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Advances in Paroxysmal Nocturnal Hemoglobinuria (PNH). Bart Scott, MD Assistant Professor of Medicine, Division of Oncology, University of Washington Director of Hematology and Hematologic Malignancies, Seattle Cancer Care Alliance Seattle, WA.

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Advances in paroxysmal nocturnal hemoglobinuria pnh

Advances in Paroxysmal Nocturnal Hemoglobinuria (PNH)

Bart Scott, MD

Assistant Professor of Medicine, Division of Oncology, University of Washington

Director of Hematology and Hematologic Malignancies, Seattle Cancer Care AllianceSeattle, WA


Paroxysmal nocturnal hemoglobinuria pnh a chronic systemic and life threatening disease

Actuarial Survival From the Time ofDiagnosis in 80 Patients With PNH2

100

80

Age- and Gender-Matched Controls

60

Patients Surviving (%)

40

Patients With PNH

20

0

0

5

10

15

20

25

Years After Diagnosis

Paroxysmal Nocturnal Hemoglobinuria (PNH):A Chronic, Systemic, and Life-Threatening Disease

  • Prevalence: 15.9 / million1

  • Diagnosed at all ages

    • Median age early 30s3,4

  • Progressive disease2–4

    • Uncontrolled complement activation underlies the morbidities and mortality

  • Despite best supportive care

    • 5 year mortality: 35%2

The expected survival of an age- and gender-matched control group is shown for comparison (Hillmen et al. 1995)

1. Hill A et al. Blood 2006;108:290a. Abstract 985;2. Hillmen P 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;348:573–577.


What is pnh

What is PNH?

  • PNH is a disease of chronic complement-mediated hemolysis characterized by a somatic (acquired) mutation of the PIG-A gene in which blood cells lack key, naturally occurring terminal complement inhibitors (e.g. CD55 and CD59) on cell surfaces1-4

    • This mutation results in a deletion of GPI anchors, rendering proteins unable to attach to the surface of the cell

  • PNH is a progressive and destructive disease that leads to:

    • Thrombosis5

    • End-organ damage1,6

    • Increased mortality1,7

1. Brodsky R. Paroxysmal nocturnal hemoglobinuria. In: R Hoffman et al., eds. Hematology - Basic Principles and Practices. 4th ed. Philadelphia, PA: Elsevier Churchill Livingstone 2005;419–427; 2. Rosse WF et al.Hematology (Am SocHematolEduc Program) 2004:48–62; 3. Wiedmer T et al.Blood 1993;82:1192–1196; 4. Rother RP et al.JAMA 2005;293:1653–1662; 5. Hillmen P et al. Blood 2007;110:4123–4128; 6. Hillmen P et al.Am J Hematol 2010;85:553–559; 7. Hillmen P et al.N Engl J Med 1995;333:1253–1258.


Pnh what it s not

PNH: What it’s Not

  • It is not paroxysmal1

    • Even in the absence of symptoms, destructive progression of hemolysis is ongoing

  • It is not nocturnal1

    • Hemolysis in PNH is subtle and constant, 24 hours a day

  • Hemoglobinuria is a less commonly seen complication

    • ¾ patients present without hemoglobinuria2

1. RotherR et al. Nature Biotechnology 2007;25,11:1256–1264; 2. International PNH Interest Group. Blood. 2005;106:3699–3709.


The defect in pnh

The Defect in PNH

PNH clones are defined as PNH cells with a deficiency of proteins that require a GPI anchor for attachment to the cell membrane1

  • CD59 (MIRL)

    • Forms a defensive shield for red blood cells (RBCs) from complement-mediated lysis

    • Inhibits the assembly of the membrane attack complex

  • CD55 (DAF)

    • Prevents formation and augments instability of the C3 convertases, attenuating the complement cascade

CD59

CD55

GPI-anchor

GPI = glycerophosphatidylinositol.

1. Borowitz MJ et al.Cytometry B ClinCytom 2010;78:211–230.

Adapted from: Johnson RJ et al. J ClinPathol: Mol Pathol 2002;55:145–152;Brodsky R. Paroxysmal nocturnal hemoglobinuria. In: R Hoffman et al, eds. Hematology - Basic Principles and Practices. 4th ed. Philadelphia, PA: Elsevier Churchill Livingstone; 2005;419–427.


Advances in paroxysmal nocturnal hemoglobinuria pnh

Autoreactive T Cells from Patients with PNH Specifically RecognizeGlycosyl-Phosphatidyl-Inositol (GPI)

Abstract 647

Gargiulo et al


Advances in paroxysmal nocturnal hemoglobinuria pnh

PIG-A

Etn-P

GlcN

glycan

nucleus

PIG-A

Inositol-P

X chr.

GPI anchor

+

GPI

protein

ER

Paroxysmal Nocturnal Hemoglobinuria

Pathogenesis

PIG-A

PIG-A

nucleus

GPI anchor

X chr.

protein

ER

Normal cell

PNH cell

Hematopoietic Stem Cells


Advances in paroxysmal nocturnal hemoglobinuria pnh

Intravascular Hemolysis

Absence of complement regulators

Thrombosis

Absence of complement regulators

Bone Marrow Failure and cytopenia

Mechanism?

PNH Triad


Advances in paroxysmal nocturnal hemoglobinuria pnh

crippled

PIG-A+ cells

Noxious agent

Parodoxical Expansion of PNH Clone(Escape Theory)

Time

PIG-A+

cells

PIG-A null

cells

Rotoli & Luzzatto, 1989


Advances in paroxysmal nocturnal hemoglobinuria pnh

Evidence for a role of autoimmunity in PNH

  • PNH is closely related to aplastic anemia – a T-cell-mediated autoimmune disorder: T cells are the likely agents suppressing normal hematopoiesis in PNH.

  • The target of T cells could be either a GPI-linked protein or GPI itself.

  • GPIhas been found within the presentation groove of CD1d(Joyce et al. Science 1998; De Silva et al.J Immunol. 2002)

  • Identical or quasi-identical TCRβ CDR3 sequences found in CD8+CD57+ T cells in a group of HLA- disparate PNH patientssuggesting antigen not HLA -restricted(Gargiulo et al. Blood 2005)

  • CD1d is expressed on human and murine hematopoietic stem and progenitor cells(Kotsianidis et al. Blood 2006; Broxmeyer et al. Blood 2012)


Hypothesis gpi specific cd1d restricted t cells responsible for selection of pnh cells

Hypothesis: GPI-specific, CD1d-restricted T cells responsible for selection of PNH cells

T cell

T cell

T cell receptor

No Killing

Killing

GPI

CD1d/b2m

GPI-anchored

protein

GPI+

GPI-

Karadimitris and Luzzatto, Leukemia 2001


Advances in paroxysmal nocturnal hemoglobinuria pnh

*p=0,0355

C1R C1R- CD1d

with GPI addition

6 PNH Patients

CD1d-dependent GPI-specific T cells in PNH

*Wilcokson Rank Test


Advances in paroxysmal nocturnal hemoglobinuria pnh

Normal Controls

PNH Patients

Increased frequency of novel invariant TCRVa21 mRNA chain

within the whole TCRVa21 family repertoire of PNH patients


Summary

Summary

CD1d-restricted GPI-specific CD8+ T cells are present and expanded in PNH patients.

T cells with a novel invariant TCRa chain have been discovered in some PNH patients.

These T cells could be the “noxious agent” responsible for the pathogenesis of PNH.


Advances in paroxysmal nocturnal hemoglobinuria pnh

GPI-specific, CD1d-restricted T cells are present in PNH patients and could be the responsible of the suppression of GPI+ HSC.

T cell

T cell

No Killing

T cell receptor

Killing

GPI

CD1d/b2m

GPI-anchored

protein

GPI+

GPI-

Future work: further structural and functional characterization


Expansion of the pnh clone is necessary to result in clinical pnh

Expansion of the PNH Clone Is Necessary to Result in Clinical PNH

Step 1

Somatic Mutation of PIG-A

Step 2

Immunologic Attack

Selective Damage

Step 3

Growth Advantage

  • Expansion may be due to another somatic mutation

  • The need for both selection and expansion may explain the rarity of PNH

Selected Cells

Expanded Cells

GPI-Deficient Cell

Normal HematopoieticStem Cells

GPI-Anchor Deficiency

Immunologic

Selection

Benign Tumor- Like Expansion

Adapted from: Inoue N et al.Int J Hematol2003;77:107.


The role of complement

The Role of Complement


The complement system always on strongly amplified dependent on natural regulators

The Complement System: Always on, Strongly Amplified, Dependent on Natural Regulators

The complement system is a vital component of the natural (innate) protective immune system1

  • Complement is activated by three mechanisms (classical, alternative, and lectin) which allow the system to respond to inflammatory, infectious, ischemic, necrotic, as well as foreign and self antigens

  • Always ‘on’ to allow rapid immune response1

    • Rapid amplification leads to powerful and destructive immune reactions2

    • Natural inhibitors of complement keep amplification in check and prevent uncontrolled complement activation2

1. Holers VM et al. ImmunolRev 2008;223:300–316; 2. Zipfel PF et al.CurrOpinNephrolHypertens2010;4:372–378.


Factors that amplify complement activation

Factors That Amplify Complement Activation

Glovsky MM et al.Ann Allergy Asthma Immunol2004;93:513–523; Rubio MT et al.Bone Marrow Transplant 2008;41(Suppl. 1):S220. Abstract P766; Mastellos D et al. Immunologic Res 2003;3:367–385; Mergenhagen STE et al. J Infect Dis 1973;128:S86; Chenoweth DE et al.N Engl J Med 1981;304:497–503; Giradi G. Am J ReprodImmunol2008;59:183–192.


