Sarzi puttini piercarlo i nuovi inibitori del tnf torino gennaio 2011_14° convegno patologia immune...

I nuovi inibitori

del TNF-α

Piercarlo Sarzi-Puttini

L Sacco University Hospital

Via GB Grassi 74, MIlano

The Journal of Immunology, 2010, 185: 791–794.

Background

In the early 1980s, rheumatoid arthritis (RA), a

disease affecting ~1% of the population

worldwide, was a major clinical problem.

Twenty-five years later, RA is far from curable,Twenty-five years later, RA is far from curable,

but it is much more manageable, less crippling,

and less lethal.

Research in immunology has had time to bear

fruit and yield clinical benefit, resulting in

reduced disease activity and progression.

Cellular processes involved in the

pathogenesis of rheumatoid arthritis

Atzeni F, Sarzi-Puttini P - Current Opinion in Investigational Drugs 2009 10(11):1204-1211

TNF-αmacrophage

Innate immunity

(non specific)

Acquired immunity

(specific)

T LymphocyteHepatic acute Phase responseAlbumin responseGlyconeogenesisGluconeogenesis and Amino Acid intake

CNS ResponsesFeverMyalgias

Il-1IL-12IL-18

Th2 ResponseIL-4IL-10IL-13

Th1 ResponseIL-1TNF-α

TNF-α, IL-1 and IL-6 regulationof innate and acquired immunity

IL-1

IL-6

macrophage

T lymphocyte or NK Cells

TNF-α

MyalgiasAltered sleep behaviorAnorexiaHPA activity

TNF-α

IL-2IL-12IL-18IFN-γSomatic tissue response

Muscle proteolysisAdypocyte Lipolysis

Immunological responsesMacrophage activationRelease of NeutrophilsTrace mineral redistribution

Cytotoxic response

Inflammation

Autocrine

activation and

differentiation

factormacrophage

Prothrombotic

action

Induction of

endothelial adhesion

molecules

TNF-α

Induces other

cytokines

Defence againts

intracellular

pathogens

Comitogen for

T and B cellsRegulates

haematopoiesis

Growth factor

TNFα

�Citochina pro-infiammatoria rilasciata da:

�monociti attivati

�macrofagi

�T-linfociti �T-linfociti

� Il TNFα si lega a 2 recettori espressi da alcuni tipi di cellule: il recettore TNF p55 ed il recettore TNF p75

nucleus

TACEnucleus

Biology of TNFBiology of TNF--aa

membraneTNF-a

dimer

trimermonomer

TNFTNF--R1R1(p55)(p55)

sTNFsTNF--R1R1

InjuryInjury

TACE

26kDa 17kDa

solubleTNF-a

TACE(ADAM17)

dimer

TNFTNF--R2R2(p75)(p75)

sTNFsTNF--R2R2TACE

TNF-a trimer

Ligandpassing3’-AU-mRNA

PC-PLC SODD TRIP

FLIP

aSMasePKC

FAN

MADD

RIP

nSMase

ASK1

CK-1

TRAF1MAPK

I-TRAF

cIAP

PC

DAG

SM

SM

Ceramide

TNF-R1 TNF-R2

?

Trasduzione del segnale di TNF- αααα

TRAF2TRADDTRAF 2?

FADD

RAIDO NIK MKKs PLA2 A20

IKKαααα/IKKββββ

IκκκκB

JNK

p50/p65

geni NF- κκκκB-dipendenti

SM

Ceramide

?

ApoptosiAttivazione di JNK

Apoptosi

Apoptosi

Casp-2

?

Degradazione c-Jun

NF-κκκκB

NF-κκκκB

Casp-8

FADD

Key Actions Attributed to TNF-a in inflammation

Introduzione

Gli antagonisti del tumor necrosis factor (TNF)-α

hanno determinato un nuovo standard terapeutico per

il trattamento dell’artrite reumatoide (AR) e di altre

patologie reumatiche.patologie reumatiche.

L’utilizzo di qualunque agente farmacologico che alteri

la funzione immunitaria aumenta la possibilità di

determinati effetti collaterali, quali, per esempio,

infezioni e neoplasie

Biologic DMARDs: TNF Antagonists

Approved

Chimeric anti-TNF-α mAb Infliximab IgG1

TNF-receptor p75 IgG1 Etanercept IgG1construct

Fully human anti-TNF-α mAb Adalimumab IgG1

Compound

Fully human anti-TNF-α mAb Adalimumab IgG1

Pegylated humanizedanti-TNF-α Fab-fragment Certolizumab

Fully human anti-TNF-α mAb Golimumab

Human Mouse Synthetic element Polyethylene glycol

ActivatedT cell

MHC+antigenTCR

CD80/86

CD28

Co-stimulation modulation

Cytokine inhibition

APC

Pathogenesis of rheumatoid arthritis

Activated macrophage

ActivatedB cell

Osteoclast Chondrocyte

IFN-γ

IL-6 TNF IL-1 Autoantibodies, e.g. RF IL-6

RANK

Inflammation and destruction

IL-2

TNF

MMPs

RANK-LCytokine inhibition• Anti-TNF• Anti-IL-1R • Anti-IL-6R

B-cell depletion•Anti-CD20

Choy EHS et al. N Engl J Med 2001

Quali modificazioni nel nostrocomportamento clinico individuale edelle raccomandazioni dettate delladelle raccomandazioni dettate delladelle società scientifiche hannoindotto l’avvento dei farmaci biologici ?

