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

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,
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

Innate immunity Acquired immunity
TNF-α, IL-1 and IL-6 regulation
(non specific) (specific)
of innate and acquired immunity

Hepatic acute Phase response Th2 Response
Albumin response T Lymphocyte IL-4
Glyconeogenesis IL-10
Gluconeogenesis and Amino Acid intake IL-13
Il-1
IL-12
IL-18
CNS Responses Th1 Response
Fever TNF-α IL-1
Myalgias
Altered sleep behavior macrophage TNF-α
Anorexia IL-1
HPA activity
IL-2
IL-6 IL-12
IL-18
Somatic tissue response TNF-α IFN-γ
Muscle proteolysis
Adypocyte Lipolysis Inflammation

Immunological responses Cytotoxic response
Macrophage activation T lymphocyte or NK Cells
Release of Neutrophils
Trace mineral redistribution

Induction of
Prothrombotic endothelial adhesion
action molecules

Autocrine
activation and
differentiation
macrophage factor

TNF-α Defence againts
Growth factor intracellular
pathogens

Comitogen for
Induces other Regulates T and B cells
cytokines haematopoiesis

TNFα

Citochina pro-infiammatoria rilasciata da:
monociti attivati
macrofagi
T-linfociti

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

Injury Biology of TNF-a
TNF-
TNF-
TNF-R1
TACE
membrane soluble
(p55)
sTNF-
sTNF-R1
TNF-a TNF-a
26kDa 17kDa

nucleus monomer trimer

nucleus
TACE dimer Ligand
3’-AU-mRNA (ADAM17) passing

TNF-a trimer

sTNF-
sTNF-R2 TNF-
TNF-R2
TACE (p75)

α
Trasduzione del segnale di TNF-α
TNF-R1 TNF-R2

PC FAN SM
PC-PLC SODD TRIP nSMase
CK-1
FLIP MADD Ceramide I-TRAF
DAG ?
? TRAF 2 TRAF1
TRADD MAPK TRAF2
ASK1 cIAP
PKC RIP
aSMase FADD
SM A20
RAIDO NIK MKKs PLA2
Casp-8

Casp-2

Ceramide κ
NF-κB

? ? α β
IKKα/IKKβ JNK

Apoptosi
Apoptosi κ
IκB Degradazione c-Jun
Apoptosi
Attivazione di JNK
κ
NF-κB p50/p65

κ
geni NF-κB-dipendenti

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.

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 Compound
Chimeric anti-TNF-α mAb Infliximab IgG1
TNF-receptor p75 IgG1 Etanercept IgG1
construct

Fully human anti-TNF-α mAb Adalimumab IgG1

Pegylated humanized
anti-TNF-α Fab-fragment Certolizumab
Fully human anti-TNF-α mAb Golimumab

Human Mouse Synthetic element Polyethylene glycol

Pathogenesis of rheumatoid arthritis

APC

MHC+
Co-stimulation CD80/86 antigen
TCR
modulation CD28

Activated
T cell
Cytokine inhibition
• Anti-TNF Activated RANK-L TNF Activated
B-cell depletion
macrophage IFN-γ IL- B cell
• Anti-IL-1R •Anti-CD20
2
• Anti-IL-6R
IL-6 TNF IL-1 Autoantibodies, e.g. RF IL-6
RANK

Osteoclast Chondrocyte

MMPs

Inflammation and destruction

Choy EHS et al. N Engl J Med 2001

Quali modificazioni nel nostro
comportamento clinico individuale e
delle raccomandazioni dettate della
delle società scientifiche hanno
indotto 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
Inflammation

Destruction
Erosions
on X-ray

Start of Begin Tx Time Start of Start of Time
symptoms symptoms damage

Today’s Goals in RA Treatment
Reduce Inflammation AND Prevent Joint Damage

– Treat early – Minimize disease activity
– Strive for remission – Prevent destruction