Chronic uncontrolled c omplement activation leads to devastating consequences in pnh

Chronic Uncontrolled Complement ActivationLeads to Devastating Consequences in PNH

Lectin pathway

Classical pathway

Alternative pathway

Immune complex clearanceMicrobial Opsonization

C3

C3 + H2O: always active (chronic)

Proximal

Amplification

Weak anaphylatoxin

C3a

Natural inhibitor:

CD59

-

Natural inhibitors:

CD55

-

C3b

iC3b

C5-convertase

C5

Terminal

C5b

C6

C7

C8

C9

  • C5a

  • Potent anaphylatoxin

  • Chemotaxis

  • Pro-inflammatory

  • Leucocyte activation

  • Endothelial activation

  • Pro-thrombotic

    • C5b-9Membrane attack complex

  • Cell lysis

  • Pro-inflammatory

  • Platelet activation

  • Leucocyte activation

  • Endothelial activation

  • Pro-thrombotic

  • Anaphylaxis

    Inflammation

    Thrombosis

    Cell destruction

    Inflammation

    Thrombosis

    Consequences

    Consequences

    1. Zipfel PF et al. Vaccine. 2008;26(Suppl 8):I67-74; 2. Figueroa JE, Densen P. ClinMicrobiolRev. 1991;4:359-95; 3. Walport MJ. N Engl J Med. 2001;344:1058-66; 4. Rother RP et al. Nat Biotechnol. 2007;25:1256-64; 5. Meyers G et al. Blood. 2007;110:abs 3683; 6. Hill A et al. Br J Haematol. 2010;149:414-25; 7. Hillmen P et al. Am J Hematol. 2010;85:553-9; 8. Parker C et al. Blood.2005;106:3699-709; 9. Hillmen P et al. N Engl J Med. 1995;333:1253-8; 10. Nishimura J et al. Medicine (Baltimore). 2004;83:193-207; 11. Caprioli J et al. Blood. 2006;108:1267-79; 12. Noris M et al. Clin J Am Soc Nephrol. 2010;5:1844-59; 13. George JN. Blood. 2010;116:4060-9; 14. Loirat C et al. PediatrNephrol. 2008;23:1957-72; 15. Ståhl AL et al. Blood. 2008;111:5307-15; 16. Hosler GA et al. Arch Pathol Lab Med. 2003;127;834-9; 17. Ariceta G et al. PediatrNephrol.2009;24:687-96.


    Absence of cd59 allows terminal complement complex formation

    AdBoard Master_Sept 14, 2010

    Absence of CD59 Allows Terminal Complement Complex Formation

    C5a

    C8

    C6

    C6

    C6

    C6

    C6

    C5

    CD59

    CD59

    C7

    C7

    C7

    C7

    C7

    C5b

    C5b

    C5b

    C5b

    C5b

    C9

    C9

    x 12 - 15

    C8

    X

    X

    C5

    convertase

    C5

    convertase

    C9

    C8

    C8

    C5b-9

    C5b,6,7

    C5b-8

    Adapted from: Cellular and Molecular Immunology AK Abbas, AH Litchman and JS Pober, 3rd Edition. 1991 WB Saunders; Philadelphia.


    Chronic uncontrolled complement activation leads to tissue and end organ damage

    Chronic Uncontrolled Complement Activation Leads to Tissue and End Organ Damage

    • Strict regulation is needed to avoid unnecessary damage to self due to overt or mistargeted activation1,2

      • Tight control needed especially for the alternative pathway which is continuously turned on

    Membrane Attack Complex (MAC)

    on PNH Erythrocyte

    Photo: W Rosse. Reprinted with Permission.

    Endothelial Cells Damaged by Complement Attack

    Photo: S. Meri, Univ. of Helsinki.

    Reprinted with Permission.

    1. HolersVM et al. ImmunolRev 2008;223:300–316; 2. ZipfelPF et al. CurrOpinNephrolHypertens 2010;4:372–378.


    Historically viewed as a hemolytic anemia

    Historically Viewed as a Hemolytic Anemia

    Normal red blood cells (RBCs) are protected from complement attack by a shield of terminal complement inhibitors

    Without this protective complement inhibitor shield, PNH RBCs are destroyed

    ComplementActivation

    Lack of Bound CD55, CD59 Leads to Uncontrolled Complement Activation

    Intact RBC

    Reduced Red Cell Mass

    Anemia

    Free Hemoglobin

    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 Shattilet 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.


    Hemolysis leads to no consumption in pnh patients

    Hemolysis Leads to NO Consumption in PNH Patients

    R=0.5094, P<0.001

    R=0.9529, P<0.0001

    NO consumption assay: NO chemiluminescence

    100

    100

    Plasma Free Hb (µmol/l)

    Plasma Free Hb (µmol/l)

    10

    10

    1

    1

    1

    100

    10

    1000

    10000

    LDH (u/l)

    NO Consumption (µmol/l)

    • LDH significantly correlates with free hemoglobin (Hgb)1

      • Confirms LDH as a biomarker for hemolysis

      • LDH ≥1.5x at diagnosis had a 4.8-fold greater mortality2

    • Free Hgb significantly correlates with NO consumption

      • Hgb is in reduced state and reactive with NO

    1. Hill A et al. Br J Haematol 2010;149:414–425; 2. Lee JW et al. ASH 2011. Abstract 3166.


    Consequences of nitric oxide no depletion

    Consequences of Nitric Oxide (NO) Depletion

    Reduced Nitric Oxide Can Cause

    • Smooth muscle dystonias1

      • Vascular constriction – pulmonary and systemic hypertension, erectile dysfunction2

      • Gastrointestinal contractions – dysphagia, abdominal pain

    • Platelet activation and aggregation1–4

      • Platelet hyperreactivity

      • Hypercoagulability

    1. Rother R et al. JAMA 2005;293:1653–1662; 2. Hill A et al.Br J Haematol 2010;149:414–425; 3. Weitz I. Thrombosis Res 2010;125:S106–S107; 4. Helley D et al.Haematologica2010;95:574–581.


    Chronic uncontrolled complement activation leads to devastating consequences

    Chronic Uncontrolled Complement Activation Leads to Devastating Consequences

    Thrombosis

    Renal Failure

    Significant Impact on Survival

    Pulmonary Hypertension

    Abdominal Pain

    ComplementActivation

    Chest Pain

    Dyspnea

    Elevated LDH

    Dysphagia

    Free Hemoglobin

    Significant Impact on Morbidity

    Fatigue

    Decreased NO

    Hemoglobinuria

    Erectile Dysfunction

    LDH = lactate dehydrogenase.

    1. International PNH Interest Group. Blood 2005;106:3699–3709; 2. Brodsky R.Paroxysmal nocturnal hemoglobinuria. In: R Hoffman et al, eds. Hematology - Basic Principles and Practices. 4th ed. 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.Hematologica2010;95(s2): Abstracts 505 and 506; 7. Hill A et al.Br J Haematol 2010;149:414–425;8. Hillmen P et al.Am J Hematol 2010;85:553–559.


    Historical management of pnh

    Historical Management of PNH

    Supportive care options do not impact progression and risk for severe morbidities and mortality1

    • Transfusions1 – risk of iron overload

    • Anticoagulants1 – ineffective in many patients

    • Red cell supplements1 – may expand clone and elevate hemolysis

    • Steroids/androgen hormones1 – adverse events

      Although BMT is the only potentially curative therapy for PNH, BMT is associated with significant morbidities and mortality2,3

    • In a study examining PNH patients (n=23)2

      • 50% chronic GVHD; 42% acute GVHD3

      • Transplant-related mortality was 42%

    • BMT has a significant impact on quality of life (QoL) post-transplant4,5

    1. International PNH Interest Group. Blood 2005;106:3699–3709; 2. Santaraone S et al. Haematologica2010;95:983–988; 3. de Latour PF et al.EBMT 2009:Abstract 316; 4. Bieri S et al.Bone Marow Transplant 2008;42:819–827; 5. Fraser CJ et al. Blood 2006;108:2867–2873.


    Morbidities and mortality in pnh

    Morbidities and Mortality in PNH


    Thrombosis is the leading cause of death in pnh 1

    Thrombosis

    Thrombosis Is the Leading Cause of Death in PNH1

    • Accounts for 40–67% of deaths2

      • First thrombotic event (TE) can be fatal2,3

      • First TE increases risk for death 5- to 10-fold2

    • Up to 44% of patients experience clinical thrombotic events2

    • Occurs in typical and atypical sites4

    • Is not adequately managed with anticoagulation2

    • All patients with PNH are at risk for thrombosis2

    1. International PNH Group et al.Blood 2005;106:3699–3709; 2. Hillmenet al. Blood 2007;110:4123–4128; 3. AudebertHJ et al.J Neurol 2005;252:1379–1386; 4. Lee JW et al.Hematologica2010;95(s2): Abstract 506.