Yesterday’s Approach to Treating RA has

Hidden Consequences

– Control pain and inflammation

– Respond to joint damage only after it is grossly evident

Infl

am

ma

tio

n

De

stru

ctio

n

Begin Tx

Erosions

on X-ray

Time TimeStart of

symptoms

Start of

symptoms

Start of

damage

Today’s Goals in RA TreatmentReduce Inflammation AND Prevent Joint Damage

– Treat early

– Strive for remission

– Minimize disease activity

– Prevent destruction

Non-intensive

therapy

Intensive

therapy

Time

Infl

am

ma

tio

n

Time

De

stru

ctio

n

Start of

symptoms

Start of

symptoms

Start of

damage

Recommandations for Recommandations for treatingtreating RA RA fromfrom an an international international tasktask forceforce

While remission should be a clear target, based on available evidence low disease activity may be an acceptable alternative therapeutic goal, particularly in establishedlong-standing diseaseAn ACR/EULAR initiative on defining remission is currently ongoing

Smolen et al. ARD online March 9th 2010 doi: 10.1136/ard.2009.123919

Classification criteria for RA (Scores for A–D ≥6/10 for classification of definite RA)

A. Joint involvement (swelling, tenderness or synoviti s)

1 large joint 0

2−10 large joints 1

1−3 small joints (with or without involvement of large joints) 2

4−10 small joints (with or without involvement of large joints) 3

>10 joints (at least one small joint) 5

B. Serology (at least 1 test result is needed for clas sification)

Negative RF and negative ACPA (anti-CCP) 0

Low-positive RF or low-positive ACPA 2

High-positive RF or high-positive ACPA 3

C. Acute-phase reactants (at least 1 test result is ne eded for classification)

Normal CRP and normal ESR 0

Abnormal CRP or normal ESR 1

D. Duration of symptoms

<6 weeks 0

≥6 weeks 1

Aletaha D et al. Ann Rheum Dis 2010;69:1580-1588.

EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-

modifying antirheumatic drugs

Josef S Smolen, Robert Landewé, Ferdinand C Breedveld, Maxime Dougados, Paul Emery, Cecile Gaujoux-Viala, Simone Gorter, Rachel Knevel, Jackie Nam, Monika Schoels, Daniel Aletaha, Maya Buch, Laure Gossec,

Tom Huizinga, Johannes W J W Bijlsma, Gerd Burmester, Bernard Combe, Maurizio Cutolo, Cem Gabay,Juan Gomez-Reino, Marios Kouloumas, Tore K Kvien, Emilio Martin-Mola, Iain McInnes, Karel Pavelka, Piet van Riel, Marieke Scholte, David L Scott, Tuulikki Sokka, Guido Valesini, Ronald van Vollenhoven,

Kevin L Winthrop, John Wong, Angela Zink, Désirée van der Heijde

[Austria, Czech Republic, Finland,France, Germany, Italy, Spain,Sweden, Switzerland, The Netherlands, UK, USA]

Smolen JS et al. Ann Rheum Dis 2010;69:964-975.

EULAR Algorithm: RA management Phase II


* Treatment target is clinical remission, or if remission is unlikely to be achievable, at least low disease activity

EULAR Algorithm: RA management Phase III

* Treatment target is clinical remission, or if remission is unlikely to be achievable, at least low disease activity


Unmet needUnmet need in pazienti trattati in pazienti trattati con antiTNFcon antiTNF

Unmet Medical Need

Terapia Gold standardantiTNF + MTX Non tutti i pazienti

beneficiano del trattamento

Inibitore TNF + MTX

Unmet Medical Need

Solo antiTNF

Solo MTX

ACR 70＝70％miglioramento in:•Attività globale della malattia - paziente•Attività globale della malattia - medico•Percezione del paziente del dolore•Disabilità fisica•Fase acuta di reazione – PCR,VES

(Breedveld et al, 2006)

Treatment discontinuation

0,8

0,9

1,0

Survival on Anti-TNFα TherapyLORHEN

0,4

0,5

0,6

0,7

0 6 12 18 24 30 36 Months

Sur

viva

l

Any cause

Inefficacy

Adverse event

Other

At riskTotal events

10640

924120

746218

585 294

482331

353374

247405

Strategie terapeutiche per pazienti TNFStrategie terapeutiche per pazienti TNF--IRIR

Adalimumab

Nessuna indicazione ufficiale approvata Indicazione approvata in Pazienti in TNF-IR

InfliximabEtanercept

TNF cycling o

Cambiare meccanismo d’azione

QualiQuali le le caratteristichecaratteristiche di di nuovinuovi farmacifarmaci antianti--

TNF ?TNF ?

• Stessi meccanismi d’azione e funzioni effettrici dei

farmaci anti-TNF esistenti (miglioramento delle

tecniche di produzione del mAb)

• Stessa specificità, ma maggiore affinità • Stessa specificità, ma maggiore affinità

• Ridotta immunogenicità

• Miglioramento della risposta clinica (maggior e

percentuale di remissione o LDA)

• Minori effetti collaterali

• Minori costi

Systematic review and meta-analysis of 21 randomized, placebo-

controlled trials (eight adalimumab, seven infliximab, sixcontrolled trials (eight adalimumab, seven infliximab, six

etanercept).

Adults with RA who received ADA (1524 patients), IFN (1116

patients), ETN (1029 patients), or placebo (2834 patients) with or

without concomitant methotrexate in all groups.

Efficacy and Safety of anti-TNF

• ADA and ETN demonstrated greater efficacy results than did

infliximab for short-term treatment (12-30 weeks).