Non-intensive
Inflammation

Destruction
therapy

Intensive
therapy

Start of Time Start of Start of Time
symptoms symptoms damage

Recommandations for treating RA from an
international task force

While remission should be a clear target, based on available evidence low disease
activity may be an acceptable alternative therapeutic goal, particularly in established
long-standing disease
An 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 synovitis)
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 classification)
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 needed 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 need in pazienti trattati
con antiTNF
Terapia Gold standard
antiTNF + MTX Non tutti i pazienti
beneficiano del
trattamento

Unmet Medical Need

Inibitore TNF + MTX
Solo antiTNF

Solo MTX
ACR 70＝70％ miglioramento in:
•Attività globale della malattia - paziente
•Attività globale della malattia - medico
•Percezione del paziente del dolore
(Breedveld et al, 2006)
•Disabilità fisica
•Fase acuta di reazione – PCR,VES

Survival on Anti-TNFα Therapy
LORHEN
Treatment discontinuation

1,0

0,9

0,8
Survival

0,7

0,6 Any cause
Inefficacy
0,5 Adverse event
Other
0,4
0 6 12 18 24 30 36 Months
At risk 1064 924 746 585 482 353 247
Total events 0 120 218 294 331 374 405

Strategie terapeutiche per pazienti TNF-IR
TNF-

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

Cambiare
TNF cycling meccanismo d’azione
o

Infliximab
Etanercept

Quali le caratteristiche di nuovi farmaci anti-
anti-
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
• 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, 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 background

LPSRC approvato giugno 2010 CZP-SCT- 007157
32

Therapeutic indication from the Summary of Product
Characteristics (SmPC):
Cimzia®, in combination with methotrexate (MTX), is indicated
for the treatment of moderate to severe, active rheumatoid
arthritis (RA) in adult patients when the response to disease-
modifying antirheumatic drugs (DMARDs) including MTX, has
been inadequate. Cimzia® can be given as monotherapy in
case of intolerance to MTX or when continued treatment 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 on one day)
at weeks 0, 2 and 4, followed by a maintenance dose of 200 mg
every 2 weeks. MTX should be continued during treatment
with Cimzia® where appropriate.

GPSRC INF 062 0908 CZP

Com/CZP/2009/08
LPSRC approved November 2009
For Response to Unsolicited Questions Only
33

Structure of Certolizumab Pegol (CZP)
Fab′

CZP is the only PEGylated anti-TNF

Site-specific PEGylation results in:
Designed half life of ~14 days
Enhanced penetration of CZP into
inflamed tissue (in animal models)
PEG
No Fc region
May avoid potential Fc-mediated effects
PEGylated such as CDC or ADCC
Fab′ fragment
40 kDa PEG (2x20 kDa)

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


Com/CZP/2009/08
34
Three different approaches to TNF inhibition:
Fusion proteins, Antibodies, Pegylated Fab′ Fragments

Certolizumab
Etanercept Infliximab Adalimumab
pegol
(Enbrel®) (Remicade®) (Humira®)
(Cimzia®)
Receptor Fab Fab′

IgG1 IgG1
Fc Fc PEG

PEGylated
Recombinant Fab′ fragment
receptor/Fc fusion Monoclonal
40 kDa PEG
protein antibody
(2×20 kDa)

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


Com/CZP/2009/08
35

Potential advantages of PEGylation

May improve the pharmacokinetics of PEGylated molecules are well hydrated
therapeutic agents.1
May improve bioavailability.1
May enhance penetration and
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) http://www.nektar.com/platform_technologies.html

1. Chapman et al., Adv Drug Deliv Rev 2002;54:531-545
2. Palframan R. Ann Rheum Dis 2007; 66 (Suppl): A117
3. Harris et al., Clin. Pharmacokinet 2005;44:331-347

LPSRC approvato giugno 2010 CZP-SCT- 007157
36

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

PEGylation extended the half-life of Fab′
Concentration (% injected dose / gram of blood)

10

1 Fab Fv

Fc
0.1

0.01 IgG
Fab'-
Fab'-PEG SH
Fab'
Fab′
0.001
hinge
0 25 50 75 100 125 150
Time (hr) human murine
Data obtained in animal model Chapman AP, Adv Drug Deliv Rev 2002; 54:531-545


