What Is PNH

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What Is PNH?

• And What Can Be Done About It.

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PNH Is

• A disorder of blood
• Rare
• Due to a glitch in a gene in a single cell
• Manifest in a variety of ways
• Able to be treated

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What We Will Cover Today

• How does PNH get started?
• What are the ways PNH affects one?
• What can be done to treat PNH?

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How Does PNH Get Started?

• PNH is due to a change in a gene in a blood stem
  cell

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What A Gene Does
Makes a protein
Gene
Protein
Copies itself for a new cell
In egg and sperm, carries characteristics to
next generation
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What Is A Mutation?

• A mutation is a mistake in a gene that arises
  during copying and is not corrected
• The mutation is transmitted to daughter cells
• The effect of a mutation
• None
• An altered protein
• No protein is produced

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Stem Cells
Egg
Sperm
Egg
Embryonic Stem Cell
Egg or Sperm
Blood
Muscle
Nerve
Etc.
Somatic Stem Cells
The Cells of Each Specific Organ
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Stem Cells
Egg
Sperm
Egg
Embryonic Stem Cell
Egg or Sperm
Blood
Muscle
Nerve
Etc.
Somatic Stem Cells
The Cells of Each Specific Organ
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Stem Cells
Egg
Sperm
Egg
Embryonic Stem Cell
Egg or Sperm
Blood
Muscle
Nerve
Etc.
Somatic Stem Cells
The Cells of Each Specific Organ
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• A Stem Cell Can Give Rise To All The Cells Of The
  Blood

T LYMPHOCYTES
STEM CELL
B LYMPHOCYTES
ERYTHROCYTES
GRANULOCYTES
MONOCYTES
PLATELETS
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• In PNH, a single mutation occurs in one blood
  stem cell

T LYMPHOCYTES
STEM CELL
B LYMPHOCYTES
ERYTHROCYTES
GRANULOCYTES
MONOCYTES
ALTERED GENE
PLATELETS
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• Evolution of PNH in Marrow

NORMAL
CLONES
ABNORMAL
CLONE
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The Beginning of PNH

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

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• The GPI Anchor Defect in PNH

PNH
O
O-P-O
O
CH
CH
CH
2
2
O
O
CO
(180,1)
(224,5)
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The Beginning of PNH

• The change that occurs in PNH stops the
  production of an anchor that ties protein
  molecules to the outside of the cell
• Sometimes the stop is only partial and PNH II
  cells occur
• About 25 molecules are not attached but only one
  plays a major role in causing PNH
• This is CD59, which protects the cells from
  complement

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How Do These Abnormal Cells Take Over The Bone
Marrow?

• Many normal people have blood stem cells with the
  abnormality characteristic of PNH in very small
  numbers (perhaps 6 per 1,000,000 bone marrow
  cells)
• In PNH, something allows the abnormal cells to
  become a major population in the marrow and blood
  (anywhere from 1 to over 90)
• This something may be related to aplastic
  anemia, a disease of poor production of blood
  from the marrow

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What Does PNH Have To Do With Aplastic Anemia

• Many PNH patients have aplastic anemia or a
  history of aplastic anemia
• Many PNH patients show signs of inadequate blood
  cell formation
• Low granulocyte (white cell) and low platelet
  counts are such signs
• All patients have evidence of a lazy bone
  marrow
• Therefore, whatever causes aplastic anemia
  (immune suppression?) may allow PNH to develope

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What is Complement and What Does It Have To Do
With PNH?

• Complement is the name given to a group of blood
  proteins that act together to help the body get
  rid of microbiological invaders
• One of the ways it does this is by penetrating
  the membrane (outside surface) of the invading
  organism
• When this happens to red cells, they burst,
  releasing their hemoglobin

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What is Complement?

• Complement circulates in an inactive form
• It is activated spontaneously and by a variety of
  events (infections, trauma, etc.)
• It is normally activated more at night

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How Are Our Cells Normally Protected From
Complement

• Proteins in the serum inactivate complement when
  it is activated
• Proteins on the cell surface inactivate
  complement to prevent breakdown (lysis)
• The most important of these is CD59, which is
  missing on the abnormal cells of PNH
• For this reason, PNH red cells are extremely
  sensitive to very small amounts of activated
  complement

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What Happens in PNH When Complement Is Activated?

• Complement successfully attacks the red cells and
  they break up (hemolysis)
• This releases hemoglobin (the red pigment in red
  cells) into the plasma (the fluid part of the
  blood)
• The red cells are destroyed, resulting in anemia

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What Are The Effects of Releasing Hemoglobin?

