p aroxysmal n octurnal h emoglobinuria

PParoxysmalaroxysmalNNocturnalocturnalHHemoglobinuriaemoglobinuria

New ideas about an old New ideas about an old diseasedisease

Ahmad Shihada Silmi Msc, FIBMSStaff Specialist in Hematology

Medical Technology DepartmentIslamic University of Gaza

ObjectivesObjectives Try to answer some of the frequently Try to answer some of the frequently

asked questions about:asked questions about:

The cause of the PNHThe cause of the PNH The clinical presentation of PNHThe clinical presentation of PNH Diagnosing PNHDiagnosing PNH The complications of PNHThe complications of PNH New treatments for PNHNew treatments for PNH

What is PNH?What is PNH? A disorder of blood affecting all the cells which A disorder of blood affecting all the cells which

come the bone marrow. come the bone marrow. Prevalence 1-4 per million The disease is quite rare, only 10, 000 patients The disease is quite rare, only 10, 000 patients

in the US and Europe.in the US and Europe. There is no ethnic preference for the disorder.There is no ethnic preference for the disorder. It may present early or late in life.It may present early or late in life. The manifestations may be “classic” or obscure. The manifestations may be “classic” or obscure.

PNH Prognosis Significant morbidity and mortality Patients have lived for extended periods of time and

have seen spontaneous recovery Report of 80 patients showed that 60% of deaths due

to venous thrombosis or bleeding Retrospective study of 220 patients

Kaplan-Meier survival 78, 65, and 48% at 5, 10, and 15 years 8 year rates of major complications of PNH (pancytopenia,

thrombosis, MDS) 15, 28, and 5% Up to 5% of patients can develop acute leukemia; onset about 5

years after Dx of PNH Likely incident of leukemia lower than 5%

What is PNH Mutation? What is PNH Mutation? PNH is due to a mutation in a gene in a blood PNH is due to a mutation in a gene in a blood

stem cell.stem cell. The gene is called the The gene is called the PIG-APIG-A gene gene

(phosphatidylinositol glycan complementation group A) and is located on the X chromosome. and is located on the X chromosome. >100 mutations in PIG - A gene known in PNH The mutations (mostly deletions or insertions)

generally result in stop codons - yielding truncated proteins which may be non or partially functional - explains heterogeneity seen in PNH

What is PNH?What is PNH? In most cases of PNH, the change in In most cases of PNH, the change in

the gene (mutation) is acquired, the gene (mutation) is acquired, not not something you are born with. When something you are born with. When and why is unknown.and why is unknown.

The gene contains the genetic The gene contains the genetic information for the information for the GPI anchorsGPI anchors which which link proteins to the cell membranelink proteins to the cell membrane

What is PNH?What is PNH? A mutation is a “mistake” or a “change” in A mutation is a “mistake” or a “change” in

the gene that arises during copying and is the gene that arises during copying and is not correctednot corrected

When the cell divides, the mutation is When the cell divides, the mutation is transmitted to daughter cellstransmitted to daughter cells

The effect of a mutation:The effect of a mutation: NoneNone An altered protein (sickle hemoglobin)An altered protein (sickle hemoglobin) No protein is produced as in PNH, hemophilia No protein is produced as in PNH, hemophilia

etcetc

Stem CellsStem Cells

Embryonic Stem Cell

Somatic Stem Cells

Blood

Muscle Nerve

Etc.Egg or Sperm

Egg

Egg Sperm

The Cells of Each Specific Organ


STEM CELL

T LYMPHOCYTES

B LYMPHOCYTES

ERYTHROCYTES

GRANULOCYTES

MONOCYTES

PLATELETS


STEM CELL

T LYMPHOCYTES

B LYMPHOCYTES

ERYTHROCYTES

GRANULOCYTES

MONOCYTES

PLATELETSALTERED GENE


ABNORMAL CLONE

NORMAL CLONES

GPI-AP Biosynthesis:GPI-AP Biosynthesis:Involves 10 Steps and >20 Involves 10 Steps and >20

GenesGenes

N NN

PIG-A

Endoplasmic Reticulum

Plasma Membrane

Raft

GlcNAc-PIPI

The Beginning of PNHThe Beginning of PNH

The change that occurs in PNH stops The change that occurs in PNH stops the production of an anchor that ties the production of an anchor that ties protein molecules to the cellprotein molecules to the cell Sometimes the stop is only partial and Sometimes the stop is only partial and

