practice. 3rd ed. New York: Churchill-Livingstone; 2000:331-342. 8. Clark DA, et al. Blood. 1981;57:83-89.
12
Impact of PNH on Quality of Life
~75% of Patients Reported Symptoms as Moderate to Severe
59% patients were transfusion-free for at least 12 mo or had never been transfused
76% were forced to modify their daily activities to manage their PNH
17% were unemployed due to PNH
*Moderate to severe; N=29.
Meyers G et al. Blood. 2007;110 (11): Abstract 3683.
13
13
Abdominal Pain and Ischemia in
• Abdominal pain is associated
with hemolysis1
PNH
• Hemolysis causes nitric oxide consumption
•
leading to vasoconstriction, smooth muscle
contraction, and ischemia1,2
Severe abdominal pain observed with intestinal
ischemia:3,4
– Marked elevation of d-dimers5,6
– Electron microscopic findings of ischemia on biopsy3
– Venous blockage by angiography or MRI6
1. Hill A et al. Haematologica. 2005;90(e-case)40. 2. Rother R et al. JAMA.2005;293:1653-62.
3. Adams T et al. Digestive Diseases and Sciences. 2002; 47(1):58–64.
4. Quentin V et al. Gastroenterol Clin Biol. 2003;27(10):927-31.
5. Weitz I et al. Blood. 2008; 112: Abstract 407.
6. Khoshini R et al. Med Gen Med. 2004; 6(1): 23.
14
14
Common Symptoms of Hemolysis
Signal the Underlying Threat of Catastrophic Consequences
Dyspnea
Dysphagia
Abdominal Pain
Impaired QoL
Fatigue
Hemoglobinuria
Erectile Dysfunction
Anemia
DVT
Acute Renal Failure
Chronic
Kidney Disease
Stroke / TIA
Hepatic Failure
Cardiac
Dysfunction
Ischemic Bowel
Pulmonary Hypertension
15
15
Thrombosis in PNH:
• 40% of patients with clinical thrombotic events1
• Leading cause of death2
– Accounts for 40–67% of deaths1
– First thrombotic event can be fatal2
– Median time to TE was 2.1-2.3 years from diagnosis3
– First TE increases risk for death 5 to 10-fold1
• Risk of thrombosis with smaller clone size4
– 4-fold increase in thrombotic risk for every 10%
increase in clone size2
1. Hillmen et al. Blood 2007; 110: 4123-4128. 2. International PNH Group et al. Blood. 2005;106(12):3699-3709. 3. De Latour. Blood 2008 p. 3102
4. Audebert HJ et al. J Neurol. 2005;252:1379-1386.
16
16
Common Sites of Thrombosis
Occur Frequently in PNH
Hillmen P et al.
1995 (N=80)
Hillmen P et al.
2007 (N=195)
DVT or PE
33%
40%
CVA/MI
16%
15%
Typical VTE most common
VTE in PNH
√
√
Atypical VTE more common
in PNH than in the general
population3
√
√
TE Type
Higher proportion of PE and/or DVT sites of thrombosis consistently found in PNH
patients – Socie et al. 1996 (29%)4 and Nishimura and Rosse. 2004 (27%)5
1. Hillmen P et al. N Engl J Med. 1995;333:1253-8. 2. Hillmen P et al. 12. Blood. 2007; 100:4123-8.
3. Fowkes FJI et al. Eur J Vasc Endovasc Surg. 2003;25:1-5. 4. Socie G et al. Lancet. 1996;348:573-7. 5. Nishimura J et al. Medicine. 2004;83(3):193-207.
17
17
Thrombosis Event Rate (TE Per 100 Pt-Yrs)
Elevated Thrombotic Rate in
Antithrombotic-Treated Patients
12
10.61
10
8
6
4
2
(n=103)
0
Antithrombotic-Treated Patients
91 Were Receiving Anticoagulants
Hillmen et al. Blood. 2007;110:4123-4128.