Com/CZP/2009/08
37

Imaging CZP Distribution in Inflamed and Normal
Tissue in Vivo
Normal tissue Diseased tissue
Image
Min = -4.4803e-05
Max = 0.00065361
efficiency
5 5
4 4

3 3

2 2

-4 -4
10 10
8 8
7 7
6 6
ROI 1=2.3231e-05 ROI 2=1.5441e-05 5 5
ROI 1=4.25e-05 ROI 2=0.00010276
4 4

Color Bar
Min = 3.268e-05
Max = 0.00053026 Color Bar
Min = 3.268e-05
fluor sub Max = 0.00053026
flat-fielded
cosmic

• 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

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


Com/CZP/2009/08
38

Ratio of Level of Anti-TNF Between
Normal and Inflamed Tissue in an Animal Model
5
Certolizumab Pegol-Alexa680
*** Adalimumab-Alexa680
Ratio inflammed: normal tissue

4
** ***
3
***
NS
2

1

0
0 3 6 9 12 15 18 21 24 26
Time (h)
*p<0.05, **p<0.01, ***p<0.001 (certolizumab pegol-Alexa680 vs adalimumab-Alexa680)

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


Com/CZP/2009/08
39

Formation of Immune Complexes

TNF TNF TNF TNF

Certolizumab pegol + TNF-a Antibodies + TNF-a
• “Monovalent” • “Bivalent”
• No immune complex • Large immune complexes
formation are formed
Taylor PC., Curr Opin Pharmacol 2010, 10:1–8
Henry et al, Gastroenterology 2007; 132: A-231 (No. S1609)


Com/CZP/2009/08
40

RAPID: Study Designs
n=636 CZP 400 mg every 2 weeks + MTX
Adult
patients
with active n=639 400 mg, 0, 2, 4 wk CZP 200 mg every 2 weeks + MTX
RA on
treatment
2:2:1 n=326 Placebo + MTX

Week 16 mandatory escape* Open-Label
Extension Study
RAPID 1 ACR20 mTSS change
Co-primary endpoints
(lyophilized)

0 16 24 52

OLE
RAPID 2 ACR20
(liquid) Primary endpoint

0 16 24
* 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 Keystone et al., Arthritis Rheum. 2008;58(11):3319-29
Smolen et al., Ann Rheum Dis. 2008 Nov 17 (Epub ahead of print)
Mease et al., Int. J. Clin. Rheumatol. 2009; 4(3): 253-266


Com/CZP/2009/08
41

Significant Improvement in Signs and Symptoms
over the first 12 wks of Therapy
(RAPID 1: ACR 20 and 50 response rates)
80 80
**
63,8

ACR 50 (% of Patients)
ACR 20 (% of Patients)

60 **
54,2
60
**
43,6
40
** 40 **
32,9
33,5 **
** 25,7
22,9 **
18,3 20 16
20
12,6
15,3 *
9
8,1 4,4 6,1 6,6
5,6 2 2,5 3,5

0 0
wk 1 wk 2 wk 4 wk 8 wk 12 wk 1 wk 2 wk 4 wk 8 wk 12

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

*p ≤ 0.05 versus placebo
**p < 0.001 versus placebo
Adapted from Keystone E, et al. Ann Rheum Dis 2007; 66(Suppl II): 55


Com/CZP/2009/08
42

Rapid and Sustained Improvement in Signs and
Symptoms With CZP in RAPID 1

80
ACR20
Patients (%)

60
ACR50
40

ACR70
20

0
0 4 8 12 16 20 24 28 32 36 40 44 48 52
Weeks
CZP 200mg + MTX vs. Placebo
ACR20: p<0.001 at weeks 1 to 52
ACR50: p<0.01 at week 2; p<0.001 at weeks 4 to 52 CZP 200mg + MTX Q2W (n=393)
ACR70: p≤0.05 at week 4; p≤0.01 at week 6 and 8; Placebo + MTX Q2W (n=199)
p<0.001 at weeks 10 to 52
Keystone et al. Arthritis Rheum. 2008;58(11):3319-29


