jack goldberg session 1 and 2 pnh- · 0.2 0.4 0.6 0.8 1 1.2 43 92% reduction in thrombotic events...

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PNH

Jack Goldberg MD FACP

Clinical Professor of Medicine University of Pennsylvania

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Anemia

Reduced Red Cell MassFree Hemoglobin

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 RBC

ComplementActivation

Historically Viewed as a Hemolytic Anemia

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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SOLIRIS® (eculizumab)

SOLIRIS® is a Complement Inhibitor Indicated for the Treatment of Patients With

PNH to Reduce Hemolysis

SOLIRIS® (eculizumab) [package insert]. Alexion Pharmaceuticals; 2009.

SOLIRIS® is the First and Only Approved Therapy for PNH

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

Hinge

CH

3C

H2

Human IgG4 Heavy ChainConstant Regions 2 and 3

(Eliminates complement activation)

Complementarity Determining Regions(murine origin)

Human Framework Regions• No mutations• Germline

Human IgG2 Heavy ChainConstant Region 1 and Hinge

(Eliminates Fc receptor binding)

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

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SOLIRIS® Blocks Terminal Complement

C3 C3a

C3b

C5

Pro

xim

alTe

rmin

al

Figueroa JE, Densen P. Clin Microbiol Rev. 1991;4(3):359-395.

Walport MJ. N Engl J Med. 2001;344(14):1058-66.

SOLIRIS® (eculizumab) [package insert]. Alexion Pharmaceuticals; 2009. Rother RP et al. Nature Biotech. 2007;25(11):1256-64.

C5b-9Cause of Hemolysis

in PNH

C5a

C5b

SOLIRIS®

• Proximal functions of complement remain intact

• Weak anaphylatoxin

• Immune complex clearance

• Microbial opsonization

• Terminal complement - C5a and C5b-9 activity blocked

• SOLIRIS® binds with high affinity to C5

Complement Cascade

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Long-Term Extension Trial Hillmen Blood. 2007

Evaluated long-term safety, efficacy and effect on

thrombosis; Placebo patients switched to SOLIRIS®

N = 187

Pilot Study – NEJM. 2004N = 11

Primary endpoint: reduction of hemolysis

TRIUMPH – NEJM. 2006 Pivotal Phase III, Double-Blind, Placebo-Controlled Trial, N = 87

SHEPHERD – Blood. 2008Broader patient population, including

those receiving minimal transfusions or with thrombocytopenia, N = 97

SOLIRIS® PNH Clinical Studies

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Dosing Schedule

Pretreatment Induction Phase Maintenance Phase

2 weeks before

induction

Week→ 1 2 3 4 5 6 7 8

9 and every

2 weeks thereafter

Neisseria meningitidis vaccination

SOLIRIS®

dose, mg→

600 600 600 600 900 X 900 X 900

In clinical trials all patients received a meningococcal vaccination

SOLIRIS® should be administered via IV infusion over 35 minutes every 7 days during induction and every 14 days during maintenance

SOLIRIS® dose adjustment to every 12 days may be necessary for some patients to maintain LDH reduction

Concomitant medications allowed:– Steroids, immunosuppressant drugs, anti-clotting agents and hematinics1


1. Hillmen P et al. N Engl J Med. 2004;350(6):552-9. 40

86% Reduction in LDH:TRIUMPH and SHEPHERD

P<0.001 at all measured time points.

Hillmen P et al. Blood. 2007;110(12):4123-8.

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

TRIUMPH – Placebo/Extension

TRIUMPH – SOLIRIS®/Extension

SHEPHERD – SOLIRIS®

Lac

tate

Deh

ydro

gen

ase

(U

/L)

0

500

1000

1500

2000

2500

3000

Time, Weeks

0 4 8 12 16 20 24 28 32 36 40 44 48 52

100% response after the first dose

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

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

1. Hillmen P et al. N Engl J Med. 2006;355;1233-1243. 2. Schubert J. Br. J Haematol. 2008;142(2):263-72.

Patients not on SOLIRIS® (n=44)

SOLIRIS® (n=43)

*

**

*

(n=87) (n=30) (n=35) (n=22)0

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8

10

12

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Overall 4-14 15-25 >25

Pre-treatment Transfusion Strata◘

Med

ian

Un

its

Tran

sfu

sed

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• 51% of SOLIRIS patients achieved transfusion independence vs 0% of patients not on SOLIRIS1

• Patients with concomitant bone marrow dysfunction may continue to require minimal transfusions

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Patients Report Rapid and Sustained Improvement Across Broad Range of Measures

*P<0.05.◘P<0.001.

Brodsky R et al. Blood. 2006;108(11): Abstract 3770. Data on file. Alexion Pharmaceuticals.