    Multifactorial pathogenesis of thrombosis in pnh

    Thrombosis

    Multifactorial Pathogenesis of Thrombosis in PNH

    • Pathogenesis of thrombosis in PNH is a result of uncontrolled complement activation1

    • Activation of complement C5b–9

      • Hemolysis leads to reduced nitric oxide levels and vasoconstriction2–4

      • Platelets undergo morphological changes, release microparticles, and aggregate2,4

    • Activation of complement C5a

      • Leukocytes release tissue factor and inflammatory cytokines (IL-6) to initiate coagulation2,3,5

      • Leukocytes decrease expression of plasminogen activator receptor (PAR) leading to impaired fibrinolysis4

    1. McKeage K. Drugs 2011;71:2327–2345; 2. Hill A et al.Br J Haematol 2007;137:181–192; 3. Weitz I. Thrombosis Res 2010;125:S106–S107; 4. Helley D et al.Hematologica.2010;95:574–581; 5. Markiewski MM et al.Trends Immunol 2007;28:184–192.


    Chronic uncontrolled complement activation leads to vasoconstriction and thrombosis

    Thrombosis

    Chronic Uncontrolled Complement Activation Leads to Vasoconstriction and Thrombosis

    Impaired regulation of

    smooth muscles

    Local vasoconstriction

    Pro-inflammatory effect

    on endothelial cells

    Chronic hemolysis

    Platelet activation

    Local vasoconstriction

    Chronic

    Hemolysis

    Chronic

    UncontrolledComplementActivation

    [NO]

    C5b-9

    C5b-9

    C5a

    CLOT

    Inflammation

    Endothelial cell injury

    Systemic thrombosis

    Platelet

    Activation

    Inflammation

    Platelet

    Aggregation

    Leukocyte

    Activation

    Adapted from: Gladwin MT et al.Free Rad Biol & Med 2004;36:707–717; Rother RP et al. JAMA 2005;293:1653–1662.


    The incidence of te is increased in patients with elevated ldh at diagnosis

    Thrombosis

    The Incidence of TE is Increased in Patients with Elevated LDH at Diagnosis

    P<0.001

    • Univariate analysis showed that the incidence of TE was significantly increased in patients with LDH ≥1.5x ULN at diagnosis (43/171; 25.1%) compared with patients with LDH <1.5x ULN (2/53; 3.8%; OR 8.57)

    Data from South Korean National Registry.

    Lee JW et al. Presented at the 54th Annual Meeting of the American Society of Hematology; December 8–11, 2012; Atlanta, GA. Abstract 1273.


    Risk of first ever ischemic stroke feis elevated in pnh

    Thrombosis

    Risk of First Ever Ischemic Stroke (FEIS) Elevated in PNH

    Age of FEIS in PNH patients is markedly less than in the general population1

    2,3

    1

    2,3

    1

    1. Gostynski M et al.J Neurol 2006;253:86–91; 2.Hillmen P et al. Blood 2007;110:4123–4281; 3. Data on file. Alexion Pharmaceuticals, Inc.


    Thrombosis is associated with risk of early mortality

    Thrombosis

    Thrombosis is Associated With Risk of Early Mortality

    TE increases risk of death 15-fold over patients with no TE

    • TE was an independent prognostic factor related to poor survival (HR 15.4; 95% CI 9.3–25.4; P<0.001) in a large cohort of French PNH patients

    (n=415)

    de Latour RP et al.Blood 2008;112:3099–3106.


    Thrombosis occurs in both typical and atypical sites

    Thrombosis

    HillmenP et al.Blood 2007;110:4123–4128.

    Thrombosis Occurs in Both Typical and Atypical Sites*

    Myocardial Infarction/

    unstable angina

    ARTERIAL

    Superficial vein thrombosis

    Cerebrovascular accident/ transient ischemic attack

    Cerebral/internal

    jugular thrombosis

    Pulmonary embolus

    Deep vein thrombosis*

    Hepatic/portal vein

    thrombosis

    VENOUS

    Mesenteric/splenic vein thrombosis

    *124 events, 63 patients

    *Includes 18.5% lower extremity and 14.5% other (inferior vena cava, bilateral lower extremity, pelvic, ureter, axillary, subclavian, and brachiocephalic veins).


    Pnh patients are at risk of thrombosis despite anticoagulation or minimal transfusion requirements

    Thrombosis

    PNH Patients are at Risk of Thrombosis Despite Anticoagulation or Minimal Transfusion Requirements

    (n=91)

    (n=22)

    HillmenP et al. Blood 2007;110:4123–4128.


    Thrombosis can occur regardless of clone size

    Thrombosis

    Thrombosis Can Occur Regardless of Clone Size

    (n=43)

    Data from South Korean National Registry.

    Lee JW et al.Hematologica 2010;95(s2): Abstract 505.


    Thrombosis in pnh conclusions

    Thrombosis

    Thrombosis 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

      • LDH 1.5× ULN at diagnosis is associated with TE and mortality3

    • DVT or PE most common clinical presentation1

      • Arterial thromboses are also common1

    • Anticoagulant therapy may not be adequate to control thrombosis in PNH1

    • Clinical thrombosis evident in PNH patients:

      • No transfusion history1

      • Smaller clone size4

    1. Hillmen P et al.Blood 2007;110:12:4123–4128; 2. International PNH Group et al.Blood 2005;106:3699–3709; 3. Lee JW et al. Blood (ASH Annual Meeting Abstracts) Nov 2011;118:3166; 4. Lee JW et al.Hematologica2010;95(s2): Abstract 506.


    Kidney pathology in pnh

    Chronic Kidney Disease

    1. Brodsky R. Hematology: Paroxysmal nocturnal hemoglobinuria. In: R Hoffman et al, eds. Hematology - Basic Principles and Practices. 4th ed. Philadelphia, PA: Elsevier Churchill Livingstone 2005;419–427; 2. Rother R et al.JAMA 2005;293:1653–1662; 3. Clark DA et al.Blood 1981;57:83–89; 4. Hillmen P et al.Am J Hematol 2010;85:553–559; 5. McKeage K. Drugs 2011;71:2327–2345.

    Kidney Pathology in PNH

    • Complement-mediated hemolysis and cell-free plasma hemoglobin lead to chronic kidney disease in PNH1–5

    • Repetitive exposure of tissue to cell-free hemoglobin may lead to renal damage in PNH3,4

    Micrograph of a Renal Biopsy from a PNH Patient, Indicative of Vascular Damage

    Normal tissue on the right

    Interstitial scarring on the left

    Clark DA, et al. Blood. 1981;57:83-89. Reprinted with Permission.


    Chronic kidney disease morbidity and mortality in pnh

    Chronic Kidney Disease

    1.Hillmen P, et al. Am J Hematol 2010;85:553–559; 2. Brodsky R. Hematology: Paroxysmal nocturnal hemoglobinuria. In: R Hoffman et al, eds. Hematology - Basic Principles and Practices. 4th ed. Philadelphia, PA: Elsevier Churchill Livingstone 2005;419–427. 3. Hill A. et al. Blood 2006;108: Abstract 979.

    Chronic Kidney Disease: Morbidity and Mortality in PNH

    • Kidney failure is the cause of 8–18% of PNH-related deaths1

    • 80% of PNH patients (median age of 31.5 years) had MRI evidence of significant renal hemosiderosis2,3

      • Marked hemosiderin deposits in the proximal renal tubule are a common feature in all autopsy and biopsy reports dealing with PNH

      • Demonstrable by MRI even when no overt hemoglobinuria is seen


    64 of pnh patients exhibit clinical chronic kidney disease ckd

    Chronic Kidney Disease

    64% of PNH Patients Exhibit Clinical Chronic Kidney Disease (CKD)

    1. HillmenP et al. AmJ Hematol 2010;85:553–559.


    Kidney disease in pnh conclusions

    Chronic Kidney Disease

    Kidney Disease in PNH: Conclusions

    • Kidney failure is the cause of 8–18% of PNH-related deaths1

    • Kidney disease in PNH is caused by complement-mediated hemolysis2,3

    • 64% of patients with PNH exhibit chronic kidney disease at any one time4

    • Kidney disease is underappreciated in PNH4

    1. Nishimura JI et al. Medicine 2004;83:193–207; 2. Clark DA et al.Blood 1981;57:83–89; 3. McKeage K. Drugs 2011;71:2327–2345; 4. Hillmen P et al.Am J Hematol 2010;85:553–559; 5. Kim JSet al.Hematologica 2011;96(s2): Abstract 271.


    Clone size does not correlate to symptom severity

    Common Symptoms of PNH

    Clone Size Does Not Correlate to Symptom Severity

    1. Urbano-Ispizua A et al. Hematologica 2010;95(s2): Abstract 1022.


    Common pnh symptoms are associated with te

    Common Symptoms of PNH

    Common PNH Symptoms are Associated With TE

    P=0.0004

    P=0.024

    P=0.015

    Elevated LDH (≥1.5× ULN) in combination with abdominal pain, chest pain,

    and dyspnea are associated with a higher risk of TE

    Study description: a retrospective analysis of the medical charts of 286 PNH patients in a South Korean National Registry.