18
18
Thrombosis
Fatigue / Impaired QOL
Pulmonary Hypertension
End Organ Damage
Anemia
Renal Damage in PNH
• Renal failure has been identified as the cause of
death
in approximately 8 – 18% of PNH patients1
• Renal function impaired in PNH patients2
– 13/19 (68%) with significant reduction in creatinine clearance
– 6/19 (32%) GFR <60
1.Nishimura JI, et al. Medicine. 2004;83:193-207. 2. Clark DA et al. Blood. 1981 Jan;57(1):83-9;
19
19
64% of Patients Exhibit Clinical
Chronic Kidney Disease (CKD)
59% of patients with minimal (0-1) transfusion history had CKD (n=22)
Hillmen et al. Blood. 2007; 110 (11): Abstract 3678.
20
20
PNH and Pulmonary Hypertension
• Hemolysis results in cell-free hemoglobin
•
•
•
and Nitric oxide (NO) consumption leading to
pulmonary hypertension1, 2
47% of PNH patients have pulmonary
hypertension3
PNH patients with pulmonary hypertension
have cardiac dysfunction3
66% of PNH patients report dyspnea4
1. Rother R. et al. JAMA. 2005; 293: 1653-1662. 2. Hill A et al. BJH. 2010:1-12; 3. Hill A et al. Br J Haematol. 2006;133 (suppl 1):119:Abstract 316.
4. Meyers G et al. Blood. 2007;110(11):Abstract 3683;
21
21
Who Should be Tested for PNH?
• Patients with unexplained hemolytic anemia
• Patients with bone marrow failure, including
aplastic anemia and MDS
• Patients with hemoglobinuria
• Patients with unusual/repetitive thrombosis,
and arterial thrombosis otherwise
unexplained.
• Patients with episodic swallowing problems or
abdominal pain of unclear etiology with
associated hemolysis
22
23
How is PNH diagnosed?
•
physicians need to consider the disease as a
potential diagnosis when evaluating their patients
and eventually request the diagnostic test.
•
Flow cytometry, typically performed on peripheral
blood, allows for the detection of cells deficient in
the GPI anchor and it’s associated proteins . It
estimates:
– 1. The size of the PNH clone
– 2. The extent of deficiency of membrane proteins
(Type II, partial, and type III complete deficiency of
CD55 and CD59)
•
Flow tests should be followed periodically monitor
the size of the clone.
It is important that flow tests be performed on both
red and white cells.
•
24
Diagnosis of PNH in Red Blood Cells
Normal RBC’s with normal
CD59 expression (Type I
cells)
PNH clone with complete
CD59 deficiency (Type III
cells)
Gating on GPA+ RBC’s
PNH clone with complete
CD59 deficiency (Type III
cells) and partial CD59
deficiency (Type II cells)
25
Why look beyond RBCs for PNH?
• Percentages of PNH RBCs may be affected
•
•
by:
• Hemolysis
• Blood Transfusion
Granulocyte clone size provides true PNH
clone size
PNH reports should provide quantitative
results expressing clone size on both
granulocytes and erythrocytes1
1. Hall & Rosse. Blood. 1996;87:5332-5340.
26
White Cell Staining with anti-CD59
From Hall SE and Rosse WF, Blood 1996; 87: 5332
27
PNH Patient with an 80% WBC clone size and 31% RBC
clone size indicating Hemolysis
28
Evidence of PNH Cells in Aplastic Anemia
EXPLORE Trial
Percent Positive: WBC PNH cells/clone >
0.01%
•
AA
(N = 451)1
69.6%
(314 / 451)
Percent Positive : WBC PNH clone ≥ 1%
25.1%
(113 / 451)
Median Clone Size: WBC PNH clone ≥ 1%
7.4%
(n=113)
Mean Clone Size: WBC PNH clone ≥ 1%
24.1%
(n=113)
% of patients with clone ≥1% and LDH > ULN
38.1%
(n=113)
Interim Results from EXPLORE, a Multi-center Prevalence Study of PNH Clone Size in Patients
with AA, MDS, and other BMF
1. Galili N et al. Poster presentation at: American Society of Clinical Oncology 45th Annual Meeting; May 29–June 2, 2009; Orlando, FL..