Moderate Impact

Small Impact

Large Impact

Sta

nd

ard

Eff

ect

Siz

e (S

ES

)

EORTCFunctioning

EORTC Symptoms

FAC

IT-F

atig

ue◘

EO

RT

C F

atig

ue◘

Glo

bal

Hea

lth

◘

Ph

ysic

al◘

Ro

le◘

Co

gn

itiv

e*

Dys

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ea◘

Pai

n*

Inso

mn

ia*

Co

nst

ipat

ion

Nau

sea

Dia

rrh

ea

0

0.2

0.4

0.6

0.8

1

1.2

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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

PI: There were fewer thrombotic events with SOLIRIS® treatment than during the same period of time prior to treatment.

1.Brodsky R et al. Blood. 2008;111(4):1840-47. 2.SOLIRIS® (eculizumab) [package insert]. Alexion Pharmaceuticals; 2009.

3.Hillmen P, et al. Blood. 2007;110:4123-4128.

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3

05

1015202530354045

Pre-SOLIRIS® Treatment SOLIRIS® Treatment

Th

rom

bo

tic

Eve

nts

(#)

P=0.0001

N=195

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

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TRIUMPH Demonstrated that Improvement in Fatigue Occurred Independent of Hemoglobin

Response

FACIT = Functional Assessment of Chronic Illness Therapy

Adapted from: Hillmen P et al. NEJM. 2006;355:1233-43. Brodsky R et al. Blood Rev. 2008; 22: 65-74. Hill A et al. Haematologica. 2008; 93 (Suppl 1): 359. Abstract 0904.

1. Brodsky R et al. Blood. 2008;111:1840-1847.

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

Time, Weeks

9.0

9.5

10.0

10.5

11.0

11.5

12.0

Hem

og

lob

in,

g/d

L

8.5

Ch

ang

e fr

om

Bas

elin

e FA

CIT

-Fat

igu

e S

core

-6

-4

-2

0

2

4

6

8

FACIT-Fatigue Score

FACIT-Fatigue Score

Hgb Level

P<0.001

≥3 or more points denotes a clinically significant improvement

SOLIRIS® (n=43)

SOLIRIS® HgbPatients not on SOLIRIS® (n=44)

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

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What Is The Long-Term Experience with SOLIRIS®?

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SOLIRIS® PNH Clinical Studies

Long-Term Extension Trial Hillmen Blood. 2007

Evaluated long-term safety, efficacy and effect on

thrombosis; Placebo patients switched to SOLIRIS®

N = 187

Pilot Study – NEJM. 2004N = 11

Primary endpoint: reduction of hemolysis

TRIUMPH – NEJM. 2006 Pivotal Phase III, Double-Blind, Placebo-Controlled Trial, N = 87

SHEPHERD – Blood. 2008Broader patient population, including

those receiving minimal transfusions or with thrombocytopenia, N = 97

Patient (n)

187/149 173 171 171 68 21 10

86% Reduction in LDH Sustained Out Past 4 ½Years: Long-Term Extension Results

10 patients who participated in the pilot study demonstrated sustained reduction in LDH out past 5 years

– Patients followed for up to 54 months

Socié G et al. Blood. 2007;110(11): Abstract 3672. SOLIRIS® (eculizumab) [package insert]. Alexion Pharmaceuticals; 2009.

Study Year

*P<0.001P=0.002

* * * *

◘

◘

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Summary of Clinical EfficacyIn clinical trials, SOLIRIS® significantly reduced hemolysis1 the underlying cause of morbidity and mortality in PNH

86% sustained reduction in hemolysis as measured by LDH2

Fewer thrombotic events were observed with SOLIRIS in clinical trials1,3

– The majority of patients (63%) received concomitant anticoagulant therapy1

– The effect of anticoagulant withdrawal during SOLIRIS treatment has not been studied1

78% clinically meaningful improvement in fatigue– Fatigue in PNH impacted by hemolysis – Significant improvement noted in pain and dyspnea along with a

broad range of QoL measures4

73% reduction in need for transfusions across all patient populations2

1. SOLIRIS® (eculizumab) [package insert]. Alexion Pharmaceuticals; 2009. 2. Hillmen P et al. N Engl J Med. 2006;355:1233-43.

3. Hillmen P et al. Blood. 2007;110(12):4123-8. 4. Socie G et al. Blood. 2007;110(11)::Abstract 3672.

Important Safety Information About SOLIRIS®

All Patients Should Receive a Medication Guide Before Starting

SOLIRIS® Treatment

Please See Full Prescribing Information for SOLIRIS®

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Warning

WARNING: SERIOUS MENINGOCOCCAL INFECTION

SOLIRIS® increases the risk of meningococcal infections. Meningococcal infection may become rapidly life-threatening or fatal if not recognized and treated early.