Com/CZP/2009/08
43

OLE Study Design and Patient Disposition
RAPID 1 Open-label Extension

CZP 400mg Q2W + MTX CZP 400mg Q2W + MTX
n=390a n=274c n=265d n=246e

Completers
CZP 400mg
CZP 200mg Q2W + MTX CZP 400mg Q2W + MTX
Wk 0,2,4
n=393a n=255c n=243d n=216e

PBO + MTX CZP 400mg Q2W + MTX
n=199a n=43c n=41d n=38e

Withdrawers
(Wk 16)
400 mg n=74b n=66d n=51e
200 mg n=91b n=86d CZP 400mg Q2W + MTX n=61e
PBO n=137b n=135d n=106e

0 16 52 100
Weeks
aRAPID 1 ITT population
bpatients who withdrew from RAPID 1 at Week 16/per protocol selection
cpatients who completed RAPID 1
dpatients who entered the OLE
epatients remaining in the OLE at Week 100 from RAPID 1 baseline. Keystone et al., Poster Presentation THU0196, EULAR2009


Com/CZP/2009/08
44

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

RAPID 2 Open-Label Extension
Wk24 Wk92a
CZP 200 mg Q2W + MTX CZP 400 mg Q2W + MTX CZP 200 mg Q2W + MTX

CZP 400 mg Q2W + MTX CZP 400 mg Q2W + MTX CZP 200 mg Q2W + MTX
Figure 1.
Figure 1.
Patients Responding (%)

ACR20
Observeda ACR
20/50/70 response rates
ACR50 in CZP completers over
3 years
Week 148:
ACR70 CZP 200 mg EOW + MTX, n=100;
CZP 200 mg EOW + MTX, n=106

Weeks
Figure 2.
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


Com/CZP/2009/08
45

ACR Responder Rates at Week 24 (ITT)
RAPID 1 RAPID 2
Combination Therapy Combination Therapy
80 80

*
60,8 *
* 57,6
Percent Responders (%)

58,8
60 60 *
57,3

*
39,9
40
*
37,1 *
40 * 33,1
32,5
*
* 20,6
21,4 †
20 20 †
13,6 15,9
7,6 10,6
8,7
3 3,1
0,8
0 0
ACR20 ACR50 ACR70 ACR20 ACR50 ACR70

RAPID 1 RAPID 2
*Significantly different from placebo, * p < 0.001; †p ≤ 0.01
Placebo + MTX (n=199) Placebo + MTX (n=127)
CZP 200 mg + MTX (n=393) CZP 200 mg + MTX (n=246) Patients who withdrew or used rescue medication were considered non-responders
CZP 400 mg + MTX (n=390) CZP 400 mg + MTX (n=246) Mease et al., Int. J. Clin. Rheumatol. 2009; 4(3): 253-266


Com/CZP/2009/08
46

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

60 * *
54,9 Placebo + MTX (n=199)
53,1
Percent Responders (%)

CZP 200mg + MTX (n=393)
CZP 400mg + MTX (n=390)
50

* *
39,9
40 38

30
* *
23,2
21,2
20
13,1

10 7,6
3,5

0
ACR20 ACR50 ACR70

*Significantly different from placebo, p < 0.001 Keystone et al., Arthritis Rheum. 2008;58(11):3319-29
Patients who withdrew or used rescue medication were considered non-responders Keystone EC, et al. EULAR 2008, Paris, #THU0157


Com/CZP/2009/08
47
Change From Baseline in mTSS, ES, and JSN

3.5 RAPID 1 RAPID 2
3.5

Placebo + MTX (n=199) Placebo + MTX (n=127)
3.0 2.8 3.0
Mean Change From Baseline