    Lee JW et al. Hematologica2010;95(s2): Abstracts 505 and 506.


    Advances in paroxysmal nocturnal hemoglobinuria pnh

    Common Symptoms of PNH

    Data from South Korean National Registry.

    Lee JW et al. Presented at the 54th Annual Meeting of the American Society of Hematology; December 8–11, 2012; Atlanta, GA. Abstract 1273.

    Chronic Complement-Mediated Hemolysis in Combination With Clinical Symptoms Increase the Risk of Thrombosis

    Odds Ratio for TE (Multivariate Analysis)

    The risk of TE in patients with LDH ≥1.5× ULN was 7.01 times greater than in patients with LDH <1.5× ULN (P=0.013).


    Common symptoms of pnh conclusions

    Common Symptoms of PNH

    Common Symptoms of PNH: Conclusions

    • Common symptoms in PNH associated with TE should be considered as part of a comprehensive clinical assessment

      • Abdominal pain, chest pain, dyspnea, hemoglobinura

    • Abdominal pain and dyspnea are linked by underlying hemolysis and the threat of thrombosis2

      • 66% of patients report shortness of breath3

      • 59% of patients report abdominal pain4

    • 97% of patients report fatigue1

      • Fatigue and severe dyspnea are prominent clinical features that can be associated with pulmonary hypertension and cardiac dysfunction

    • 76% of patients with PNH have disruptions in daily activities1

    • Clone size does not correlate to symptom severity5

    1. Weitz I et al. Intern Med J. 2012; 2. Lee JW et al. Hematologica 2010;95(s2): Abstract 506. 3. Meyers G et al. Blood 2007;110: Abstract 3683;

    4. Lee JW et al. Hematologica 2010;95(s2): Abstract 505; 5. Urbano-Ispizua A et al. Hematologica 2010;95(s2): Abstract 1022.


    Early identification of patients at high risk for pnh

    Early Identification of Patients at High Risk for PNH


    Advancements in treatment o ptions w arrant e arly d iagnosis and intervention

    Advancements in Treatment Options Warrant Early Diagnosis and Intervention

    • Early diagnosis is essential for improved patient prognosis:

      • PNH

      • Bone marrow failure1

    • International PNH Registry

      • Provides evidence to inform clinical decision making

      • Over 2100 patients from 26 countries are currently enrolled in the PNH registry

    1. Sugimori C et al. Blood 2006;107:1308–1314.


    Two independent international groups recommend testing high risk patients for pnh

    Two Independent International Groups Recommend Testing High-Risk Patients for PNH

    Guidelines for the diagnosis and monitoring of paroxysmal nocturnal hemoglobinuria and related disorders by flow cytometry

    Michael J. Borowitz *, Fiona E. Craig, Joseph A. DiGiuseppe, Andrea J. Illingworth, Wendell Rosse, D. Robert Sutherland, Carl T. Wittwer, Stephen J. Richards, On behalf of the Clinical Cytometry Society

    Borowitz MJ et al. International Clinical Cytometry Society. Part B Clin Cytometry 2010;78B:211–230; International PNH Interest Group. Blood 2005;106:3699–3709.


    Suggestions for pnh testing by iccs pnh guidelines

    Suggestions for PNH Testing by ICCS PNH Guidelines

    Borowitz MJ et al; Clinical Cytometry Society. Cytom B Clin Cytom 2010;78B:211–230


    Advances in paroxysmal nocturnal hemoglobinuria pnh

    Incidence of PNH Clones by Diagnostic Code in the Clinical Setting Utilizing High-Sensitivity Flow Cytometry (HSFC)

    Objective:

    To use multi-parameter HSFC to analyze the incidence of PNH clones in patients recommended for testing in the clinical setting

    Key Results:

    • 6987 individuals were screened for PNH clones utilizing HSFC

    • 421 of 6987 patients (6.1%) across all high-risk populations recommended for testing were found to be PNH positive

      • PNH clinical clone (>1%) detection rate was 3.8%

      • Subclinical clone (<1%) detection rate was 2.3%

    Movalia MK et al. Presented at the American Society of Hematology 53rd Annual Meeting; December 10–13, 2011; San Diego, CA. Abstract 1033.


    Incidence of pnh clones in high risk patient populations

    Incidence of PNH Clones in High-Risk Patient Populations

    ICD-9 = International Classification of Diseases, 9th revision.

    *Includes patients already diagnosed as having PNH.

    Patients with PNH clone ≥ 0.01%

    High-risk patients may be included in more than 1 ICD-9 category.

    • MovaliaMK et al.Presented at the American Society of Hematology 53rd Annual Meeting; December 10–13, 2011; San Diego, CA. Abstract 1033.


    Pnh clonal expansion in an aa representative population

    PNH Clonal Expansion in an AA Representative Population

    At the Last ofFollow Up

    At the Start ofFollow Up

    Transitional patternn (%)

    n=75

    (Classic PNH)(8) (11%)

    Expansion13 (17%)

    PNH+Patients

    Persistent44 (59%)

    Newly developed5 (4%)

    Disappearance18 (24%)

    n=114

    109 (96%)

    PNH-Patients

    Sugimori C et al. BJH. 2009;147:102-112.


    Immunosuppressive therapy ist has increased efficacy in aa patients with pnh cells

    AA

    Immunosuppressive Therapy (IST) Has Increased Efficacy in AA Patients With PNH Cells

    *

    • The presence of PNH cells was the only significant predictor of response to IST in 140 AA patients (P<0.01) in multivariate analysis2

    *

    Patients With Response

    Complete response (CR) was defined as hemoglobin normal for age, neutrophil count more than 1.5 × 109/L, and platelet count more than 150 × 109/L; Partial response (PR) was defined as transfusion independent and no longer meeting criteria for severe disease in patients with severe AA.1 Overall response = CR + PR

    *P value = complete response, P=0.03; Overall response, P<0.001.

    • 1. Sugimori C et al. Blood 2006;107:1308–1314; 2. Sugimori C et al.ExpHematol 2007;35:13–20.


    Advances in paroxysmal nocturnal hemoglobinuria pnh

    AdBoard Master_Sept 14, 2010

    Considerations for Managing the PNH/AA Patient

    PNH

    AA/PNH

    PNH with hemolysis

    PNH Intermediate + hemolysis

    Severe AA without hemolysis

    Moderate AA with hemolysis

    Moderate AA without hemolysis

    ?

    IST

    BMT

    ProphylacticAnticoagulaion

    Eculizumab

    De Latour RP, Amoura Z, and Socie G. La revue de medecine interne. 2010; 200-207.


    Evidence of pnh cells in ra mds

    RA-MDS

    Evidence of PNH Cells in RA-MDS

    • Interim Results from EXPLORE, a Multi-center Prevalence Study of PNH Clone Size in Patients with AA, MDS, and other BMF

    Galili N et al. Poster presentation at: American Society of Clinical Oncology 45th Annual Meeting; May 29–June 2, 2009; Orlando, FL..


    Patients with unexplained cytopenias are at high risk for pnh 1

    Unexplained Cytopenias

    Patients With Unexplained Cytopeniasare at High Risk for PNH1

    Test the Following Cytopenic Patients for PNH5,6

    Unexplained Cytopenia

    Cytopenia and Evidence of Hemolysis

    Cytopenia With Any of These Coexisting Findings

    • After thorough work-up

    • LDH

    • Haptoglobin

    • Reticulocyte count(with or without anemia)

    • Thrombosis

    • Anemia

    • Coombs-negative hemolytic anemia

    • Bone marrow failure disorder

    • Hemoglobinuria(dark colored urine)

    *0.01% PNH cell threshold.

    • 1. Movalia MK et al. Blood 2011;118: Abstract 1033; 2. Barzi A, Sekeres MA. ClevClin J Med 2010;77:37–44; 3. Jordan MB et al. Blood 2011;118:4041–4052; 4. Moreno C et al.Blood 2010;116:4771–4776; 5. Borowitz MJ et al;Clinical Cytometry Society. Cytom BClinCytom2010;78B:211–230; 6. Brodsky RA. Blood 2009;113:6522–6527.


    93 of patients with pnh have peripheral blood abnormalities

    Unexplained Cytopenias

    93% of Patients With PNH Have Peripheral Blood Abnormalities

    No concomitant cytopenias

    Other combinations*

    Anemia and

    neutropenia

    Anemia and

    thrombocytopenia

    Anemia: hemoglobin <12.0 g/L .

    Neutropenia: ANC <1.5×109/L.

    Thrombocytopenia: platelet count <1.5×1011/L.

    *Other combinations: thrombocytopenia alone, neutropenia alone, both thrombocytopenia and neutropenia.

    Socieet al. Lancet 1996;348:573–577.


    How do you test for pnh

    How Do You Test for PNH?


    Standard diagnostic test for pnh

    Standard Diagnostic Test for PNH

    • Flow cytometry performed on peripheral blood

    • Granulocytes and at least one additional cell line should be evaluated

      • RBCs

      • Monocytes

    • Quantitative results

      • Optimal–high sensitivity analysis: ≥0.01%

      • Routine analysis: ≥1%

    • Easy to understand PNH reports

    • Use more than one reagent against GPI-anchored proteins

    Borowitz MJ et al.; Clinical Cytometry Society. Cytom B Clin Cytom 2010;78B:211–230.