PNH II cells occurPNH II cells occur

The GPI Anchor Defect in The GPI Anchor Defect in PNHPNH

2 2CH CH CH

C=OO

OO-P-O

O

O

(18:0,1)

(22:4,5)

C=O

Asp

C=O2 2

O

O=P=OO

O

CH CH CH

C=OO

CH2 CH2 NH

CH2CH2

NH

O2

OO-P=O

O-P-OO

O

(18:0,1)

(22:4,5)

(16:0)

N

( 1-2)

( 1-6)

( 1-4)

PROTEIN

NORMAL PNH

PIG - A gene codes for 60 kDa protein glycosyltransferase which effects the first step in the synthesis of the glycolipid GPI anchor (glycosylphosphatidylinositol). Results in clones lacking GPI anchor - in turn, attached proteins

Pathogenesis - The DefectGPI GPI AnchorAnchor

PIG - APIG - A protein protein

What is PNH?What is PNH?

As a result of the PIG-A mutation, As a result of the PIG-A mutation, there is little of no GPI anchor there is little of no GPI anchor produced.produced. PNH II cells- mild reductionPNH II cells- mild reduction PNH III cells- severely reduced.PNH III cells- severely reduced. When the anchor is reduced, certain When the anchor is reduced, certain

proteins can’t attach to the cells. proteins can’t attach to the cells. The most important proteins for PNH The most important proteins for PNH

are CD 59, CD55are CD 59, CD55..

Proteins anchored by GPI Anchorand

Surface Proteins Missing on PNH Blood CellsSurface Proteins Missing on PNH Blood CellsAntigen Expression PatternAntigen Expression Pattern

EnzymesEnzymesAcetylcholinesterase (AchE) Acetylcholinesterase (AchE) Red blood cellsRed blood cellsEcto-5'-nucleotidase (CD73) Ecto-5'-nucleotidase (CD73) Some B- and T-Some B- and T-lymphocyteslymphocytesNeutrophil alkaline phosphatase(NAP) Neutrophil alkaline phosphatase(NAP) NeutrophilsNeutrophilsADP-rybosyl transferase ADP-rybosyl transferase Some T-lymphs, Some T-lymphs, NeutrophilsNeutrophils

Adhesion moleculesAdhesion moleculesBlast-I/CD48 Blast-I/CD48 LymphocytesLymphocytesLymphocyte function- Lymphocyte function- associated antigen-3(LFA-3 or CD58) associated antigen-3(LFA-3 or CD58) All blood cellsAll blood cellsCD66bCD66b NeutrophilsNeutrophils

Complement regulating surface proteinsComplement regulating surface proteinsDecay accelerating factor (DAF or CD55) Decay accelerating factor (DAF or CD55) All blood cellsAll blood cellsHomologous restriction factor,Homologous restriction factor,Membrance inhibitor of reactive lysis Membrance inhibitor of reactive lysis All blood cellsAll blood cells(MIRL or CD59)(MIRL or CD59)


ReceptorsReceptorsFc-Fc- receptor III (Fc receptor III (Fc Rlll or CD16) Rlll or CD16) Neutrophils, NK-cells, Neutrophils, NK-cells, macrophages,macrophages,

some T-lymphocytessome T-lymphocytesMonocyte differentiation antigen Monocyte differentiation antigen Monocytes, macrophagesMonocytes, macrophages(CD14)(CD14)Urokinase-type Plasminogen Urokinase-type Plasminogen Monocytes, granulocytesMonocytes, granulocytesActivator Receptor (u-PAR, CD87)Activator Receptor (u-PAR, CD87)

Blood group antigensBlood group antigensComer antigens (DAF) Comer antigens (DAF) Red blood cellsRed blood cellsYt antigens (AchE) Yt antigens (AchE) Red blood cellsRed blood cellsHolley Gregory antigen Holley Gregory antigen Red blood cellsRed blood cellsJohn Milton Hagen antigen (JMH) John Milton Hagen antigen (JMH) Red blood cells, lymphocytesRed blood cells, lymphocytesDombrock reside Dombrock reside Red blood cellsRed blood cells