• For treatments longer than 1 year, ADA seemed to be more

effective than ETN, whereas infliximab seemed to have a decrease

in its efficacy

Safety results, when

analyzed separately, were

not statistically significant

among the anti–TNF drugs;

Withdrawals due to adverse events

were higher in IFN-treated patients

than in ADA- treated patients,

whereas in patients who received

etanercept, these withdrawals were

not statistically significant

compared with placebo

Certolizumab Pegol

scientific backgroundscientific background

32LPSRC approvato giugno 2010 CZP-SCT- 007157

Therapeutic indication from the Summary of Product Characteristics (SmPC):

Cimzia ®, in combination with methotrexate (MTX), is indica ted for the treatment of moderate to severe, active rhe umatoid arthritis (RA) in adult patients when the response to disease-modifying antirheumatic drugs (DMARDs) including MT X, has been inadequate. Cimzia ® can be given as monotherapy in case of intolerance to MTX or when continued treatm ent with MTX is inappropriate.

Posology from SmPC:

The recommended starting dose of Cimzia ® for adult patients with RA is 400 mg (as 2 injections of 200 mg each o n one day) at weeks 0, 2 and 4, followed by a maintenance dose of 200 mg every 2 weeks. MTX should be continued during treat ment with Cimzia ® where appropriate.

33GPSRC INF 062 0908 CZP

Com/CZP/2009/08LPSRC approved November 2009

For Response to Unsolicited Questions Only

Structure of Certolizumab Pegol (CZP)

�CZP is the only PEGylated anti-TNF

�Site-specific PEGylation results in:� Designed half life of ~14 days� Enhanced penetration of CZP into

Fab′

� Enhanced penetration of CZP into inflamed tissue (in animal models)

�No Fc region� May avoid potential Fc-mediated effects

such as CDC or ADCC

Chapman A, et al. Nature Biotech. 1999;17:780-3Weir N, Athwal D, et al. Therapy. 2006;3:535-45

PEG

PEGylated Fab′ fragment

40 kDa PEG (2x20 kDa)




Three different approaches to TNF inhibition: Fusion proteins, Antibodies, Pegylated Fab ′ Fragments

Infliximab(Remicade ®)

Adalimumab(Humira ®)

Fab

Etanercept(Enbrel ®)

Receptor Fab′

Certolizumab pegol

(Cimzia ®)

IgG1Fc

IgG1Fc

Monoclonal antibody

Recombinant receptor/Fc fusion

protein

PEG

PEGylated Fab′ fragment40 kDa PEG

(2×20 kDa)

Weir N, Athwal D, et al. Therapy. 2006;3:535-45




Potential advantages of PEGylation

� May improve the pharmacokinetics of therapeutic agents.1

� May improve bioavailability.1

� May enhance penetration and retention of macromolecules into

PEGylated molecules are well hydrated

retention of macromolecules into various diseased tissues.1,2

� May reduce immunogenicity of some proteins (at this time this has not been shown for certolizumab pegol) (1,3)

1. Chapman et al., Adv Drug Deliv Rev 2002;54:531-5452. Palframan R. Ann Rheum Dis 2007; 66 (Suppl): A117

3. Harris et al., Clin. Pharmacokinet 2005;44:331-347

http://www.nektar.com/platform_technologies.html

36LPSRC approvato giugno 2010 CZP-SCT- 007157

11

1010

Con

cent

ratio

n (%

inje

cted

dos

e / g

ram

of b

lood

)C

once

ntra

tion

(% in

ject

ed d

ose

/ gra

m o

f blo

od)

FabFab FvFv

FcFc

The effect of PEGylation on the half-life of Fc-fre e Fab′

� PEGylation extended the half-life of Fab ′

00 2525 5050 7575 100100 125125 1501500.0010.001

0.010.01

0.10.1

IgGIgGFab'Fab'--PEGPEGFab'Fab'

Time (hr)Time (hr)

Con

cent

ratio

n (%

inje

cted

dos

e / g

ram

of b

lood

)C

once

ntra

tion

(% in

ject

ed d

ose

/ gra

m o

f blo

od)

FcFc

Fab′Fab′

SHSH

hingehinge

humanhuman murinemurine

Chapman AP, Adv Drug Deliv Rev 2002; 54:531-545Data obtained in animal model




Normal tissue Diseased tissue

2

3

4

5

2

3

4

5

ImageMin = -4.4803e-05Max = 0.00065361

efficiency

Imaging CZP Distribution in Inflamed and Normal Tissue in Vivo

• Mice with active arthritis and normal mice administered 2 mg/kg dye-labeled CZP• Imaging and peripheral blood samples taken over the following 24-h period

4

5

678

10-4

Color BarMin = 3.268e-05

Max = 0.00053026

ROI 1=2.3231e-05 ROI 2=1.5441e-05

fluor subflat-fieldedcosmic

4

5

678

10-4

Color BarMin = 3.268e-05

Max = 0.00053026

ROI 1=4.25e-05 ROI 2=0.00010276

Palframan R et al. Journal Imm. Meth.2009;348:36-41




Ratio of Level of Anti-TNF Between Normal and Inflamed Tissue in an Animal Model

3

4

5

Rat

io in

flam

med

: nor

mal

tiss

ue **

***

***

***

Certolizumab Pegol-Alexa680Adalimumab-Alexa680

Adattato da Palframan A. J Immunol Methods 348 (2009) 36–41

*p<0.05, **p<0.01, ***p<0.001 (certolizumab pegol-Alexa680 vs adalimumab-Alexa680)

0

1

2

0 3 6 9 12 15 18 21 24

Rat

io in

flam

med

: nor

mal

tiss

ue

26

Time (h)

***NS




TNF TNF TNFTNF

Formation of Immune ComplexesFormation of Immune Complexes

Certolizumab pegol + TNF-a

• “Monovalent”

• No immune complex

formation

Antibodies + TNF-a

• “Bivalent”