    Testing for pnh in rbcs

    Patient 1:

    Normal RBCs with normal CD59 expression (Type I cells)

    Patient 2:

    PNH clone with complete CD59 deficiency (Type III cells)

    Patient 3:

    PNH clone with complete CD59 deficiency (Type III cells) and partial CD59 deficiency (Type II cells)

    Testing for PNH in RBCs

    Gating on GPA+ RBCs

    • GPA = glycophorin A.

    • Data Source: Dahl-Chase Diagnostic Services..


    Why look beyond rbcs for pnh

    Why Look Beyond RBCs for PNH?

    • Granulocytes provide more accurate representation of PNH clone size1

    • Percentages of PNH RBCs may be affected by:

      • Hemolysis

      • Blood transfusion

    PNH reports should provide quantitative results expressing clone size on both granulocytes and RBCs

    1. Borowitz MJ et al; Clinical Cytometry Society. Cytom B Clin Cytom 2010;78B:211–230.


    Pnh patient with an 80 wbc clone size and 31 rbc clone size indicating hemolysis

    PNH Patient With an 80% WBC Clone Size and 31% RBC Clone Size Indicating Hemolysis

    WBC

    RBC

    CD24- Granulocytes

    FLAER- GPI Anchor Binding Marker

    CD59 – GPI Anchored Protein

    80.1 % of Granulocytes lack GPI proteins

    31.4% RBCs are Type III PNH cells

    Data Source: Dahl-Chase Diagnostic Services.


    Iccs recommendations for follow up testing of patients with an identified pnh clone

    ICCS Recommendations for Follow-Up Testing of Patients With an Identified PNH Clone

    • Annual monitoring1

      • Stable patients

      • Patients with aplastic anemia and small PNH clone

      • Patients with refractory cytopenia with unilineage dysplasia (RCUD) and small PNH clone

    • More frequent monitoring to evaluate for expanding clones

      • Patients with changing symptoms or lab values

      • Patients in early stages of treatment

    1. Borowitz MJ et al.; Clinical Cytometry Society. Cytom BClinCytom2010;78B:211–230.


    Importance of monitoring granulocytes and rbcs over time

    December 2008

    May 2009

    March 2009

    CD14-Granulocytes

    CD24-Granulocytes

    CD24-Granulocytes

    CD24-Granulocytes

    FLAER-GPI Anchor Marker

    FLAER-GPI Anchor Marker

    FLAER-GPI Anchor Marker

    Gran clone: 7.6%

    RBC clone: 1.6%

    Gran clone: 23.3%

    RBC clone: 2.4%

    Gran clone: 14.2%

    RBC clone: 1.8%

    CD59 –GPI Anchor Protein

    CD59 –GPI Anchor Protein

    CD59 –GPI Anchor Protein

    6 Months

    3 Months

    9 Months

    Importance of Monitoring Granulocytes and RBCs Over Time

    September 2008

    CD24-Granulocytes

    FLAER-GPI Anchor Marker

    Gran clone: 3.8%

    RBC clone: 0.8%

    CD59 –GPI Anchor Protein

    PNH Clone Expanded in <1 Year

    Data Source: Dahl-Chase Diagnostic Services.


    Advances in paroxysmal nocturnal hemoglobinuria pnh

    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 2000 patients enrolled

    Participation in 24 countries, including Argentina, Australia, Belgium, Canada, Denmark, Finland, France, Germany, The Netherlands, New Zealand, Russia, South Korea, Spain, Sweden, Switzerland, Taiwan, United Kingdom, United States

    Enrollment information: www.pnhsource.com


    Soliris eculizumab humanized first in class anti c5 antibody

    SOLIRIS® (eculizumab) Humanized First in Class Anti - C5 Antibody

    • Human Framework Regions

    • No mutations

    • Germline

    Complementarity Determining Regions

    (murine origin)

    Human IgG4 Heavy Chain

    Constant Regions 2 and 3

    (Eliminates complement activation)

    Human IgG2 Heavy Chain

    Constant Region 1 and Hinge

    (Eliminates Fc receptor binding)

    Hinge

    CH1

    CL

    CH2

    CH3

    Rother R et al. Nat Biotech 2007;25:1256


    Eculizumab blocks terminal complement 1 2

    Eculizumab Blocks Terminal Complement1,2

    Complement Cascade2,3

    Soliris

    • Eculizumab binds with high affinity to C51,2

    C3

    C3a

    Proximal

    • Terminal complement - C5a and C5b-9 formation blocked1,2

    C3b

    • Proximal functions of complement remain intact1,2

      • Weak anaphylatoxin2,4

      • Immune complex clearance2

      • Microbial opsonization2

    C5

    C5a

    Terminal

    C5b

    C5b-9

    Please see full prescribing information for Soliris® (eculizumab).

    1. Soliris® (eculizumab) Summary of Product Characteristics. Alexion Europe SAS; 2012;2. Rother RP et al. Nature Biotech 2007;25:1256–1264; 3. Walport MJ. N Engl J Med 2001;344:1058–1066; 4. Figueroa JE, Densen P. Clin MicrobiolRev 1991;4:359–395.


    Therapeutic indications and usage

    Therapeutic Indications and Usage

    Eculizumab is a Complement Inhibitor Indicated for:

    • The treatment of patients with paroxysmal nocturnal hemoglobinuria(PNH) to reduce hemolysis

    • The treatment of patients with atypical hemolytic uremic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy

      The effectiveness of Eculizumabin aHUS is based on the effects on thrombotic microangiopathy (TMA) and renal function

      Prospective clinical trials in additional patients are ongoing to confirm the benefit of Eculizumabin patients with aHUS

    Please see full prescribing information for Soliris® (eculizumab).

    Soliris® (eculizumab) Summary of Product Characteristics. Alexion Europe SAS; 2012.


    Warning serious meningococcal infections

    WARNING: SERIOUS MENINGOCOCCAL INFECTIONS

    Eculizumab increases the patient’s susceptibility to meningococcal infection due to its mechanism of action

    • To reduce the risk of infection, a tetravalent vaccine against serotypes A, C, Y and W135 (preferably conjugate), is strongly recommended to vaccinate patients at least 14 days prior to receiving the first dose of eculizumab

      • Patients less than 2 years of age or not vaccinated at least 14 days before starting treatment with eculizumab must receive treatment with appropriate prophylactic antibiotics until 14 days after vaccination. Revaccinate according to current medical guidelines for vaccine use

    • Vaccination may not be sufficient to prevent meningococcal infection and the use of antibacterial agents may need to be considered

    • Monitor patients for early signs of meningococcal infection; evaluate immediately if infection is suspected and treat with antibiotics if necessary

    Please see full prescribing information for Soliris® (eculizumab). Soliris® (eculizumab) Summary of Product Characteristics. Alexion Europe SAS; 2012.


    What is the long term experience with eculizumab

    What is the Long-Term Experience With Eculizumab?

    Pilot Study – NEJM2004

    N=11

    Primary endpoint: reduction of hemolysis

    Long-Term Extension Trial HillmenBlood2007

    Evaluated long-term safety, efficacy and effect on thrombosis; Placebo patients switched to eculizumab

    N=187

    TRIUMPH – NEJM2006

    Pivotal Phase III, Double-Blind, Placebo-Controlled Trial, N=87

    SHEPHERD – Blood2008

    Broader patient population, including those receiving minimal transfusions or with thrombocytopenia, N = 97

    Please see full prescribing information for Soliris® (eculizumab).

    Soliris® (eculizumab) Summary of Product Characteristics. Alexion Europe SAS; 2012.


    Eculizumab is a chronic treatment for a chronic disease

    In clinical trials all patients were vaccinated against Neisseria meningitidis¹

    Concomitant medications allowed:

    Steroids, immunosuppressant drugs, anti-clotting agents and hematinics²

    Eculizumab should be administered via IV infusion within 25-45 minutes every 7 days during induction and every 14 days during maintenance¹

    Eculizumabdose adjustment to every 12 days may be necessary for some patients to maintain LDH reduction¹

    Eculizumab is a Chronic Treatment for a Chronic Disease

    q14d

    Dose within ±2 days.

    Please see full prescribing information for Soliris® (eculizumab).

    1. Soliris® (eculizumab) Summary of Product Characteristics. Alexion Europe SAS; 2012. 2. Hillmen P et al. N Engl J Med 2004;350:552–559.


    86 reduction in ldh triumph and shepherd

    TRIUMPH – Placebo/Extension

    TRIUMPH – Soliris/Extension

    SHEPHERD – Eculizumab

    0

    4

    8

    12

    16

    20

    24

    28

    32

    36

    40

    44

    48

    52

    Time, Weeks

    86% Reduction in LDH: TRIUMPH and SHEPHERD

    3000

    2500

    2000

    1500

    100% response after the first dose

    LDH (U/L)

    1000

    500

    0

    • TRIUMPH placebo patients switched to Eculizumabafter Week 26

    • All TRIUMPH patients entered the long-term extension study

    P<0.001 at all measured time points.

    Please see full prescribing information for Soliris® (eculizumab). Soliris® (eculizumab) Summary of Product Characteristics. Alexion Europe SAS; 2012.