Neutrophil antigensNeutrophil antigensNB1/NB2 NB1/NB2 NeutrophilsNeutrophils


Other surface proteins Other surface proteins of unknown functionsof unknown functionsCAMPATH-1 antigen (CDw52) CAMPATH-1 antigen (CDw52) Lymphocytes, Lymphocytes, monocytesmonocytesCD24 CD24 B-lymphocytes, B-lymphocytes, Neutrophils, Neutrophils,

eosinophilseosinophilsp5O-80p5O-80 NeutrophilsNeutrophilsGP500 GP500 PlateletsPlateletsGPI75 GPI75 PlateletsPlatelets

PathogenesisCD 55

Also known as decay accelerating factor Accelerates decay of enzyme that

destroys red cell membranes CD55 inhibits the formation or destabilizes

complement C3 convertase (C4bC2a) When GPI anchor absent, CD55 not

available and RBC membranes hemolyze

PathogenesisCD59

Also known as membrane inhibitor of reactive lysis, protectin, homologous restriction factor, and membrane attack complex inhibitory factor

CD59 Protects the membrane from attack by the C5-C9 complex

Absence or reduction of CD59 leads to increased hemolysis and perhaps thrombosis

Pathogenesis of CD55 & CD59

Inherited absences of both proteins in humans have been described

Most inherited deficiencies of CD55 - no distinct clinical hemolytic syndrome

Inherited absence of CD59 - produces a clinical disease similar to PNH with hemolysis and recurrent thrombotic events

Pathogenesis

Many normal people have very small numbers Many normal people have very small numbers (perhaps 6 per 1,000,000 bone marrow cells)(perhaps 6 per 1,000,000 bone marrow cells)

In PNH, the abnormal cells have an advantage In PNH, the abnormal cells have an advantage and become a major population in the marrow and become a major population in the marrow and blood (anywhere from 1% to over 90%)and blood (anywhere from 1% to over 90%) This may be a result of change in the immune This may be a result of change in the immune

system –inability to recognize something system –inability to recognize something foreign. foreign.

Or it may be related to aplastic anemia, a Or it may be related to aplastic anemia, a disease of poor production of blood from the disease of poor production of blood from the marrow-WHY?marrow-WHY?

Pathogenesis - Clonal evolution and cellular selection

Expansion of abnormal hematopoietic stem cell required for PNH disease expression Theories for expansion

Blood cells lacking GPI-linked proteins have intrinsic ability to grow abnormally fast

In vitro growth studies demonstrate that there are no differences in growth between normal progenitors and PNH phenotype progenitors

In vivo - mice deficient for PIG -A gene also demonstrates no growth advantage to repopulation of BM.

Additional environmental factors exert selective pressure in favor of expansion of GPI anchor deficient blood cells

Close association with AA - PNH hematopoitic cells cells may be more resistant to the Immune System than normal hematopoitic cells.

Evidence in AA is that the decrease in hematopoitic cells is due to increased apoptosis via cytotoxic T cells by direct cell contact or cytokines (escape via deficiency in GPI linked protein???)

PNH Clinical FeaturesPNH Clinical Features Aplastic Anemia Aplastic Anemia

Some PNH patients have aplastic anemia Some PNH patients have aplastic anemia or a history of aplastic anemiaor a history of aplastic anemia

Many PNH patients have evidence of a Many PNH patients have evidence of a bone marrow that doesn’t work well or well bone marrow that doesn’t work well or well enough to maintain normal blood countsenough to maintain normal blood counts

Therefore, whatever causes aplastic Therefore, whatever causes aplastic anemia (immune suppression or anemia (immune suppression or dysregulation or damage to the stem cells) dysregulation or damage to the stem cells) may allow PNH to developmay allow PNH to develop

What is PNH?What is PNH? ComplementComplement

Complement is a group of blood Complement is a group of blood proteins that act together to help the proteins that act together to help the body get rid of microbiological invadersbody get rid of microbiological invaders One of the ways it does this is by One of the ways it does this is by

penetrating the membrane (outside penetrating the membrane (outside surface) of the invading bacteria or surface) of the invading bacteria or viruses.viruses.

When this happens to PNH blood When this happens to PNH blood cells, the cells are destroyed.cells, the cells are destroyed.