• Large immune complexes

are formed

Taylor PC., Curr Opin Pharmacol 2010, 10:1–8

Henry et al, Gastroenterology 2007; 132: A-231 (No. S1609)



For Response to Unsolicited Questions Only40

RAPID: Study Designs

Open-Label Extension Study

Placebo + MTX

CZP 200 mg every 2 weeks + MTX 400 mg, 0, 2, 4 wk

CZP 400 mg every 2 weeks + MTX n=636

n=639

n=326

Adult patients

with active RA on

treatment2:2:1

Week 16 mandatory escape *Extension Study

mTSS change

0 5224

ACR20Co-primary endpointsRAPID 1 (lyophilized)

0 24

Primary endpoint

16

ACR20

16

OLERAPID 2 (liquid)

Keystone et al., Arthritis Rheum. 2008;58(11):3319-29Smolen et al., Ann Rheum Dis. 2008 Nov 17 (Epub ahead of print)

Mease et al., Int. J. Clin. Rheumatol. 2009; 4(3): 253-266

* Patients who failed to respond (ACR 20) at both Weeks 12 and 14 were designated as treatment failures, were withdrawn and had the option entering into an open-label extension study at Week 16. X-rays were taken at withdrawal




Significant Improvement in Signs and Symptoms over the first 12 wks of Therapy

(RAPID 1: ACR 20 and 50 response rates)

32,940

60

80

AC

R 5

0 (%

of P

atie

nts)

33,5

43,6

54,2

63,8

40

60

80

AC

R 2

0 (%

of P

atie

nts)

****

**

******

6,64,49

16

25,732,9

2 2,5 3,5 6,1

0

20

40

wk 1 wk 2 wk 4 wk 8 wk 12

AC

R 5

0 (%

of P

atie

nts)

18,322,9

33,5

5,6 8,112,6 15,3

0

20

40

wk 1 wk 2 wk 4 wk 8 wk 12

AC

R 2

0 (%

of P

atie

nts)

****

****

*p ≤ 0.05 versus placebo**p < 0.001 versus placebo

Adapted from Keystone E, et al. Ann Rheum Dis 2007; 66(Suppl II): 55

**

*

Placebo + MTX Q2W (n = 199) CZP 200 mg + MT X Q2W (n = 393)




40

60

80

Pat

ient

s (%

)Rapid and Sustained Improvement in Signs and

Symptoms With CZP in RAPID 1

ACR20

ACR50

42

0

20

40

0 4 8 12 16 20

Pat

ient

s (%

)

24 28 32 36 40 44 48 52

Keystone et al. Arthritis Rheum. 2008;58(11):3319-29

CZP 200mg + MTX vs. PlaceboACR20: p<0.001 at weeks 1 to 52ACR50: p<0.01 at week 2; p<0.001 at weeks 4 to 52ACR70: p≤0.05 at week 4; p ≤0.01 at week 6 and 8; p<0.001 at weeks 10 to 52

Placebo + MTX Q2W (n=199)CZP 200mg + MTX Q2W (n=393)

Weeks

ACR70




CZP 200mg Q2W + MTX

CZP 400mg Q2W + MTX CZP 400mg Q2W + MTX

CZP 400mgWk 0,2,4 CZP 400mg Q2W + MTX

n=390a

n=393a

n=274c

n=255c

n=265d

n=243d

Com

plet

ers

RAPID 1 Open-label Extension

OLE Study Design and Patient Disposition

n=246e

n=216e

CZP 400mg Q2W + MTX

PBO + MTXn=199a

400 mg n=74 b n=66d

200 mg n=91 b n=86d

PBO n=137b n=135d

Weeks0 16 52 100

n=43c

CZP 400mg Q2W + MTXn=41d

With

draw

ers

(Wk

16)

aRAPID 1 ITT populationbpatients who withdrew from RAPID 1 at Week 16/per protocol selectioncpatients who completed RAPID 1dpatients who entered the OLEepatients remaining in the OLE at Week 100 from RAPID 1 baseline.

n=38e

n=51e

n=61e

n=106e

Keystone et al., Poster Presentation THU0196, EULAR2009




ACR20

ACR50

CZP 200 mg Q2W + MTX CZP 400 mg Q2W + MTX

CZP 400 mg Q2W + MTX CZP 400 mg Q2W + MTX

RAPID 2 Open-Label Extension

CZP 200 mg Q2W + MTX

CZP 200 mg Q2W + MTX

Pat

ient

s R

espo

ndin

g (%

) Figure 1. Observed a ACR 20/50/70 response rates in CZP completers over 3 years

Week 148:

Wk24 Wk92a

44

Efficacy and Safety of CZP + MTX: 3 Year Data - Resu lts

Figure 1.

ACR70

Weeks

Pat

ient

s R

espo

ndin

g (%

)

CZP 200 mg EOW + MTX, n=100;CZP 200 mg EOW + MTX, n=106

Figure 2. DAS28 scores in CZP completers over 3 years (LOCF)

a CZP dose decreased per protocol after ≥6 months in the OLE

Completers population only JS Smolen et al. EULAR 2010

Figure 2.