– Vaccinate patients with a meningococcal vaccine at least 2 weeks prior to receiving the first dose of SOLIRIS®

– Revaccinate according to current medical guidelines for vaccine use

– Monitor patients for early signs of meningococcal infections, evaluate immediately if infection is suspected, and treat with antibiotics if necessary

SOLIRIS® (eculizumab) [package insert]. Alexion Pharmaceuticals; 2009. 52

Safety: Contraindications

SOLIRIS® is contraindicated for patients with unresolved serious Neisseria meningitidis infection or who are not currently vaccinated against Neisseria meningitidis


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Safety: Warnings and Precautions

SOLIRIS® therapy increases the risk of meningococcal infections. Meningococcal infection may become rapidly life-threatening or fatal if not recognized and treated early

All patients must be vaccinated against Neisseria meningitidis ≥ 2 weeks prior to receiving SOLIRIS®

Use caution when administering SOLIRIS® to patients with any systemic infection

Other infections: SOLIRIS blocks terminal complement; therefore patients may have increased susceptibility to infections, especially with encapsulated bacteria– Use caution when administering SOLIRIS to patients

with any systemic infection


Safety: Warnings and Precautions (cont)

The effect of withdrawal of anticoagulant therapy during SOLIRIS® treatment has not been established. Therefore, treatment with SOLIRIS® should not alter anticoagulant management

Patients who discontinue SOLIRIS® must be monitored closely for signs of serious hemolysis– If serious hemolysis occurs after SOLIRIS discontinuation, consider

the following procedures/treatments: blood transfusion (packed RBCs), or exchange transfusion if the PNH RBCs are >50% of the total RBCs by flow cytometry; anticoagulation; corticosteroids; or reinstitution of SOLIRIS

– In clinical trials, 16 of 196 PNH patients discontinued SOLIRIS®

treatment; no serious hemolysis was observed


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Safety: Warnings and Precautions (cont)

LDH levels may be used to monitor hemolysis– SOLIRIS® dose adjustment to every 12 days may be

necessary for some patients to maintain LDH reduction

Infusion reactions may occur– In clinical trials, no patients experienced infusion

reactions that required discontinuation– SOLIRIS® treatment should be interrupted in all patients

experiencing severe infusion reactions and appropriate medical therapy administered


Serious Adverse Events:Clinical Trial Experience

Meningococcal infections are the most important adverse events that may be experienced by patients receiving SOLIRIS®

In clinical studies, 2 out of 196 patients developed serious meningococcal infections while receiving treatment with SOLIRIS– Both patients had been vaccinated

In clinical studies among non-PNH patients, meningococcal meningitis occurred in one patient, who was unvaccinated

In post-marketing experience, cases of serious or fatal meningococcal infections have been reported


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Adverse Reactions Reported in ≥ 5% of SOLIRIS® Treated Patients in TRIUMPH

Patients, n (%)

Reaction SOLIRIS® (n = 43) Placebo (n = 44)

Headache 19 (44) 12 (27)

Nasopharyngitis 10 (23) 8 (18)

Back pain 8 (19) 4 (9)

Nausea 7 (16) 5 (11)

Fatigue 5 (12) 1 (2)

Cough 5 (12) 4 (9)

Herpes simplex virus infections 3 (7) 0

Sinusitis 3 (7) 0

Respiratory tract infection 3 (7) 1 (2)

Constipation 3 (7) 2 (5)

Myalgia 3 (7) 1 (2)

Pain in extremity 3 (7) 1 (2)

Influenza-like illness 2 (5) 1 (2)


Patient Counseling

Prior to treatment, patients should be informed and fully understand:– The risks and benefits of SOLIRIS®, in particular the risk

of meningococcal infection– Meningococcal vaccine does not prevent all

meningococcal infections– They are required to receive a meningococcal vaccination

at least 2 weeks prior to receiving the first dose of SOLIRIS®, if they have not previously been vaccinated

– There is a potential for serious hemolysis when SOLIRIS®

is discontinued and that they will be monitored by their healthcare professional for at least 8 weeks following SOLIRIS® discontinuation


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SOLIRIS® OneSource Program

OneSource provides education, assistance with access and treatment support for people living with paroxysmal nocturnal hemoglobinuria (PNH) and their caregivers.

It is staffed by Alexion Nurse Case Managers, who are registered nurses with healthcare and insurance experience.

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Patient Safety Card

Patients should be informed that they will be provided with a Patient Safety Card

Patients should carry the card with them at all times

The card describes symptoms, which if experienced, should prompt the patient to seek immediate medical attention

Instruct patients to show the card to all health care providers involved in their care


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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 500 patients enrolled – Participation in 14 countries, including the United States, Argentina,

Denmark, Netherlands, Belgium, Australia, France, New Zealand, Germany, and Taiwan

Enrollment information: (800) 913-4893 or www.pnhsource.com

Thank You

Jack Goldberg M.D. FACP

Clinical Professor of Medicine

University of Pennsylvania

jack goldberg session 1 and 2 pnh- · 0.2 0.4 0.6 0.8 1 1.2 43 92% reduction in thrombotic events...

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