    Hillmen P et al. Blood 2007;110:4123–4128.


    92 reduction in thrombotic events

    45

    39

    40

    35

    30

    N=195

    25

    Thrombotic Events (#)

    20

    15

    P=0.0001

    10

    3

    5

    0

    EculizumabTreatment

    Pre-EculizumabTreatment

    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

    • There were fewer thrombotic events with Eculizumab treatment than during the same period of time prior to treatment2

    Please see full prescribing information for Soliris® (eculizumab).

    1. Brodsky R et al.Blood 2008;111:1840–1847; 2. Soliris® (eculizumab) Summary of Product Characteristics. Alexion Europe SAS; 2012; 3. HillmenP et al.Blood 2007;110:4123–4128.


    Eculizumab reduced thrombosis in patients treated with anticoagulants 1

    94% reduction in event rate with Eculizumab

    Eculizumab Reduced Thrombosis in Patients Treated with Anticoagulants1

    P<0.001

    N=91

    *Excludes patients on antiplatelet agents.

    Please see full prescribing information for Soliris® (eculizumab). Soliris® (eculizumab) Summary of Product Characteristics. Alexion Europe SAS; 2012.1. Hillmen P et al. Blood 2007;110:4123–4128.


    Effect of eculizumab on chronic kidney disease in pnh

    Effect of Eculizumab on Chronic Kidney Disease in PNH


    64 of patients exhibit chronic kidney disease ckd 1

    59% of patients with minimal (0–1) transfusion history had CKD (n=22)

    64% of Patients Exhibit Chronic Kidney Disease (CKD)1

    1. Hillmen P et al. Am J Hematol 2010;85:553–559.


    Renal function w ith eculizuamb in different baseline pnh populations 6 months 1

    Renal Function With Eculizuamb in Different Baseline PNH Populations – 6 Months1

    80

    75.0

    70

    64.2

    60.3

    60

    P<0.001

    P=0.05

    50

    Proportion of Patients (%)

    40

    31.7

    30

    24.7

    20.0

    20

    11.1

    7.9

    5.0

    10

    0

    Overall(n=189)

    Stage 1–2(n=81)

    Stage 3–5(n=40)

    Segment of PNH Population

    No Change

    Improvement

    Worsening

    Please see full prescribing information for Soliris® (eculizumab). Soliris® (eculizumab) Summary of Product Characteristics. Alexion Europe SAS; 2012.

    1. Hillmen P et al. Am J Hematol 2010;85:553–559.


    Renal function w ith eculizumab in different baseline pnh populations 18 months 1

    Renal Function With Eculizumabin Different Baseline PNH Populations – 18 Months1

    80

    71.4

    67.1

    70

    60.2

    60

    P<0.001

    P<0.001

    P=0.05

    50

    Proportion of Patients (%)

    40

    34.3

    30.1

    30

    22.9

    20

    5.4

    5.7

    10

    2.7

    0

    Overall(n=189)

    Stage 1–2(n=81)

    Stage 3–5(n=40)

    Segment of PNH Population

    No Change

    Improvement

    Worsening

    Please see full prescribing information for Soliris® (eculizumab). Soliris® (eculizumab) Summary of Product Characteristics. Alexion Europe SAS; 2012.

    1. Hillmen P et al. Am J Hematol 2010;85:553–559.


    Chronic kidney disease in pnh summary

    Chronic Kidney Disease in PNH: Summary

    • Early intervention with eculizumab has shown a time-dependent improvement in renal function in protecting against progression of renal damage1

    Please see full prescribing information for Soliris® (eculizumab). Soliris® (eculizumab) Summary of Product Characteristics. Alexion Europe SAS; 2012.

    1. Hillmen P et al. Am J Hematol 2010;85:553–559.


    Is the primary cause of fatigue in pnh anemia or hemolysis

    Is the Primary Cause of Fatigue in PNH Anemia or Hemolysis?


    Triumph demonstrated that improvement in fatigue occurred independent of hemoglobin response

    12.0

    8

    11.5

    6

    Ecu(n=43)

    Patients not on Ecu(n=44)

    EcuHgb

    Placebo Hgb

    11.0

    4

    10.5

    2

    Change From Baseline FACIT-Fatigue Score

    Hemoglobin, g/dL

    0

    10.0

    –2

    9.5

    –4

    9.0

    –6

    8.5

    0

    2

    4

    6

    8

    10

    12

    14

    16

    18

    20

    22

    24

    26

    Time, Weeks

    TRIUMPH Demonstrated That Improvement in Fatigue Occurred Independent of Hemoglobin Response

    P<0.001

    FACIT-Fatigue Score

    ≥3 or more points denotes a clinically significant improvement

    Hgb Level

    FACIT-Fatigue Score

    Hgb Placebo

    • In SHEPHERD, 78% of patients reported a significant improvement in fatigue1

    FACIT = Functional Assessment of Chronic Illness Therapy.

    Please see full prescribing information for Soliris® (eculizumab). Soliris® (eculizumab) Summary of Product Characteristics. Alexion Europe SAS; 2012.

    Adapted from: Hillmen P et al. N Engl J Med 2006;355:1233–1243;Brodsky R et al. Blood Rev 2008;22:65–74; Hill A et al.Haematologica 2008;93(Suppl. 1):359. Abstract 0904; Brodsky R et al.Blood 2008;111:1840–1847; Schubert J, et al. Br J Haematol2008;142(2):263-72.


    73 reduction in mean units transfused across all subgroups triumph

    Patients not on Ecu(n=44)

    Ecu(n=43)

    73% Reduction in Mean Units Transfused Across All Subgroups: TRIUMPH

    18

    16

    14

    12

    10

    Median Units Transfused

    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 Ecupatients achieved transfusion independence vs 0% of patients not on Ecu1

    • Patients with concomitant bone marrow dysfunction may continue to require transfusions2

    *P<0.001. †Transfusion data obtained during 12 months before treatment; values were normalized for a 6-month period.

    Please see full prescribing information for Soliris® (eculizumab). Soliris® (eculizumab) Summary of Product Characteristics. Alexion Europe SAS; 2012.

    1. Hillmen P et al. N Engl J Med 2006;355;1233–1243; 2. Schubert J. Br J Haematol2008;142:263–272.


    Advances in paroxysmal nocturnal hemoglobinuria pnh

    Eculizumab Treatment Results in Large and Clinically Meaningful Improvements in Patient-Reported Outcomes

    1.2

    1.13

    1.12

    Large Clinical Impact

    1

    0.8

    0.69

    Moderate Clinical Impact

    0.65

    0.6

    Standard Effect Size (SES)

    Small Clinical Impact

    0.4

    0.2

    0

    FACIT-Fatigue*

    EORTC Fatigue*

    Dyspnea*

    Pain†

    (P<0.001)

    (P<0.001)

    (P=0.002)

    (P<0.001)

    Please see full prescribing information for Soliris® (eculizumab). Soliris® (eculizumab) Summary of Product Characteristics. Alexion Europe SAS; 2012.

    1. Brodsky R et al. Blood 2006;108: Abstract 3770; 2. Data on file. Alexion Pharmaceuticals. 3. Weitz I, et al. Internal Medicine Journal2012.Accepted Article; doi: 10.1111/j.1445-5994.2012.02924.x


    Eculizumab reduces hemolysis and improves fatigue in ist treated patients

    Eculizumab Reduces Hemolysis and Improves Fatigue in IST-Treated Patients

    IST

    • IST: Severe hemolysis

    • Ecu: Significant and sustained reduction in hemolysis

    • IST: Severe fatigue

    • Ecu: Significant and sustained reduction in fatigue

    • Demonstrates effectiveness of treatment with Eculizumab to reduce hemolysis and fatigue in AA patients despite concomitant IST treatment

    Mean LDH (U/IL)

    LDH

    *

    *

    *

    N=12

    Months of Eculizumab

    ¥

    ¥

    ¥

    FACIT-Fatigue

    Mean FACIT Fatigue

    N=10

    Months of Eculizumab

    * P<0.01 when prior and post months compared. . P<0.05 when prior and post months compared.

    Schrezenmieier et al Blood 2009


    How does eculizumab impact pulmonary hypertension and dyspnea in pnh

    How Does Eculizumab Impact Pulmonary Hypertension and Dyspnea in PNH?


    Reduction of pulmonary hypertension with eculizumab as measured by nt probnp

    Reduction of Pulmonary Hypertension With Eculizumab as Measured by NT-ProBNP

    Solirisvs Placebo (P<0.001)

    50% Reduction

    60

    52.5

    50

    P<0.037

    43.8

    39.4

    40

    Proportion of Patients With Evidence of Pulmonary Hypertension

    30

    26.3

    20

    10

    0

    Baseline

    Week 26

    Baseline

    Week 26

    Placebo

    Eculizumab

    Treatment Group - TRIUMPH (n=73)1

    Pulmonary Hypertension Defined as NT-proBNP ≥160 pg/mL2

    Please see full prescribing information for Soliris® (eculizumab). Soliris® (eculizumab) Summary of Product Characteristics. Alexion Europe SAS; 2012.

    1. Hill A et al. Br J Haematol2012;158:409–414. 2. Machadaet al.JAMA. 2006.


    What is the long term experience with eculizumab1

    What is the Long-Term Experience With Eculizumab?