ACR Responder Rates at Week 24 (ITT)

58,8

39,9

60,8

60

80

Per

cent

Res

pond

ers

(%) 57,3

57,6

60

80

**

**

**

RAPID 1Combination Therapy

RAPID 2Combination Therapy

*Significantly different from placebo, * p < 0.001; †p ≤ 0.01

Patients who withdrew or used rescue medication were considered non-responders

13,6

7,63

37,1

21,420,6

0

20

40

ACR20 ACR50 ACR70

Per

cent

Res

pond

ers

(%)

Mease et al., Int. J. Clin. Rheumatol. 2009; 4(3): 253-266

8,7

3,10,8

32,5

15,9

33,1

10,6

0

20

40

ACR20 ACR50 ACR70

*

**

**

†

Placebo + MTX (n=199)

CZP 200 mg + MTX (n=393)

CZP 400 mg + MTX (n=390)


CZP 200 mg + MTX (n=246)

CZP 400 mg + MTX (n=246)

RAPID 1 RAPID 2

†




RAPID 1: ACR Responder Rates at Week 52 (ITT Population)

53,1

38

54,9

39,940

50

60 Placebo + MTX (n=199)

CZP 200mg + MTX (n=393)

CZP 400mg + MTX (n=390)

Per

cent

Res

pond

ers

(%)

* *

* *

*Significantly different from placebo, p < 0.001

Patients who withdrew or used rescue medication were considered non-responders

13,1

7,63,5

21,223,2

0

10

20

30

ACR20 ACR50 ACR70

Per

cent

Res

pond

ers

(%)

* *

Keystone et al., Arthritis Rheum. 2008;58(11):3319-29Keystone EC, et al. EULAR 2008, Paris, #THU0157




Change From Baseline in mTSS, ES, and JSN

RAPID 1 RAPID 2

Mea

n C

hang

e F

rom

Bas

elin

e

Mea

n C

hang

e F

rom

Bas

elin

e

2.8

1.41.5

1.5

2.0

2.5

3.0

3.5

1.5

2.0

2.5

3.0

3.5


CZP 200 mg + MTX (n=393)

CZP 400 mg + MTX (n=390)


CZP 200 mg + MTX (n=246)

CZP 400 mg + MTX (n=246)

*p<0.001 versus placebo. †p≤0.006 versus placebo.

†

†

Week 52 Week 24*p<0.001 versus placebo.†p≤0.005 versus placebo.

Mea

n C

hang

e F

rom

Bas

elin

e

Mea

n C

hang

e F

rom

Bas

elin

e

1.4

0.4

0.1

0.40.2

00.2

0.0

0.5

1.0

1.5

mTSS Erosion JSN

1.2

0.70.5

0.20.1 0.1

-0.5

0.0

0.5

1.0

1.5

mTSS Erosion JSN

-0.4 --0.30.3 --0.10.1

** *

*

†

*†

*†

†

Keystone et al., Arthritis Rheum. 2008;58(11):3319-29Smolen et al., Ann Rheum Dis. 2008 Nov 17 (Epub ahead of print)ITT/LinExt population.




RAPID 1 and 2: Safety Data Overview

� Adverse events reported to date by patients receiving CZP are consistent with the mechanism of action and route of administration for anti-TNF-α agents

� There was a low incidence of drop-outs due to adverse events

� No new unexpected safety signals have been identified to date during these trialsdate during these trials

� The complete safety profile of CZP will be based on the pooled analysis of all the clinical studies

Keystone et al., Arthritis Rheum. 2008;58(11):3319-29Smolen et al., Ann Rheum Dis. 2008 Nov 17 (Epub ahead of print)

Mease et al., Poster presentation (Abstract 941), ACR Congress 2007




A More Rapid Clinical Response Following Certolizumab Pegol Treatment is Associated

with Better 52-Week Outcomes in Patients with Rheumatoid Arthritis

Edward C Keystone, Jeffrey R Curtis, Roy Fleischmann, Philip Mease, Dinesh Khanna,

Josef Smolen, Daniel E Furst, Geoffroy Coteur, Bernard Combe





56,1

81.5*

61.0*60

80

100

Pat

ient

s (%

)

Week 12 responders (n=57)Week 6 responders (n=200)

ACR20/50/70 responder rates at Week 52 by DAS28 1.2 response to CZP treatment

56,1

36,8

12,3

37.0*

0

20

40

60

ACR20 ACR50 ACR70

Pat

ient

s (%

)

* P < 0.01 vs Week 12 responders Keystone et al., Poster Presentation THU0163, EULAR2009




Assessment of Kinetics of Response onLong-term Outcomes- Authors’ Conclusions

� In patients with active RA, a more rapid response to treatment with CZP + MTX (at Wk 6) was associated with a higher probability of improved long-term response than a response at Wk 12/14.

�Rapid (Week 6) responders demonstrated:

� Significantly greater improvements in ACR20/50/70, pain relief, and improvements in physical function than the later (Week 12/14) responders.


GolimumabGolimumabSIMPONISIMPONI ®®

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use Infliximab, Adalimumab, and GolimumabInfliximab, Adalimumab, and Golimumab

StructuresStructures

Evolution of Technology

Infliximab GolimumabAdalimumab

The difference in their variable domains and their CDRs is

primarily due the the different technologies that were used to

create the variable domain of each

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Baker D, et al. Rev Gastroenterol Dis. 2004;4(4):196-210.

Chimeric TransgenicPhage Display

create the variable domain of each antibody

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More Human, Less Immunogenic?More Human, Less Immunogenic?

Immunogenicity?Immuno-genicity

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Mouse origin Human origin

Murine Chimeric HumanHumanized

…mumab…ximab …zumab…omab

Pendley et al. Curr Op Mol Therap 2003; 5: 172; Koren et al. Curr Pharm Biotech 2002; 3: 349

Golimumab (Simponi) 2009

Trastuzumab (Herceptin)Palivizumab (Synagis)Gemtuzumab (Mylotarg)

Adalimumab (Humira) 2002

1990 McCaffertyPhage Display synthetic mAb‘s

Transgenic human mAb‘s1994 Lonberg et al.; 1994 Green et al.

CDR0-modified mAb‘s1986 Jones et al.

