PowerPoint Presentation · 2016-05-03 · 3/22/2016 1 Paroxysmal Nocturnal Hemoglobinuria (PNH): Current Thinking on the Disease Rodrigo T. Calado, MD/PhD Ribeirão Preto School of

3/22/2016

1

Paroxysmal Nocturnal Hemoglobinuria (PNH):

Current Thinking on the Disease

Rodrigo T. Calado, MD/PhDRibeirão Preto School of Medicine

University of São Paulo

Bone Marrow Failure Disease Scientific SymposiumRockville, March 17-18, 2016

Extracellular

space

Cytoplasm

Transmembrane

COOH

GPI-

Anchored

NH2

COOH

1189 1452982849716

63 52 4

1

PIG-A gene

GPI-anchored protein

glycosylphosphoinositol

(GPI) anchor

C OC OO

CH CH2

O POO

O

O

CH2

INOS

GLU

MAN

O

O

O

(a 1-2)

(a 1-6)

C O

N

CH2

CH2

NH

O P O

O

O

MANO

PHOSPHATIDYL

-INOSITOL

GLYCAN COREPHOSPO-

ETHANOLAMINE

PROTEIN

MAN

PATHOGENESIS OF PNH

C3

PNH

CD59C3

conv CD55

PIG-A mutation: Absent GPI (anchor)Absent CD55 - higher C3 convertase

C3

b

Adapted from Abbas AK et al. Cellular and Molecular Immunology, 3rd ed.WB Saunders: Philadelphia, 1991

Adapted from Abbas AK et al. Cellular and Molecular Immunology, 3rd ed.WB Saunders: Philadelphia, 1991

C5b,6,7 C5b-8

C5b-9

C5b

C5 C5a C7C8

C5b

C7

C6

C7

C6

C5bC6

x 12–15

C5

con

vert

ase

C5

con

vert

ase

C8

CD59

C9

X

PNH

PIG-A mutation: Absent GPI (anchor)Absent CD55 - higher C3 convertaseAbsent CD59 – MAC formation

Adapted from Abbas AK et al. Cellular and Molecular Immunology, 3rd ed.WB Saunders: Philadelphia, 1991

C5b,6,7 C5b-8

C5b-9

PNH, paroxysmal nocturnal haemoglobinuria

C5b

C5 C5a C7C8

C5b

C7

C6

C7

C6

C5bC6

C9

C7

C5bC6

C7

C8

C5bC6

x 12–15

C5

con

vert

ase

C5

con

vert

ase

C8 C8C9

PNH

PIG-A mutation: Absent GPI (anchor)Absent CD55 - higher C3 convertaseAbsent CD59 – MAC formation

Anemia

Reduction in circulating

RBC mass

Free hemoglobin

Normal red blood cells are

protected from complement

CD55- and CD59-negative

RBCs are destroyed

Intact Red

Blood Cell

Complement

Activation

PNH

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 Shattil et 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.

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2

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

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

Intact RBCHemoglobin released from destroyed PNH

RBCs

ComplementActivation

Anaemia and release of free Hb Haemoglobinuria

Thrombosis

Fatigue

Renal Failure

Significant Impact on Morbidity

Significant Impact on Survival

Pulmonary Hypertension

Erectile Dysfunction

Dyspnoea

Dysphagia

Abdominal Pain

PNH is a Progressive Disease of Unregulated Complement Activity

NO↓A Hill, Leeds8

PNH clone expansion

9

PNH clone expansion

Cytopenia

Low level of Hemolysis

Cytopenia Hemolysis

Thrombosis

Aplastic anemia > AA PNH syndrome > Hemolytic PNH

Cytopenia

Defining “Patients with PNH”• Classical haemolytic PNH patients

• PNH associated with AA or MDS also with• Haemolysis• Organ impairment due to haemolysis• Thrombosis

PAROXYSMAL NOCTURNAL HEMOGLOBINURIA (PNH)

TRIAD OF CLINICAL FEATURES

Hemoglobinuria

Intravascular Haemolysis

• Disabling Symptoms

- Abdominal pain

- Dysphagia

- Erectile failure

- Severe lethargy

Budd-Chiari

Syndrome

Thrombosis

• Liver, cerebral

• 50% of patients;

fatal in 33%

Aplastic Anemia

Bone Marrow Failure

• Often precedes PNH

• Selects for PNH clone

1. somatic mutation of PIG-A in an hematopoietic stem cell

2. aborted GPI anchor synthesis

3. absent cell surface GPI-anchored proteins

4. clonal expansion of GP-AP deficient cells = PNH

hemolysis (CD59-) BM failure (?) thrombosis (?)