What is PNH?What is PNH?Complement circulates in an inactive Complement circulates in an inactive

formform It is activated spontaneously and by a It is activated spontaneously and by a

variety of eventsvariety of events It is normally activated more at nightIt is normally activated more at night It is more active with infections, It is more active with infections,

trauma, vaccinations, surgery, trauma, vaccinations, surgery, immune complexes, autoimmune immune complexes, autoimmune diseasesdiseases

What is PNH?What is PNH?ComplementComplement

Complement activity is regulated by proteins Complement activity is regulated by proteins in the blood and on the membranes of the cell.in the blood and on the membranes of the cell.

Proteins on the cell surface interfere Proteins on the cell surface interfere with complement to prevent breakdown with complement to prevent breakdown (lysis) of the cell membrane(lysis) of the cell membrane The most important of these is The most important of these is CD59CD59, which , which

is missing on the abnormal cells of PNHis missing on the abnormal cells of PNH For this reason, PNH red cells are extremely For this reason, PNH red cells are extremely

sensitive to very small amounts of activated sensitive to very small amounts of activated complementcomplement

C5b

C5

C5a

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

C7C8

C5b

C7

C6

C7

C6

C5b,6,7

C8

C5bC6

C5b-8

C9

C7

C8

C5bC6

C9

C7

C8

C5bC6

C9 x 12 - 15

C5b-9

CD59 CD59

X X

C5

conv

erta

se

C5

conv

erta

se

Absence of CD59 Allows Absence of CD59 Allows Terminal Complement Complex Terminal Complement Complex

FormationFormation

C3b

Bb+

C3

What is PNH?What is PNH? Complement successfully attacks the red Complement successfully attacks the red

cells and they break up (hemolysis)cells and they break up (hemolysis) This releases hemoglobin (the red pigment in This releases hemoglobin (the red pigment in

red cells) into the plasmared cells) into the plasma Causes anemia Causes anemia Pieces of the membrane come off.Pieces of the membrane come off.

The white cells release granule contents The white cells release granule contents and change to express other proteins.and change to express other proteins.

The platelets form vesicles (membrane The platelets form vesicles (membrane blisters) and activate.blisters) and activate.

What is PNH?What is PNH?Normal red blood Normal red blood cells are cells are protected from protected from complement complement attack by a shield attack by a shield of terminal of terminal complement complement inhibitorsinhibitors

Complement activation

PP

Without this Without this protective protective complement complement inhibitor shield, inhibitor shield, PNH red blood PNH red blood cells are cells are destroyeddestroyed

What is PNH?What is PNH?Clinical FeaturesClinical Features

Some of the hemoglobin passes through Some of the hemoglobin passes through the kidneys and into the urine, causing the kidneys and into the urine, causing red to dark brown urine (hemoglobinuria)red to dark brown urine (hemoglobinuria) This causes a loss of iron from the This causes a loss of iron from the

bodybody In the long run, this may damage the In the long run, this may damage the

kidneykidney Free hemoglobin binds nitric oxide Free hemoglobin binds nitric oxide

causing vascular and smooth muscle causing vascular and smooth muscle spasmspasm

Causes inflammationCauses inflammation

Action of Nitric Oxide Action of Nitric Oxide (NO)(NO)

Smooth MuscleContraction

Smooth MuscleRelaxation

NONO

Free Hemoglobin Binds Free Hemoglobin Binds NONO

Smooth MuscleContraction

Smooth MuscleRelaxation

NONO

NOFree Hemoglobin

What Are The Effects of What Are The Effects of Nitric Oxide Trapping by Nitric Oxide Trapping by

HemoglobinHemoglobin Spasm of the esophagusSpasm of the esophagus Abdominal painAbdominal pain Erectile dysfunctionErectile dysfunction Other symptoms such as “fatigue”Other symptoms such as “fatigue”

What is PNHWhat is PNHClinical aspectsClinical aspects

Vascular (arterial constriction, HBP)Vascular (arterial constriction, HBP) Pulmonary artery pressure increase Pulmonary artery pressure increase

(PHTN)(PHTN) Spasm of the esophagusSpasm of the esophagus Abdominal painAbdominal pain Erectile dysfunctionErectile dysfunction Other symptoms such as “fatigue”Other symptoms such as “fatigue” Platelets are more “reactive”Platelets are more “reactive”


WBC: WBC: GranulocytesGranulocytes - release content stimulating - release content stimulating

inflammationinflammation MonocytesMonocytes - activate expressing TF which leads - activate expressing TF which leads

to blood clots. TF-Microvesiclesto blood clots. TF-Microvesicles Platelets Platelets become “activated”become “activated”