    Pilot Study – NEJM2004

    N=11

    Primary endpoint: reduction of hemolysis

    Long-Term Extension Trial HillmenBlood2007

    Evaluated long-term safety, efficacy and effect on thrombosis; Placebo patients switched to Eculizumab

    N=187

    TRIUMPH – NEJM2006

    Pivotal Phase III, Double-Blind, Placebo-Controlled Trial, N=87

    SHEPHERD – Blood2008

    Broader patient population, including those receiving minimal transfusions or with thrombocytopenia, N = 97

    Please see full prescribing information for Soliris® (eculizumab).

    Soliris® (eculizumab) Summary of Product Characteristics. Alexion Europe SAS; 2012.


    86 reduction in ldh sustained over entire course of 36 month treatment period

    86% Reduction in LDH Sustained Over Entire Course of 36 Month Treatment Period

    *P<0.0000001

    *

    *

    *

    *

    *

    *

    *

    *

    Dashed line represents the upper limit of the normal range (103–223 U/L)

    Please see full prescribing information for Soliris® (eculizumab). Soliris® (eculizumab) Summary of Product Characteristics. Alexion Europe SAS; 2012.

    Brodsky R et al. Blood 2010;116: Abstract 4237.


    Advances in paroxysmal nocturnal hemoglobinuria pnh

    What is the Clinical Data on the Long-term Outcome of Treatment with Eculizumab in Patients with PNH?


    Eculizumab in pnh 10 year multicenter experience patient characteristics at baseline

    Eculizumab in PNH: 10-Year Multicenter ExperiencePatient Characteristics at Baseline

    *Normal <430 IU/L. IU=international units.

    Please see full prescribing information for Soliris® (eculizumab). Soliris® (eculizumab) Summary of Product Characteristics. Alexion Europe SAS; 2012.

    Hill A et al. Presented at the 54th Annual Meeting of the American Society of Hematology (ASH). December 8–11, 2012, Atlanta, GA. Abstract #3472. Appears in Blood 2012;120(21).


    Eculizumab in pnh 10 year multicenter experience reduction in te with long term eculizumab therapy

    Eculizumab in PNH: 10-Year Multicenter ExperienceReduction in TE with Long-term Eculizumab Therapy

    P<0.05

    *

    *Patients received eculizumab treatment from May 2002 to April 2012

    Please see full prescribing information for Soliris® (eculizumab). Soliris® (eculizumab) Summary of Product Characteristics. Alexion Europe SAS; 2012.

    Hill A et al. Presented at the 54th Annual Meeting of the American Society of Hematology (ASH). December 8–11, 2012, Atlanta, GA. Abstract #3472. Appears in Blood 2012;120(21).


    Paroxysmal nocturnal hemoglobinuria compelling long term clinical benefits in pnh patients

    Paroxysmal Nocturnal Hemoglobinuria:Compelling Long Term Clinical Benefits in PNH Patients

    Pre-Soliris from Time ofDiagnosis in 80 Patients With PNH1

    PNH Patients on Eculizumab Compared with Age- and Gender-Matched Controls2*

    100

    100

    80

    80

    Age- and gender-matched controls

    Age- and Gender-Matched

    Normal Population

    60

    60

    Patients Surviving (%)

    Ecu-treated PNH Population

    40

    40

    Patients with PNH

    20

    20

    Patients at Risk:

    153

    93

    45

    43

    12

    0

    0

    0

    2

    4

    6

    8

    10

    0

    5

    10

    15

    20

    25

    Years After Diagnosis

    Time (Years)

    • Despite best supportive care - 5 year mortality: 35%1

    • Hazard Ratio = 2.24 (P=0.013)

    *Survival after 10-years is slightly inferior to controls with causes of death related to bone marrow failure and not hemolysis or thrombosis.

    Please see full prescribing information for Soliris® (eculizumab). Soliris® (eculizumab) Summary of Product Characteristics. Alexion Europe SAS; 2012.

    1. Hillmen P et al. N Engl J Med1995;333:1253–1258. 2. Hill A et al. Presented at the 54th Annual Meeting of the American Society of Hematology (ASH). December 8-11, 2012, Atlanta, GA. Abstract #3472. Appears in Blood 2012;120(21).


    Long term experience with eculizumab in pnh

    Long-Term Experience with Eculizumab in PNH

    Up to 10 year multicenter experience of eculizumab shows:

    • Improved survival with a well-tolerated safety profile

    • Persistent and significant improvement in symptoms and quality of life

    • Significant reduction in the number of thrombotic events

    • Significant reduction in transfusion requirements

    Long-term use of eculizumabdemonstrates the impact on quality of life and reduction in complications, thereby improving long-term outcomes for patients with PNH

    Please see full prescribing information for Soliris® (eculizumab). Soliris® (eculizumab) Summary of Product Characteristics. Alexion Europe SAS; 2012.

    Hill A et al. Presented at the 54th Annual Meeting of the American Society of Hematology (ASH). December 8–11, 2012, Atlanta, GA. Abstract #3472. Appears in Blood 2012;120(21).


    Treatment expectations what is the benefit of eculizumab therapy in pnh patients

    Treatment Expectations: What is the Benefit of Eculizumab Therapy in PNH Patients?


    Advances in paroxysmal nocturnal hemoglobinuria pnh

    Eculizumab Treatment ExpectationsPNH Patients in Clinical Trials Showed a Benefit from Eculizumab Therapy

    • In 1 Week

    • Reduction in hemolysis(as measured by LDH)3

    • Reduction in fatigue3

    • Between 2 and 3 Weeks

    • Improvement in quality of life1

    • Improvement in dyspnea4

    • Between 2 and 6 Months

    • Reduction in frequency of transfusions5

    • Stabilization of hemoglobin levels5

    Reduction in Thrombotic Event Rate2

    • >6 Months

    • Continued improvement in quality of life3,6

    • LDH levels maintained at upper limit of normal3,6

    • Continued improvement in fatigue3,6

    • Continued reduction in frequency of transfusions3,6

    • Continued stabilization of hemoglobin levels5

    Treatment with Eculizumabshould not alter anticoagulant management.1

    • At 36 Months and Up to 10 Years

    • Reduction in hemolysis (as measured by LDH) was sustained1,7,8

    • Improvement in TE was maintained1,7,8

    • Most commonly reported adverse events were mild or moderate in severity1

    Please see full prescribing information for Soliris® (eculizumab).

    1. Soliris® (eculizumab) Summary of Product Characteristics. Alexion Europe SAS; 2012. 2. HillmenP et al.Blood 2007;110:4123–4128. 3. Brodsky R et al. Blood 2008;111:1840–1847. 4. Hill A et al. Br J Haematol2012;158:409–414. 5. HillmenP et al. N Engl J Med 2006;355:1233–1243. 6. SociéG et al. Blood(ASH Annual Meeting Abstracts) 2007;110: Abstract 3672. 7. Brodsky RA et al. In: Abstracts of the 52nd ASH Annual Meeting and Exposition; December 4–7, 2010; Orlando, FL. Abstract 4237. 8. Hill A et al. In: Abstracts of the 54thAnnual Meeting of the American Society of Hematology (ASH). December 8–11, 2012, Atlanta, GA. Abstract #3472. Appears in Blood 2012;120(21). 9. Szer J et al. In: Abstracts of the 54th Annual Meeting of the American Society of Hematology (ASH). December 8–11, 2012, Atlanta, GA. Abstract #1260. Appears in Blood 2012;120(21).


    Adverse reactions reported in 5 of eculizumab treated patients in triumph

    Adverse Reactions Reported in ≥ 5% of Eculizumab Treated Patients in TRIUMPH

    Hillmen P, et al. NEJM. 2006;355:1233-1243.

    Please see full prescribing information for Soliris® (eculizumab).

    Soliris®SmPC: Soliris® (eculizumab) summary of product characteristics. Alexion Europe SAS 2012.


    Summary of clinical efficacy 1 5

    Summary of Clinical Efficacy1–5

    • 86% sustained reduction in hemolysis as measured by LDH

      • Maintained over a 36 month treatment period1–3

    • 92% reduction in thrombotic events

    • 73% reduction in transfusion requirements across all patient populations

    • 78% clinically meaningful improvement in fatigue

      • Sustained improvement in overall quality of life

    • Patients treated with eculizumabexperienced improvement in CKD and pulmonary hypertension

      • Eculizumabprovided a rapid and durable effect on dyspnea, a key marker of hemolysis-induced PHT

    Please see full prescribing information for Soliris® (eculizumab).

    1. Soliris® (eculizumab) Summary of Product Characteristics. Alexion Europe SAS; 2012 . 2. Hillmen P et al. N Engl J Med 2006;355:1233–1243; 3. Brodsky R et al.Blood 2010;116: Abstract 4237; 4. HillmenP et al.Blood 2007;110:4123–4128; 5. Socie G et al. Blood 2007;110: Abstract 3672. 4. SzerJ et al.In: Abstracts of the 54th Annual Meeting of the American Society of Hematology (ASH). December 8–11, 2012, Atlanta, GA; Abstract #1260. Appears in Blood 2012;120(21).