3/22/2016

3

complementarity determining regions

(murine origin)

CH

3C

H2

Hinge

human IgG4 heavy chain

constant regions 2 and 3

human framework regions

human IgG2 heavy chain

constant region 1 and hinge

ECULIZUMAB (ANTI-C5

ANTIBODY)TRIUMPH

Transfusion Reduction Efficacy and Safety Clinical Investigation, Randomized, Multicenter, Double-Blind, Placebo-Controlled, Using Eculizumab in

Paroxysmal Nocturnal Hemoglobinuria

Hemolytic

transfusion

dependent

PNH patient

Observation–

qualifying

transfusion

Up to 3 months

Eculizumab

Placebo

R

6 months

Extension

Study

24+ months

TRIUMPH ENTRY CRITERIA

• Inclusion criteria:

– 18 years-of-age

– 4 episodes of transfusions in the previous 12 mos

– PNH type III erythrocyte population 10%

– Platelets 100,000/mm3

– LDH 1.5 times ULN

• Exclusion criteria:

– Transfused with Hb >10.5 g/dL in prior year

– Complement deficiency

– Active bacterial infection

– Prior meningococcal disease

– Pregnancy

TRIUMPH STUDY DESIGN

• Dosing schedule: iv infusion of eculizumab over 30 min

– Induction period

• 600 mg every 7±2 days for 4 doses

– Maintenance period

• 900 mg 1 week later, followed by…

• 900 mg every 14±2 days for a total of 26 weeks

• Concomitant medications:

– No change in immunosuppressant drugs, steroids, anti-clotting agents or hematinics

– Patients were vaccinated against Neisseria meningitidis

TRIUMPH ENDPOINTS

• Co-primary endpoints:– Stabilization of Hb levels: Hb value above the Hb set

point without transfusions for entire trial period– Units of PRBCs transfused

• Secondary endpoints:– Hemolysis: lactate dehydrogenase (LDH) AUC– Fatigue assessed via the FACIT-Fatigue instrument

• Exploratory endpoints:– QoL measures including fatigue (EORTC QLQ-C30)– Thrombosis

• Safety reporting

*Value at which each patient received a qualifying transfusion

TRIUMPH PATIENT RECRUITMENT

115 Assessed for eligibility

Allocation

Follow-up

Analysis

Excluded (28 patients)

• 6 Failed inclusion criteria

• 21 Failed observation period

• 1 Randomization error87 Randomized and

received treatment

Enrollment

43 Received eculizumab

2 Discontinued treatment

• 1 inconvenience of travel

• 1 pregnant

43 Analyzed

44 Received placebo

10 Discontinued treatment

• Lack of efficacy but

monitored for duration

of study

44 Analyzed

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4

EFFECT OF ECULIZUMAB ON HEMOLYSIS – LDH

0

500

1000

1500

2000

2500

3000

-4 -2 0 2 4 6 8 10 12 14 16 18 20 22 24 26

Study Week

Placebo

Eculizumab

LD

H (

IU/L

)

P<0.001

Normal

Screening

EFFECT OF ECULIZUMAB ON TRANSFUSIONS

0

2

4

6

8

10

12

0

2

4

6

8

10

12

Placebo Eculizumab

Pre- Trial Pre- Trial Pre- Trial Pre- Trial

Placebo Eculizumab

Median Transfusions Mean Transfusions

Co-Primary Endpoint (1)

P<0.001

EFFECT OF ECULIZUMAB ON STABILIZATION OF HEMOGLOBIN

LEVELSCo-Primary Endpoint (2)