They stick together and form clumpsThey stick together and form clumps The membrane changes, allowing them to The membrane changes, allowing them to

bind to monocytesbind to monocytes Pieces of the membrane come off Pieces of the membrane come off

(microvesicles) (microvesicles)


Hemolytic anemia due to Hemolytic anemia due to complement activationcomplement activation Hemoglobinuria and, eventually, kidney Hemoglobinuria and, eventually, kidney

damagedamage Anemia to a variable degreeAnemia to a variable degree Effects of NO depletion- HBP, smooth Effects of NO depletion- HBP, smooth

muscle dystonia, reduced blood flow to muscle dystonia, reduced blood flow to the kidney and lungsthe kidney and lungs

Impaired bone marrow functionImpaired bone marrow function


Thrombosis (Blood clots)Thrombosis (Blood clots) Often in unusual places (liver veins, Often in unusual places (liver veins,

abdominal veins, cerebral veins, abdominal veins, cerebral veins, dermal veins)dermal veins)

Fatigue – overwhelming, poor Fatigue – overwhelming, poor correlation to level of hemoglobincorrelation to level of hemoglobin

inflammation inflammation anemiaanemia Portal hypertensionPortal hypertension (PHTN).PHTN).

MONOCYTES PLATELET

Endothelial cells

C5b-9HEMOLYSIS

COMPLEMENT INJURY

TF

THROMBINGENERATIONCOMPLEMEN

T

Thrombosis in PNH Thrombosis in PNH PathophysiologyPathophysiology

TF = Tissue factor.

NOPS

CYTOKINES IL-6INFLAMMATION

C5a

Laboratory Evaluation of PNH Acidified Serum Test (Ham Test 1939)

Acidified serum activates alternative complement pathway resulting in lysis of patient’s rbcs

May be positive in congenitial dyserythropoietic anemia

Still in use today Sucrose Hemolysis Test (1970)

10% sucrose provides low ionic strength which promotes complement binding resulting in lysis of patient’s rbcs

May be positive in megaloblastic anemia, autoimmune hemolytic anemia, others

Less specific than Ham test

PNH Diagnosis by Flow Cytometry (1986) Considered method of choice for

diagnosis of PNH (1996) Detects actual PNH clones lacking GPI

anchored proteins More sensitive and specific than Ham

and sucrose hemolysis test

Laboratory Evaluation of PNH

PNH Diagnosis by Flow Cytometry

AntigenAntigen Cell LineageCell Lineage FunctionFunctionCD14CD14 monocytesmonocytes LPS receptor, MDFLPS receptor, MDFCD16CD16 neutrophilsneutrophils FcFcIII receptorIII receptorCD24CD24 neutrophilsneutrophils B-cell differentiation B-cell differentiation markermarkerCD55CD55 all lineagesall lineages DAFDAFCD58CD58 all lineagesall lineages possible adhesionpossible adhesionCD59CD59 all lineagesall lineages MIRL, HRF, protectinMIRL, HRF, protectinCD66bCD66b neutrophilsneutrophils CEA-related CEA-related glycoproteinglycoprotein

Of the long list of GPI anchored protein, monoclonal Of the long list of GPI anchored protein, monoclonal antibodies to the following antigens have been used in antibodies to the following antigens have been used in the diagnosis of PNHthe diagnosis of PNH

The most useful Abs are to CD14, 16, 55, 59, and 66. The most useful Abs are to CD14, 16, 55, 59, and 66. Are all required? Probably not - more studies needed Are all required? Probably not - more studies needed

Antigen expression is generally categorized into three antigen density groups type I Normal Ag expression type II Intermediate Ag expression type III No Ag expression

Patient samples that demonstrate cell populations with diminished or absent GPI-linked proteins (Type II or III cells) with multiple antibodies are considered to be consistent with PNH.

Should examine multiple lineages (ie granulocytes & monocytes)


PNH Diagnosis by Flow CytometryExamples of variable GPI linked CD59 expression on Examples of variable GPI linked CD59 expression on granulocytes on four PNH patientsgranulocytes on four PNH patients


Example of variable Example of variable expression of expression of several GPI linked several GPI linked Ags on several Ags on several lineageslineages

From Purdue Cytometry CD-ROM vol3 97

Flow Cytometry is method of choice but only supportive for/against diagnosis

More studies are needed to better define whether the type (I, II, or III), cell lineage, and size of thecirculating clone can provide additional prognosticinformation.