    Summary of clinical efficacy and safety 1 5

    Summary of Clinical Efficacy and Safety1–5

    • In a multicenter analysis eculizumabshowed a major impact on survivalin PNH; survival is comparable to age- and gender- matched controls

      • Eculizumab significantly reduced hemolysis, the underlying cause of morbidity and mortality in PNH

      • Significant reductions in AEs were observed suggesting good tolerability and a favorable risk/benefit ratio over the long term

    Please see full prescribing information for Soliris® (eculizumab).

    1. Soliris® (eculizumab) Summary of Product Characteristics. Alexion Europe SAS; 2012 . 2. Hillmen P et al. N Engl J Med 2006;355:1233–1243; 3. Brodsky R et al.Blood 2010;116: Abstract 4237; 4. HillmenP et al.Blood 2007;110:4123–4128; 5. Socie G et al. Blood 2007;110: Abstract 3672. 4. SzerJ et al.In: Abstracts of the 54th Annual Meeting of the American Society of Hematology (ASH). December 8–11, 2012, Atlanta, GA; Abstract #1260. Appears in Blood 2012;120(21).


    Conclusions

    Conclusions

    • Chronic complement-mediated hemolysis is the underlying cause of progressive morbidities and mortality in PNH

    • Thrombosis is the leading cause of death in PNH1

    • Renal failure has been identified as the cause of death in approximately 8–18% of PNH patients2,3

    • PNH may be more common than you think

      • Delays in diagnosis range from 1 to more than 10 years4

    • High sensitivity flow cytometry, performed on peripheral blood, is the gold standard test

    • Advancements in treatment options warrant early diagnosis and intervention

    1. Hillmen P et al. Blood 2007;110:4123–4128; 2. Nishimura JI et al. Medicine 2004;83:193–207; 3. Hillmen P et al.Am J Hematol 2010;85:553–559;4. HillmenP et al.N Engl J Med 1995;333:1253–1258.


    Long term experience with soliris in pnh

    Long Term Experience with Soliris in PNH

    • Bart L. Scott, MD

    • Assistant Professor of Medicine, Division of Oncology, University of Washington

    • Director of Hematology and Hematologic Malignancies, Seattle Cancer Care AllianceSeattle, WA


    What is the impact of long term soliris treatment on clinical outcomes and survival

    What is the Impact of Long-term Soliris Treatment on Clinical Outcomes and Survival?

    Uncontrolled Complement

    Activation

    Soliris

    Decreased Mortality

    ?

    Hemolysis

    End Organ Damage

    • TE

    • Renal

    • Gastrointestinal

    • Pulmonary

    • Cardiac

    • Hepatic

    Increased Mortality

    ComplicationsAssociated With ElevatedHemolysis(LDH)


    Long term treatment with soliris in pnh sustained efficacy and improved survival

    Long-term Treatment With Soliris in PNH: Sustained Efficacy and Improved Survival

    • 153 consecutive patients with PNH treated with Soliris

      • May 2002 – April 2012

      • Duration mean of treatment 3.5 years (range <1.0 - 9.9 years)

    • Mortality and disease symptoms were evaluated


    Patient characteristics n 153

    Patient Characteristics (n=153)

    Hill A. ASH 2012.


    74 thrombotic events in 50 patients prior to soliris treatment

    74 Thrombotic Events in 50 Patients Prior to Soliris Treatment

    28 thrombotic episodes in 15 patients anticoagulated prior to initiation of Soliris therapy

    Hill A. ASH 2012.


    Thrombotic events in equivalent time periods

    Thrombotic Events in Equivalent Time Periods

    12 months prior to initiating Soliris

    36 thrombotic episodes in 22 (14.3%) patients

    In the most recent 12 months on therapy

    3 thromboses in 3 (2.0%) patients

    1 Budd-Chiari during complement blockade breakthrough caused by infection

    1 CVA during reversal of warfarin overanticoagulation

    1 TIA/lacunar infarct thought to be due to diabetic small vessel disease

    Hill A. ASH 2012.


    Discontinuing anticoagulation

    Discontinuing Anticoagulation

    Primary prophylaxis with warfarin has been safely stopped in 43/50 (86%) patients

    Secondary prophylaxis discontinued in 4 (<10%)

     due to haemorrhages, risk of bleeding from varices and/ or thrombocytopenia

    With no thromboticsequelae

    Hill A. ASH 2012.


    Reduction in intravascular haemolysis

    Reduction in Intravascular Haemolysis

    All patients had a rapid reduction in LDH

    P < 0.0001

    Hill A. ASH 2012.


    Advances in paroxysmal nocturnal hemoglobinuria pnh

    Median Transfusion Requirements in the 12 Months Prior to Soliris and Most Recent 12 Months on Soliris

    66% of transfused patients become transfusion independent

    Hill A. ASH 2012.


    Reasons for transfusion in the 25 patients in leeds not transfusion independent

    25 patients still requiring transfusions:

    The mean number of transfusions fell significantly from 24.6 units (range 4-44) to 11.4 units (range 2-45), P=0.0002

    Reasons for Transfusion in the 25 Patients in Leeds Not Transfusion Independent

    Aplasia

    Breakthrough haemolysis (required higher dosing)

    Myelodysplasia

    Breakthrough haemolysis (minimally transfused,

    maximum of 3 units in 12 months)

    Cause unclear

    Extravascular haemolysis


    Outcomes n 153 patients

    Outcomes (n=153 patients)

    137 patients on treatment as of April 2012

    7 discontinued eculizumab therapy

    1 predominant AA

    2 spontaneous remissions of PNH clone

    3 treated for indication of pregnancy alone

    1 successfully transplanted for VSAA

    9 patients died

    Hill A. ASH 2012.


    Outcomes

    Outcomes

    9 patients died

    3 due to progression of their underlying bone marrow failure to MDS/AML

    One died immediately after BMT (veno-occlusive disease)

    27 yrs old

    2000 AA

    2009 PNH

    Mar 2011 AML

    May 2011 Ecu

    Oct 2011 transplant; VOD

    Remaining 5 not directly related to PNH

    Hill A. ASH 2012.


    Causes of death

    Causes of Death

    1

    1

    4

    1

    1

    1


    Mortality with best supportive care

    Actuarial Survival from the Time ofDiagnosis in 80 Patients with PNH1

    100

    80

    Age-matched and gender-matched controls

    60

    Patients Surviving, %

    40

    Patients with PNH

    20

    0

    0

    5

    10

    15

    20

    25

    Years after Diagnosis

    Mortality With Best Supportive Care

    5 year mortality of 35% recently confirmed2

    1. Hillmen P et al. N Engl J Med. 1995;333(19):1253-1258; 2. Kelly RJ et al. Blood. 2011;117:6786-6792.


    Paroxysmal nocturnal hemoglobinuria compelling long term clinical benefits in pnh patients1

    Paroxysmal Nocturnal Hemoglobinuria:Compelling Long Term Clinical Benefits in PNH Patients

    Survival of PNH Patients TreatedWith Soliris Compared With the Normal UK Population2

    Pre-Soliris from Time ofDiagnosis in 80 Patients With PNH1

    100

    100

    80

    80

    N= 153

    Age- and gender-matched controls

    60

    60

    Age- and gender-matched normal population

    Cumulative Surviving, %

    Patients Surviving, %

    40

    Soliris Treated PNH Population

    40

    Patients with PNH

    20

    Numbers at Risk:

    153

    93

    45

    43

    12

    20

    0

    0

    5

    10

    15

    20

    25

    Years After Diagnosis

    0

    • Despite best supportive care - 5 year mortality: 35%1

    0

    2

    4

    6

    8

    10

    Time (years)

    1. Hillmen P et al. N Engl J Med. 1995;333:1253-1258. 2. Hill A. ASH 2012.


    Sustained complement inhibition leads to reduced hemolysis thrombosis and improvements in survival

    Sustained Complement Inhibition Leads to Reduced Hemolysis, Thrombosis and Improvements in Survival

    Uncontrolled Complement

    Activation

    Decreased Mortality

    Soliris

    • Reduction in LDH (P<0.0001)

    • 100% response rate in pivotal clinical trial programs (As measured by reduction in LDH)

    • 92% (P<0.0001) reduction in TE

    Hemolysis

    End Organ Damage

    • Significant reduction in abdominal pain

    • Improvement in dyspnea, dysphagia, fatigue, hemoglobinuria

    • Thrombosis

    • Renal

    • Gastrointestinal

    • Pulmonary

    • Cardiac

    • Hepatic

    Increased Mortality

    ComplicationsAssociated With ElevatedHemolysis(LDH)

    • 4 fold improvement in CKD over placebo (P<0.04)

    • Soliris appears to normalize survival in patients with PNH

    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 file. 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.


    Advances in paroxysmal nocturnal hemoglobinuria pnh

    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 2000 patients enrolled

    Participation in 24 countries, including Argentina, Australia, Belgium, Canada, Denmark, Finland, France, Germany, Japan, Luxembourg, Netherlands, New Zealand, Norway, Russia, South Korea, Spain, Sweden, Switzerland, Taiwan, United Kingdom, United States

    Enrollment information: www.pnhsource.com


    Discussion

    Discussion

    How does this data impact your motivation to more closely monitor patients with PNH?


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