0

10

20

30

40

50

60

Sta

bil

iza

tio

n o

f H

b,

% p

ati

en

ts

Placebo Eculizumab

P<0.001

EFFECT OF ECULIZUMAB ON TIME TO FIRST TRANSFUSION

P<0.001

Eculizumab

Placebo

Study Week

0 2 4 6 8 10 12 14 16 18 20 22 24 26

Pa

tie

nts

Avo

idin

g T

ran

sfu

sio

n,

%

0

10

20

30

40

50

60

70

80

90

100

44% Reduction

in PRBC Units

Transfused

51%

0%

EFFECT OF ECULIZUMAB ON QOL

*Mixed model analysis†5-10 point change is considered clinically meaningful

Osoba D et al. J Clin Oncol. 1998;16:139,

Brodsky RA et al, Blood 2008; 111:1840

Diarrhoea

Nausea/Vomiting

Constipation

Financial Difficulties

Insomnia

Appetite Loss

Dyspnoea

Pain

Fatigue

Emotional

Physical

Cognitive

Social

Role

Global Health Status

Fu

nc

tio

na

lS

ym

pto

ms

/Ite

ms

Eculizumab Placebo Difference†

-0.9

-3.2

-6.3

-10.3

-12.8

-13.6

-16.9

-17.6

-27.0

11.2

13.0

14.0

14.6

24.8

19.4

P Value*

Favors Eculizumab Favors Placebo

-40 -30 -20 -10 0 10 20 30 40

=0.008

<0.001

=0.002

=0.003

<0.001

<0.001

=0.147

=0.056

=0.199

=0.186

=0.014

<0.001

<0.001

=0.002

<0.001

5.74.8

2.8-0.4

0.0-6.3

0.0-10.3

4.9-7.9

3.3-10.3

8.9-7.9

5.3-12.3

10.0-16.9

-3.77.5

-3.59.4

-6.17.9

2.016.7

-6.917.9

-8.510.9

ECULIZUMAB: IMMUNOGENICITY:HAHA (HUMAN ANTI-HUMAN

ANTIBODIES)Timing Eculizumab Placebo

IgG First dose 0/42 (0%) 0/44 (0%)

Week 12 0/41 (0%) 0/44 (0%)

Week 26 1/39 (2.5%) 1/43 (2.3%)

IgM First dose 0/42 (0%) 0/44 (0%)

Week 12 0/41 (0%) 0/44 (0%)

Week 26 0/40 (0%) 0/44 (0%)

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EFFECT OF ECULIZUMAB ON

HEMOLYSIS – LDH

0

500

1000

1500

2000

2500

3000

-4 -2 0 2 4 6 8 10 12 14 16 18 20 22 24 26

Study Week

Placebo

Eculizumab

LD

H (

IU/L

)

P<0.001

Normal

Screening

EXTRAVASCULAR HEMOLYSIS IN PNH UNCOVERED BY

ECULIZUMAB TREATMENT

16

2003

LDH

14

12

10

8

6

4

450

300

200

150

100

0

400

K/u

L

50

250

350

g/d

L

2500

1500

1000

500

0

U/L

2000

Corticosteroids

50 20 mg Pregnancy

2u prbc

4u prbc

Eculizumab

2004 2005 20072006

Reticulocytes

Hemoglobin

ECULIZUMAB REDUCES

THROMBOSES IN PNH• Combined data from TRIUMPH, SHEPHERD, UK cohort, and

phase III extension study compared to pre-treatment events

• Pre-rx: 126 thrombotic events in 195 patients (103 on anticoagulation)

• TE events:

pre-rx = 7.5 vs post-rx = 1.22/100 patient years

(84% reduction)

Hillmen P et al, Blood, 2007

ECULIZUMAB (SOLIRIS) IN

PRACTICEAdvantages

Dramatically reduces intravascular hemolysis and related symptoms

(anemia and NO-induced)

May be effective in preventing thrombosis without bleeding risk

Well tolerated

Disadvantages

Expensive (!)

Risk of specific infections with Gram- cocci

Life-long infusions

Unmasked extravascular hemolysis in some cases