Theoretically - should be very valuable


Historical Management Historical Management Options for PNH Options for PNH

TransfusionsTransfusions AnticoagulantsAnticoagulants SupplementsSupplements

Folic acidFolic acid IronIron Erythropoiesis stimulating agentsErythropoiesis stimulating agents

Steroids/androgen hormonesSteroids/androgen hormones Allogeneic bone marrow transplantAllogeneic bone marrow transplant

(limited eligibility(limited eligibility))

Generally conservative, supportive, and dependent on symptom severity1,2

What is SolirisWhat is Soliris®®?? Monoclonal antibody (protein) that Monoclonal antibody (protein) that

blocks complement at C5 preventing blocks complement at C5 preventing the formation of the terminal the formation of the terminal complement complexcomplement complex

Quickly and markedly reduces Quickly and markedly reduces hemolysishemolysis Stops hemoglobinuriaStops hemoglobinuria Increases hemoglobin levelIncreases hemoglobin level

Reduces transfusionsReduces transfusions Hematocrit may not be quite normalHematocrit may not be quite normal

SOLIRIS Blocks Terminal SOLIRIS Blocks Terminal ComplementComplement

Lectin Classical Alternative

C3 C3a

C3b

C5

Prox

imal

Term

inal

MicroorganismsAntigen-Antibody Complexes

Constitutive/Microorganisms

Figueroa, et al. Clin Microbiol Rev. 1991;4:359-395.Walport. N Engl J Med. 2001;344:1058.SOLIRIS™ (eculizumab) [package insert]. Alexion Pharmaceuticals; 2007.

C5b-9Cause of Hemolysis in PNH

C5a

C5b

SOLIRISSOLIRIS

• Proximal functions of complement remain intact•Weak anaphylatoxin•Immune complex and apoptotic body clearance

•Microbial opsonization

• Terminal complement activity is blocked

• SOLIRIS binds with high affinity to C5

Reduction in LDH During SolirisReduction in LDH During Soliris®® Treatment in TRIUMPH and SHEPHERDTreatment in TRIUMPH and SHEPHERD

Time, WeeksTime, Weeks

Lact

ate

Deh

ydro

gena

se (U

/L)

Lact

ate

Deh

ydro

gena

se (U

/L)

TRIUMPH placebo patients switched to SOLIRIS after week 26. All TRIUMPH patients entered the long term extension study.

00

500500

10001000

15001500

20002000

25002500

30003000

00 1010 2020 3030 4040 5050

TRIUMPH – Placebo/extensionTRIUMPH – Placebo/extensionTRIUMPH – SOLIRIS/extensionTRIUMPH – SOLIRIS/extensionSHEPHERD – SOLIRISSHEPHERD – SOLIRIS

PI: All patients sustained a reduction in intravascular hemolysis over a total SOLIRIS exposure time ranging from 10 to 54 months.

4 4 7 7 5 5 8 8 5 8 4 1 1 8 1 1 1 1 1 1 1 1 1 1 1 1 1

Pre-eculizumab Post-eculizumab

Urine score 2 weeks before & after Eculizumab

1

Effect of SolirisEffect of Soliris® ® on Ability on Ability to Maintain a Good to Maintain a Good

HemoglobinHemoglobin

PP<0.000000001<0.000000001

SOLIRISSOLIRISPlaceboPlacebo

Hem

oglo

bin

Stab

iliza

tion

(%)

Hem

oglo

bin

Stab

iliza

tion

(%)

0

10

20

30

40

50

Effect of SolirisEffect of Soliris®® on on Transfusion in PNHTransfusion in PNH

PP<0.0000001<0.0000001

Tra

nsfu

sed

Tran

sfus

ed

Uni

ts/P

atie

ntU

nits

/Pat

ient

(med

ian)

(med

ian)

SolirisSoliris®®PlaceboPlacebo

0

2

4

6

8

10

What is the effect of What is the effect of SolirisSoliris®® in PNH in PNH

Stops the symptoms associated with Stops the symptoms associated with hemolysishemolysis ““Fatigue”Fatigue” Esophageal and abdominal spasmEsophageal and abdominal spasm Erectile dysfunctionErectile dysfunction Improves sense of well beingImproves sense of well being Reduced the need for transfusionReduced the need for transfusion

