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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.

slide6

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

Abstract 647

Gargiulo et al

slide7

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

slide8

Intravascular Hemolysis

Absence of complement regulators

Thrombosis

Absence of complement regulators

Bone Marrow Failure and cytopenia

Mechanism?

PNH Triad

slide9

crippled

PIG-A+ cells

Noxious agent

Parodoxical Expansion of PNH Clone(Escape Theory)

Time

PIG-A+

cells

PIG-A null

cells

Rotoli & Luzzatto, 1989

slide10

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

slide12

*p=0,0355

C1R C1R- CD1d

with GPI addition

6 PNH Patients

CD1d-dependent GPI-specific T cells in PNH

*Wilcokson Rank Test

slide13

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.

slide15
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 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, 2010Absence 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.

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.

slide45

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.

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

slide51
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 pattern n (%)

n=75

(Classic PNH) (8) (11%)

Expansion 13 (17%)

PNH+Patients

Persistent 44 (59%)

Newly developed 5 (4%)

Disappearance 18 (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.
slide55
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.

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.

slide67

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 EculizumabEculizumab 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.

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.

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.

slide85
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

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.

slide91
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).

slide97
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
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.

slide110
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.

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.

slide118

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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