• Some of the hemoglobin passes through the kidneys
  and into the urine, causing red to dark brown
  urine
• This causes a marked loss of iron from the body
• In the long run, this damages the kidney
• Free hemoglobin binds nitric oxide

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Action of Nitric Oxide (NO)
NO
NO
Smooth Muscle Relaxation
Smooth Muscle Contraction
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Free Hemoglobin Binds NO
NO
NO
Smooth Muscle Relaxation
NO
Free Hemoglobin
Smooth Muscle Contraction
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What Are The Effects of Nitric Oxide Trapping by
Hemoglobin

• Spasm of the esophagus
• Abdominal pain
• Erectile dysfunction
• Other symptoms such as fatigue

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What Happens in PNH When Complement Is Activated?

• Platelets are attacked and become activated
• They stick together and form clots

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What Happens in PNH When Complement Is Activated?

• Platelets are attacked and become activated
• They stick together and form clots
• These clots are often in unusual places
• Liver veins (Budd-Chiari syndrome
• Other abdominal veins
• Veins covering the brain

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The Clinical Picture in PNH

• Hemolytic anemia due to complement activation
• Hemoglobinuria and, eventually, kidney damage
• Anemia to a variable degree
• Effects of NO trapping
• Thrombosis due to complement activation
• Often in unusual places (liver veins, abdominal
  veins, etc)
• Lazy bone marrow (not related to complement
  activation)

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What Can Be Done For PNH?

• Symptomatic treatment
• Iron supplementation
• Folic acid
• Transfusion

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What Can Be Done For PNH?

• Treatment of thrombosis
• Prevention by coumadin
• Acute treatment by clot busters
• Use of coumadin or heparin
• Stopping the effect of complement activation
• Prednisone
• Eculizumab (Soliris), an antibody that
  inactivates one of the components of complement
  (C5)

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What Does Soliris Do?

• Quickly and markedly reduces hemolysis
• Stops hemoglobinuria
• Increases hematocrit and hemoglobin level
• Reduces transfusions
• Hematocrit may not be quite normal

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Reduction in LDH During Soliris Treatment in
TRIUMPH and SHEPHERD
3000
TRIUMPH Placebo/extension
TRIUMPH SOLIRIS/extension
2500
SHEPHERD SOLIRIS
2000
Lactate Dehydrogenase (U/L)
1500
1000
500
0
0
10
20
30
40
50
Time, Weeks
PI All patients sustained a reduction in
intravascular hemolysis over a total SOLIRIS
exposure time ranging from 10 to 54
months.
TRIUMPH placebo patients switched to SOLIRIS
after week 26. All TRIUMPH patients entered the
long term extension study.
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D.T., urine score 2 weeks before after
Eculizumab
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
1
4
Pre-eculizumab
Post-eculizumab
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Effect of Soliris on Ability to Maintain a Good
Hemoglobin
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Effect of Soliris on Transfusion in PNH
10
8
Plt0.0000001
Transfused Units/Patient (median)
6
4
2
0
Soliris
Placebo
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What Does Soliris Do?

• Stops the symptoms associated with hemolysis
• Fatigue
• Esophageal and abdominal spasm
• Erectile dysfunction
• Improves sense of well being

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What Does Soliris Do?

• Appears to reduce thrombosis
• May change role of chronic blood thinning

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Clots in Patients With and Without Soliris
7.37
8.00
7.00
6.00
5.00
(Events per 100 Pt-Years)
Thrombosis Event Rate
4.00
(Plt0.0000000000001)
3.00
2.00
1.07
1.00
0.00
Pre-Soliris Treatment
Soliris Treatment
Hillmn P, et al. Blood. First Edition Papr,
prepublished online August 16, 2007.
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What Does Soliris Do?

• Improves kidney function
• May in part be due to reduced hemoglobinuria
• May in part be due to availability of nitric
  oxide
• Improves hypertension

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What Does Soliris NOT Do?

• Does not appear to improve impaired hematopoiesis
  (lazy bone marrow)
• Low white count or low platelet count will
  persist
• Other treatments may be indicated
• Bone marrow transplantation
• ATG and other immunosuppressives

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Downside of Soliris Treatment

• Susceptibility to sepsis by meningococcal
  organism
• All patients must be vaccinated
• All patients must know to seek medical help at
  once when fever happens
• All patients must carry cards describing this
  complication
• Cost
• Inconvenience
• Must be given every 12-14 days by vein

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Who Should Get Soliris?

• Patients with significant anemia, especially
  those requiring transfusion
• Patients with clots or a history of clots,
  especially of the abdomen or brain
• Patients incapacitated by symptoms of PNH

In all cases, the decision should be made
by doctors and patients that understand PNH and
its treatment
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The End

• Any Questions?