Evolution of Antibody R&D*

Ibritumomab (Zevalin)Tositumomab (Bexxar)

Rituximab (Rituxan)Basiliximab (Simulect)Infliximab (Remicade)Cetuximab (Erbitux)

Gemtuzumab (Mylotarg)Alemtuzumab (Campath)Omalizumab (Xolair)Efalizumab (Raptiva)Bevacizumab (Avastin)

* adapted from: Nils Lonberg: Human antibodies from transgenic animals; Nat. Biotech. Sep 2005. Vol 23 No 9: 1117

1975 Koehler & MilsteinMurine monoclonal Ab‘s (mAb’s)

Muromonab-CD3 (Orthoclone OKT3) 1986

Chimeric recombinant mAb‘s1984 Morrison et al.

Abciximab (RheoPro) 1994

Daclizumab(Zenapax) 1997

Development of Human Antibodies Using Development of Human Antibodies Using Human Antibody Transgenic Mice Human Antibody Transgenic Mice

Normal mouse Human antibodytransgenic mouse

Mouse Ig genes deleted

Human Ig genes insertedHuHu

For clarity, several intermediate steps are not shown.

Normal mousetransgenic mouse

Immunize with antigen

Immunize with antigen

Mouse antibody Human antibodyLonberg et al. Nature Biotech 2005; 23(9): 1117

http://www.medarex.com/Development/Evolution.htm

IFX

chimeric

ADA

human

Comparison of Affinities for TNF

Overall mAb affinities for TNF:

Shealy et al., epub 2010

Golimumab Stability/Solubility

• Allows for a highly concentrated formulation:– Golimumab 100 mg/mL– Adalimumab 50 mg/mL– Infliximab 50 mg/mL– Etanercept 50 mg/mL

• For SubQ agents allows for low injection volume:– Golimumab Monthly 0.5 cc – Adalimumab EOW 0.8 cc– Etanercept Weekly 1.0 cc

HUMIRA (adalimumab) Prescribing Information, Abbott Labora tories.REMICADE® (infliximab) Prescribing Information, Cen tocor Inc.

ENBREL® (etanercept) Prescribing Information, Amgen Inc.Golimumab, Data on File; Centocor Inc.

GLM: similar Half-life of other anti-TNF but different Dosing Interval

TNF-blocker Half-life (days)* Dosing interval*

Etanercept s.c. 3.5 - 5 q0.5-q1 wks

Adalimumab s.c. 12 - 14# q1-q2 wksAdalimumab s.c. 12 - 14# q1-q2 wksq1 in monotherapy

Certolizumab s.c. appr. 14 q2 wks

Golimumab s.c. 12 ± 3 once per month

Infliximab i.v. 8 - 9.5 q6-q8 wks dep. on indication

*Based on most recent EMEA approved SPCs (14OCT09 for both GLM and CZP).qX wks = every X weeks. #EMEA SPC mentions "approximately 2 weeks"

Multiple Factors Determine the Dosing Regimen of s.c. anti-TNFs

Dosing Regimen = Net Biologic Effect of :

• Half-life: The time required for the plasma level of a drug to fall to half of a certain measured level

• Binding properties: Specificity (affinity) and • Binding properties: Specificity (affinity) and tightness (avidity) of binding to the target cytoki ne TNFαααα

• Potency: The amount of drug necessary to neutralize an equal amount of TNF αααα to produce a clinical effect

• Protein stability/solubility: Stability of the molecule in solution

Golimumab Rheumatology Clinical Trials Golimumab Rheumatology Clinical Trials > 2,900 Patients in Phase III> 2,900 Patients in Phase III

GO-BEFORE T05

GO-FORWARD T06

GO-AFTER T11

Active RA naive for MTX

Active RA despite MTX

Active RA w/previous anti-TNF(s)

637

444

461

Rheumatoid Arthritis

Indication Study Indication N

GO-LIVE T12

GO-REVEAL T08

GO-RAISE T09

Active RA despite MTX / IV inj.

Active PsA

Active AS

643

356

405

PsoriaticArthritis

AnkylosingSpondylitis

Golimumab, a human antibody to TNF- ααααgiven by monthly subcutaneous injections,

in active rheumatoid arthritis despite methotrexate : the GO-FORWARD Study

Keystone EC, Genovese MC, Klareskog L, Hsia EC, Hall T, Miranda PC, Pazdur J, Bae SC, Palmer W, Zrubek J, Wiekowski M, Visvanathan S, Wu Z,

Rahmann MU

Ann Rheum Dis. 2009;68:789–796

Co-Primary Endpoints

• The proportion of patients achieving American Colle ge of Rheumatology Response criteria (ACR) 20 at Week 14

• The improvement from baseline in Health Assessment Questionnaire (HAQ) at Week 24

Keystone E et al. Ann Rheum Dis 2009;68:789–796

GOGO--FORWARD: Study DesignFORWARD: Study Design

Subjects with active RA despite MTX therapy (n=444)

GLM 100 mgGLM 100 mg+ Placebo+ Placebo

n=133n=133

GLM 50 mgGLM 50 mg+ MTX+ MTXn=89n=89

PlaceboPlacebo+ MTX+ MTXn=133n=133

GLM 100 mgGLM 100 mg+ MTX+ MTXn=89n=89

Week 4

SQ injectionWeek 0

Early escape if <20%

improvement in TJC and SJC

(ethical reasons)

Co-primary Endpoints:*ACR 20 response at Week 14

**Change from baseline in HAQ at Week 24

BlindedEarly Escape

(MTX, baseline dose)

BlindedEarly Escape

(Golimumab 100 mg)

BlindedEarly Escape

(Golimumab 50 mg)