Appears to reduce thrombosis (blood Appears to reduce thrombosis (blood clots)clots)

Effect of Eculizumab on the Effect of Eculizumab on the blood clots in PNH blood clots in PNH

Equalized Patient Years (195)Equalized Patient Years (195) Patients on Antithrombotics n=103Patients on Antithrombotics n=103 ((P P < 0.000000001< 0.000000001

39

3

05

1015202530354045

Pre-Soliris Treatment Soliris Treatment

Thro

mbo

tic E

vent

s (#

)

P=0.0001

10.61

0.620.00

2.00

4.00

6.00

8.00

10.00

12.00

Pre-Soliris Treatment Soliris Treatment

Thro

mbo

sis

Even

t Rat

e(T

E pe

r 100

Pt-Y

ears

)

91% reduction in TE event rate with Eculizumab

92% reduction in TE events with Eculizumab

Pre-Eculizumab Post-EculizumabPre-Eculizumab Post-Eculizumab

What is the Effect of What is the Effect of SolirisSoliris®®??

Improves kidney functionImproves kidney function reduced hemoglobinuria and iron reduced hemoglobinuria and iron

depositiondeposition Reduced thrombosisReduced thrombosis

Improves hypertensionImproves hypertensionMay in part be due to availability of nitric May in part be due to availability of nitric

oxideoxide

Side Effects of SolirisSide Effects of Soliris®® TreatmentTreatment

Susceptibility to sepsis by meningococcal organismSusceptibility to sepsis by meningococcal organism All patients must be vaccinated at least 2 weeks before All patients must be vaccinated at least 2 weeks before

starting Solirisstarting Soliris All patients must know to seek medical help All patients must know to seek medical help at onceat once

when fever happenswhen fever happens All patients must carry cards describing this complicationAll patients must carry cards describing this complication

Headache – first week or 2Headache – first week or 2 CostCost InconvenienceInconvenience

Must be given every 12-14 days by veinMust be given every 12-14 days by vein

What SolirisWhat Soliris®® Cannot Do Cannot Do Does not appear to improve impaired Does not appear to improve impaired

bone marrow functionbone marrow function Low white count or low platelet count Low white count or low platelet count

may persist in some patients, especially may persist in some patients, especially if it is due to aplastic anemiaif it is due to aplastic anemia

Other treatments may be indicatedOther treatments may be indicated Bone marrow transplantationBone marrow transplantation immunosuppressivesimmunosuppressives

When is Soliris When is Soliris Ineffective or Less Ineffective or Less

Effective Effective Patient has been incorrectly Patient has been incorrectly

diagnosed with PNH.diagnosed with PNH. Patient has a very small PNH clone Patient has a very small PNH clone

(less than 10%)(less than 10%) bone marrow failure- AAbone marrow failure- AA Breakthrough – infections, increased Breakthrough – infections, increased

clearance, delayed dosingclearance, delayed dosing Extravascular hemolysis Extravascular hemolysis

Which PNH Patients are Which PNH Patients are Candidates for Soliris?Candidates for Soliris?

Patients with hemolysis (LDH )Patients with hemolysis (LDH ) Patients with large CD 59 deficient clones- RBC , Patients with large CD 59 deficient clones- RBC ,

WBCWBC Patients with hemolysis with evidence of renal Patients with hemolysis with evidence of renal

impairement GRF<90, proteinuria etcimpairement GRF<90, proteinuria etc Patients with history of thrombosisPatients with history of thrombosis Patients with hemolysis and elevated DdimersPatients with hemolysis and elevated Ddimers Patients with hemolysis with fatigue Patients with hemolysis with fatigue Patients with hemolysis and transfusion Patients with hemolysis and transfusion

dependencedependence Patients prior to ?BMT, surgery, ???pregnancy Patients prior to ?BMT, surgery, ???pregnancy

Who Should Get SolirisWho Should Get Soliris®®??

In all cases, the decision should be made bya physician that understand PNH, its complications and its treatment in conjunction with the patient, whose life is affected by the disorder.

p aroxysmal n octurnal h emoglobinuria

Documents

pnh mutation

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cases of pnh

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pnhthe change

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