29
Evidence of PNH Cells in MDS
•
•
EXPLORE Trial
MDS
(N = 4433)1
Percent Positive: WBC PNH cells/clone > 0.01%
55.2%
(2447 / 4433)
Percent Positive : WBC PNH clone ≥ 1%
1.2%
(54 / 4433)
Median Clone Size: WBC PNH clone ≥ 1%
13.3%
(n=54)
Mean Clone Size: WBC PNH clone ≥ 1%
33.7%
(n=54)
% of patients with clone ≥1% and LDH > ULN
44.4%
(n=54)
Interim Results from EXPLORE, a Multi-center Prevalence Study of PNH Clone Size in Patients with AA, MDS, and other BMF
PNH cells were identified in 55% of all MDS patients. Similar proportions of PNH cells were identified in all MDS subtypes including
RA, RCMD, RARS, RAEB, RCMD-RS and 5 q syndrome.
1. Galili N et al. Poster presentation at: American Society of Clinical Oncology 45th Annual Meeting; May 29–June 2, 2009; Orlando, FL..
30
Immunosuppressive Therapy With
ATG/CSA in MDS Patients
Recommendations based on:
• PNH positive cells may reflect
BM-directed T-cell activity in MDS1
Hematologic Improvement
PNH+
78% (n=9)
PNH0% (n=8; P=0.002)
89% (n=9)
27% (n=30; P=0.0015)
1. Dunn DE et al. Ann Intern Med. 1999;131:401-8.
2. Wang H et al. Blood. 2002;100(12):3897-902.
MDS Type/ Rx
RA w/CSA2
MDS w/ATG1
31
Management of PNH
• Transfusions
•
•
•
•
•
– Risk of iron overload
– Transient treatment of anemia
Anticoagulants
– Risk of hemorrhage
– Ineffective in many patients*
Red cell supplements
– Folic acid, iron,
– erythropoiesis-stimulating agents
Steroids/androgen hormones
Bone marrow transplant
Eculizumab (Soliris)
ESA=erythropoietin stimulating agents
International PNH Interest Group. Blood. 2005;106:3699-3709.
*Hillmen P et al. Blood. 2007;110:4123-8.
32
32
Bone Marrow
Transplant
BMT is associated
with significant
morbidity and
mortality, and a significant impact on quality of life post
transplant3,4 therefore patient selection is critical.
•
•
•
In a recent retrospective study in France examining
PNH patients:1
– 54% had graft versus host disease (GVHD)
In another study examining PNH patients (n=23)2
– 50% chronic GVHD; 42% acute GVHD
Allogeneic BMT recommended for PNH patients with
life-threatening cytopenias or possibly the patient with
disabling hemolysis, cytopenias, or thrombosis not
controlled with existing therapy5
1. De Latour PF et al. Abstract #316. EBMT 2009; 2. Santarone S et al. Hematogica. 2009;
3. Bieri S et al. BMT. 2008; 4. Fraser CJ et al. Blood. 2006; 5. Brodsky RA. Blood. 2009 113: 6522-6527
33
33
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.
34
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)
35
35
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.
36
36
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
37
37
Dosing Schedule
Pretreatmen
t
 2 weeks
before
induction
•
•
•
•
Induction Phase
Week
→
1
2
3
Maintenance Phase
4
5
6
7
8
9 and
every
2 weeks
thereaft
er
Neisseria SOLIRI
S®
meningitidi dose,
600patients
600 600
600 a900
X
900
Xvaccination
900
In clinical
trials
all
received
meningococcal
s
mg
→
® should
vaccination
SOLIRIS
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.
38
38
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
4
8
12
16
20
24
28
32
36
40
44
48
52
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.
39
39
73% Reduction in Mean Units Transfused Across
all Subgroups: TRIUMPH
Median Units Transfused
18
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.
40
40
Median Units Packed RBCs
SHEPHERD: SOLIRIS® Reduced Transfusions
Regardless of Historical Transfusion
Requirements
40
33.5
35
1 Year Pre-Treatment
30
1 Year Post-Treatment
25
20
17
15
10
*
8
*
§
7.5
†
‡
0
0
(n = 97)
(n = 21)
(n = 47)
(n = 15)
(n = 14)
Overall
< 4 Units
4 - 14
Units
15 - 25
Units
> 25 Units
5
0
0
8
*P < 0.001; †P = 0.422;
‡P = 0.002; §P = 0.008.
Brodsky, et al. Blood 2008; 111 (4): 1840-1847.