BlindedEarly Escape

(No Change)

Week 16

Week 8

Week 12

Week 20

Week 14*

Week 24**

Week 48:Active, Blind

Treatment


GOGO--FORWARD: ACR Responses at FORWARD: ACR Responses at Week 14Week 14

* * p< 0.001

* p< 0.01# p< 0.05

* **

**

** **

Co-primary end point

#

****

**

* *


GOGO--FORWARD: ACR Responses at FORWARD: ACR Responses at Week 24Week 24

* * p< 0.001

* p< 0.01# p< 0.05

** **

**

** ******

**

** ***


GOGO--FORWARD: DAS28 (Using ESR) FORWARD: DAS28 (Using ESR) Remission at Week 14 and Week 24Remission at Week 14 and Week 24

*p<0.001** p=0.01

* * ** **

**

Placebo + MTX (N=133)Golimumab 100 mg + Placebo (N=133)Golimumab 50 mg + MTX (N=89)Golimumab 100 mg + MTX (N=89)Golimumab + MTX Combined (N=178)


GOGO--FORWARD: DAS28 (Using CRP) FORWARD: DAS28 (Using CRP) EULAR remission at Week 14 and Week 24EULAR remission at Week 14 and Week 24

** *

**

*p<0.001

**

Placebo + MTX (N=133)Golimumab 100 mg + Placebo (N=133)Golimumab 50 mg + MTX (N=89)Golimumab 100 mg + MTX (N=89)Golimumab + MTX Combined (N=178)


Golimumab, A New Human Anti-TNF-Alpha Monoclonal Antibody, Subcutaneously Administered Every 4 Weeks in

Patients with Active Rheumatoid Arthritis who were Previously Treated with Anti-TNF-Alpha Agent(s): Results

of the Randomized, Double-Blind, Placebo-Controlled

(GO-AFTER) Study

Smolen J et al. Lancet 2009; 374: 210-21

GOGO--AFTER: Study DesignAFTER: Study Design

Week 4

SQ injectionWeek 0

Patients with active RA and previously treated with TNFαααα inhibitor(s)(n=461)

Placebo q4n=155

Golimumab 50 mg q4n=153

Golimumab 100 mg q4n=153

Early escape if <20%

improvement in TJC and SJC

(ethical reasons)

Week 16

Week 8

Week 12

Week 20

Week 14*

Week 24

Primary Endpoint:*ACR 20 response at Week 14

Double-blindedEarly Escape(Golimumab 100 mg)

Double-blindedEarly Escape(No change)

Double-blindedEarly Escape(Golimumab 50 mg)

Stratification by investigational site and baseline MTX useSmolen J et al. Lancet 2009; 374: 210-21

GLM is efficacious in antiGLM is efficacious in anti--TNF Experienced Pts TNF Experienced Pts Regardless of Type, No. of antiRegardless of Type, No. of anti--TNFs and Reason for TNFs and Reason for Discontinuation: GODiscontinuation: GO--AFTERAFTER

wk 14 wk 24

Type of 1 st anti-TNF: ADA, IFX, ETA

p=0.002 p=0.014

ACR 20 at wk 14

Number of previous anti-TNFs

Per

cent

of P

atie

nts

Per

cent

of P

atie

nts

p<0.001 p=0.027

Reason for discontinuationACR 20 at wk 14 Pts previously treated with ADA,

ETN or IFX responded to, and tolerated GLM, regardless of � the type, � number (1 or 2) or � reason for discontinuation of prior anti-TNF therapy

Smolen J et al. Lancet 2009; 374: 210-221

Proportion of ACR20Proportion of ACR20Responders at Week 14 by SubResponders at Week 14 by Sub--GroupsGroups

DMARD

Yes

No

PlaceboGolimumabCombined

OddsRatio

n (%)

(95% CI) p-value

n (%)

107

48

17.8

18.8

215

89

40

29.2

3

1.8

(1.8, 5.4)

(0.8, 4.2)

<0.0001

0.1836

Proportion of ACR20 Responders at Week 14

Odds Ratio and 95% CIGolimumab Combined vs. Placebo

CNTO 148 T11

No. of prior TNF inhibitor

1

2

3

Reason for discontinuationof prior TNF inhibitor

Non-efficacy related reasonsLack of efficacy

90

44

21

96

84

-20

-15.9

-14.3

17.7

20.2

213

71

22

173

162

-38.5

-38

-13.6

39.3

34

2.5

3.2

0.9

3

2

(1.4, 4.5)

(1.3, 8.3)

(0.2, 5.3)

(1.6, 5.5)

(1.1, 3.8)

0.0021

0.0141

0.951

0.0004

0.0265

PlaceboBetter

Golimumab CombinedBetter

GOGO--AFTER: ConclusionAFTER: Conclusion

• In patients with active RA who had received anti-TNF αααα therapy

– GLM significantly reduced RA signs and symptoms and improved physical functionsymptoms and improved physical function

• Well-tolerated

• First randomized study of a switch from a previous anti TNF alpha to second anti TNF alpha

GolimumabGolimumab, a New, Human, TNF Alpha , a New, Human, TNF Alpha Antibody Administered Subcutaneously Antibody Administered Subcutaneously

Every 4 Weeks, in Every 4 Weeks, in AnkylosingAnkylosing SpondylitisSpondylitis(AS): 24 Week Efficacy and Safety Results (AS): 24 Week Efficacy and Safety Results

of Randomized, Placebo Controlledof Randomized, Placebo Controlledof Randomized, Placebo Controlledof Randomized, Placebo ControlledGOGO--RAISE StudyRAISE Study

Inman et al. Arthritis Rheum 2008; 58(11): 3402-12

Golimumab, A New, Human, TNFGolimumab, A New, Human, TNF--alpha alpha antibody administered as a monthly antibody administered as a monthly

subcutaneous injection in psoriatic arthritis: subcutaneous injection in psoriatic arthritis: 2424--week efficacy and safety results of the week efficacy and safety results of the

randomized,placeborandomized,placebo--controlled controlled randomized,placeborandomized,placebo--controlled controlled GOGO--REVEAL studyREVEAL study

Kavanaugh A et al.Arthritis & Rheum 2009; 60: 976-986

Can we compare with other Can we compare with other anti TNFanti TNFαααααααα trials?trials?

