SOLIRIS® (eculizumab) 2.pdf · SOLIRIS® (eculizumab) SOLIRIS® is a Complement Inhibitor Indicated for the Treatment of Patients With PNH to Reduce Hemolysis SOLIRIS® (eculizumab)

7/14/2014

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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 Chain

Constant Regions 2 and 3

(Eliminates complement activation)

Complementarity Determining Regions

(murine origin)

Human Framework Regions

• No mutations

• Germline

Human IgG2 Heavy Chain

Constant 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

al

Term

inal

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. 2007Evaluated 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. 6

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®

Lacta

te D

eh

yd

rog

en

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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7

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

2

4

6

8

10

12

14

16

Overall 4-14 15-25 >25

Pre-treatment Transfusion Strata◘

Med

ian

Un

its T

ran

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 (

SE

S)

EORTC

FunctioningEORTC

Symptoms

FA

CIT

-Fati

gu

e◘

EO

RT

C F

ati

gu

e◘

Glo

bal

Healt

h◘

Ph

ysic

al◘

Ro

le◘

Co

gn

itiv

e*

Dysp

nea◘

Pain

*

Inso

mn

ia*

Co

nsti

pati

on

Nau

sea

Dia

rrh

ea

0

0.2

0.4

0.6

0.8

1

1.2

9

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

0

5

10

15

20

25

30

35

40

45

Pre-SOLIRIS® Treatment SOLIRIS® Treatment

Th

rom

bo

tic

Ev

en

ts (

#)

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

an

ge f

rom

Baselin

e

FA

CIT

-Fati

gu

e S

co

re

-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® Hgb

Patients 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. 2007Evaluated 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

14

Patient (n)

187/149 173 171 171 68 21 10

86% Reduction in LDH Sustained Out Past 4 ½

Years: 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<0.001

P=0.002

* * * *

◘

◘

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Summary of Clinical Efficacy

In 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. 18

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

Documents

SOLIRIS® (eculizumab) 2.pdf · SOLIRIS® (eculizumab) SOLIRIS® is a Complement Inhibitor Indicated for the Treatment of Patients With PNH to Reduce Hemolysis SOLIRIS® (eculizumab)