2
4
Transfusion Requirements
12 Months Prior to Treatment
41
Patients Report Rapid and Sustained
Improvement Across Broad Range of
Measures
Large
Impact
1
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
42
42
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
6
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
6
8
10
12
14
16
Time, Weeks
18
20
22
24
26
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.
43
43
Thrombotic Events (#)
92% Reduction in Thrombotic
Events
45
40
35
30
25
20
15
10
5
0
39
N=195
P=0.0001
3
Pre-SOLIRIS® Treatment
SOLIRIS® Treatment
• 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.
44
44
Sites and Types of Pre-Treatment
Thrombotic Events
Venous Thrombosis
Deep Vein Thrombosis
-Lower extremity
-Other*
Mesenteric/Splenic Vein Thrombosis
Hepatic/Portal Vein Thrombosis
Pulmonary Embolus
Cerebral/Internal Jugular Thrombosis
Superficial Vein Thrombosis
Arterial Thrombosis
Cerebrovascular Accident/Transient
Ischemic Attack
Myocardial Infarction/Unstable Angina
Total
Events
41
23
18
23
21
8
7
5
% of Total
33.1%
18.5%
14.5%
18.5%
16.9%
6.5%
5.6%
4.0%
17
2
124
13.7%
1.6%
100%
*Includes inferior vena cava, bilateral lower extremity, pelvic, ureter, axillary, subclavian and
brachiocephalic veins.
Hillmen, et al. Blood 2007; 110: 4123-4128
45
Long-Term Extension Results:
*P<0.001
◘P=0.002
*
*
*
Study Year
Patient (n)
187/149 173
◘
*
171
171
68
21
10
 10 patients who participated in the pilot study demonstrated sustained reduction in LDH out
past 5 years
– Those patients were followed for up to 54 months showing a sustainable 86% Reduction in
LDH Past 4 ½ Years.
Socié G et al. Blood. 2007;110(11): Abstract 3672. SOLIRIS ® (eculizumab) [package insert]. Alexion Pharmaceuticals; 2009.
46
Summary of Clinical Efficacy
In clinical trials, SOLIRIS® significantly reduced
hemolysis1
• 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
•
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.
47
47
Soliris: Warning
• 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.
48
48
Soliris: 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.
49
49
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.
50
50
Safety: Warnings and Precautions
• 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.
51
51
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)
2 (5)
1 (2)
SOLIRIS® (eculizumab) [package insert]. Alexion Pharmaceuticals; 2009.
Influenza-like illness
52
52
Eculizumab-Pro’s and Con’s
•
Pro’s
– Very effective at reducing
–
–
–
–
hemolysis
Well tolerated
Improvements in QOL,
reduction in transfusions
Reduction in burden of
disease
Probable reduction in
clots
•
Con’s
– $$$$!!
– Infection risk:
–
–
–
–
meningococcal
meningitis
Burden of treatment
Plan for lifetime therapy
Does not improve other
blood counts
Is not curative
55
Important questions yet to be
answered:
•
•
•
•
•
Many questions need to be answered:
– Why do PNH cells evolve the way they do?
– Who is at a higher risk of clotting?
– What is a clinically meaningful clone size?
What are the long term side effects of soliris,
and does it reverse end organ damage?
Does Soliris prolong survival in PNH
patients?
Who is the ideal candidate for
transplantation?
Can we identify a “kind” transplant regimen
with less toxicity and long term side effects?
56
Shared Experiences Around the World
Enhancing the Understanding of PNH
Outcomes
57
US and International Participation in The PNH
Registry:
•
As of August 2009: 7 Countries Enrolling
– US
– Argentina
– Denmark
– Netherlands
– Belgium
– Australia
– France
– Others are coming on board
58
Registry: Eligibility
•
•
•
All patients with any PNH clone regardless of
treatment
Patient willing to complete a questionnaire at
Baseline and every six months thereafter
Willing and able to give written informed
consent
59
Conclusions
•
•
•
•
PNH is a disease of chronic hemolysis with a
heterogeneous clinical presentation.
Stem cell transplant is the only curative
option but it has significant morbidity
associated with the procedure
Soliris is effective at reducing transfusion
frequency, risk of thrombosis & improves
QoL, but is not curative.
Advancing our understanding of disease
biology is critical for improving outcomes.
60