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with Other antiwith Other anti--TNFs TNFs P

erce

nt o

f Pat

ient

sNo head-to-head trials

49.0

61.0 58.063.062.0 65.0

73.072.0

60

80

100

Golimumab(GO-BEFORE)

Week 24

Etanercept(ERA)

6 months 2

Adalimumab(PREMIER)

1 Year 3

Infliximab(ASPIRE)Week 221

∆=13∆=13∆=13∆=13 ∆=11∆=11∆=11∆=11 ∆=7∆=7∆=7∆=7 ∆=10∆=10∆=10∆=10

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1Data on File for ASPIRE; Centocor, Inc.2Extracted from Bathon J, et al. N Engl J Med. 2000;343:1586-1593.

3Breedveld FC et al. Arthritis Rheum. 2006;54:26-37.

Per

cent

of P

atie

nts

49.0

0

20

40

60

ADA 40 mg eow + MTX

(n=268)

MTX(n=217)

ETN25 mg2x wk

(n=207)

IFXCombo + MTX

(n=648)

GLMCombo+ MTX

(n=318)

Pbo +MTX

(n=160)

Pbo + MTX

(n=245)

MTX(n=257)

p=NS p=0.022p=0.011 p=0.001

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Limitation of comparing studies : Limitation of comparing studies : substantial and variable placebo effectsubstantial and variable placebo effectMTX mono in MTX naive patients : no head to head comparison

63

75

70

80

90

100

CNTO 148 T05

This control panel show theheterogeneous responsiveness of

different patients’ populations (J Smolen Lancet 2007; 370 : 1861-74)

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49.453.6

63

29.4 32.1

46 43

15.621.2

28

19

0

10

20

30

40

50

60

70

T05 (24w) ASPIRE (54w) PREMIER (1y) TEMPO (52w)

ACR20 ACR50 ACR70

GLM monotherapy 100 mg is GLM monotherapy 100 mg is equivalent to MTX alone equivalent to MTX alone for sign and symptomsfor sign and symptoms

This is consistent with ETN and ADA

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use Anti TNFAnti TNF αααααααα monotherapies versus monotherapies versus

combination with MTXcombination with MTX

75 7685

69

60

80

100 *†

*‡

*‡

Percentage of Patients

ACR response at 52 weeksACR response at 52 weeks in in TEMPO study TEMPO study --

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MTX Etanercept MTX + Etanercept

43

19

48

24

43

0

20

40

60

ACR 20 ACR 50 ACR 70

*‡

* p<0.01 vs. MTX † p<0.05 vs. ETA ‡ p<0.01 vs. ETAKlareskog L et al. Lancet 2004; 363: 675-81


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use Anti TNFAnti TNF αααααααα monotherapies versus monotherapies versus

combination with MTXcombination with MTX

6354

73

6260

80

100*

*

*


ACR response at 1 year ACR response at 1 year in in PREMIER study PREMIER study --

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MTX Adalimumab MTX + Adalimumab

46

28

54

41

26

46

0

20

40

60

ACR 20 ACR 50 ACR 70

*

* p<0.01 vs. MTX † p<0.05 vs. ETA ‡ p<0.01 vs. ETA


Breedveld et al. Arthritis & Rheum 2006;54:26-37

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use ACR Over Time: GLM Monotherapy vs. ACR Over Time: GLM Monotherapy vs.

Etanercept MonotherapyEtanercept Monotherapy

ACR 20

ACR 50

*

**

* *

80

60

40

Pat

ient

s (%

)

*p<0.05 p=0.005

p=NS

p=NS40

60

80

p=NS

p=NS*

*

*

*

*

Etanercept (ERA) Golimumab (GO-BEFORE)

CNTO 148 T05 vs. ERA

p=NS

p=NS

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0 2 4 6 8 10 12

ACR 70

Etan 25 mg + Pbo (n=207)Placebo + MTX (n=217)

Bathon JM, et al. N Engl J Med. 2000;343:1586-1593.

*

**

*

**

* *

**

20

0

Months

Pat

ient

s (%

)

p=NS

0

20

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

Weeks

Placebo + MTX (n=160)Golimumab 100 + Pbo (n=159)

p=NS

*

*

*

*

*

*

* *

*

*

p=NS

Blockade of TNF has proved a highly successful therapeutic interventionin the treatment of certain IMIDs.

There are currentlyfive biologic therapieswithin this class

The most notable distinction with respect to efficacy and safety is thatetanercept is not efficacious in inflammatory bowel disease, and has alower associationwith TB reactivation than the mAbs.

Conclusions

lower associationwith TB reactivation than the mAbs.

Various distinctions between mAbs, either chimeric or human in sequence, aPEGylated Fab0 fragment and an IgG1–TNFR2 fusion protein have beendescribed but theexact biologic and clinical relevance of these distinctionshas yet to be fully elucidated, however.

Better understanding may permitfuture optimization of choice of biologicagent within class for an individual patient.

Sarzi puttini piercarlo i nuovi inibitori del tnf torino gennaio 2011_14° convegno patologia immune...

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