Mean Change From Baseline
CZP 200 mg + MTX (n=393) CZP 200 mg + MTX (n=246)
CZP 400 mg + MTX (n=390) CZP 400 mg + MTX (n=246)
2.5 2.5

2.0 2.0

1.5
1.5 1.4 1.5
1.2
1.0 1.0
†
0.7
* 0.4 † 0.5 † 0.5
0.5 0.4 †
* * 0.2 †
0.2 0.1 * 0.2 * 0.1 * 0.1 †
0 0.0 -0.4 -0.3 -0.1
0.0

-0.5
mTSS Erosion JSN mTSS Erosion JSN
Week 52 Week 24
*p<0.001 versus placebo. *p<0.001 versus placebo.
†p≤0.006 versus placebo. †p≤0.005 versus placebo.

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


Com/CZP/2009/08
48

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 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):3319-29
Smolen et al., Ann Rheum Dis. 2008 Nov 17 (Epub ahead of print)
Mease et al., Poster presentation (Abstract 941), ACR Congress 2007


Com/CZP/2009/08
49

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

Keystone et al., Poster Presentation THU0163, EULAR2009


Com/CZP/2009/08
50

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

100 Week 12 responders (n=57)
Week 6 responders (n=200)
81.5*
80

61.0*
Patients (%)

60 56,1

40 36,8 37.0*

20 12,3

0
ACR20 ACR50 ACR70

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


Com/CZP/2009/08
51

Assessment of Kinetics of Response on
Long-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.

Keystone et al., Poster Presentation THU0163, EULAR2009

Infliximab, Adalimumab, and Golimumab
Intended for training purposes only / Requires local regulatory review prior to external use
Structures

Evolution of Technology
The difference in their variable
domains and their CDRs is
Infliximab primarily due Adalimumab
the the different Golimumab
technologies that were used to
create the variable domain of each
antibody

Chimeric Phage Display Transgenic

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


More Human, Less Immunogenic?

Immuno- Immunogenicity?
genicity

…omab …ximab …zumab …mumab

Murine Chimeric Humanized Human

Mouse origin Human origin

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

Evolution of Antibody R&D*
Golimumab (Simponi) 2009
Transgenic human mAb‘s
1994 Lonberg et al.; 1994 Green et al.

Phage Display synthetic mAb‘s
1990 McCafferty

Adalimumab (Humira) 2002

CDR0-modified mAb‘s Trastuzumab (Herceptin)
1986 Jones et al. Palivizumab (Synagis)
Gemtuzumab (Mylotarg)
Alemtuzumab (Campath)
Daclizumab(Zenapax) 1997
Omalizumab (Xolair)
Efalizumab (Raptiva)
Bevacizumab (Avastin)
Chimeric recombinant mAb‘s
1984 Morrison et al. Rituximab (Rituxan)
Basiliximab (Simulect)
Abciximab (RheoPro) 1994 Infliximab (Remicade)
Cetuximab (Erbitux)
Murine monoclonal Ab‘s (mAb’s)
1975 Koehler & Milstein
Ibritumomab (Zevalin)
Muromonab-CD3 (Orthoclone OKT3) 1986 Tositumomab (Bexxar)

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

Development of Human Antibodies Using
Human Antibody Transgenic Mice
For clarity, several intermediate steps are not shown.

Mouse Ig genes deleted
Hu
Human Ig genes inserted

Human antibody
Normal mouse
transgenic mouse

Immunize with Immunize with
antigen antigen
IFX
chimeric

ADA
human
Mouse antibody Human antibody
Lonberg et al. Nature Biotech 2005; 23(9): 1117
http://www.medarex.com/Development/Evolution.htm

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 Laboratories.
REMICADE® (infliximab) Prescribing Information, Centocor 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 wks
q1 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
tightness (avidity) of binding to the target cytokine
TNFαα
• Potency: The amount of drug necessary to
α
neutralize an equal amount of TNFα to produce a
clinical effect
• Protein stability/solubility: Stability of the molecule
in solution

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

GO-BEFORE T05 Active RA naive for MTX 637

Rheumatoid GO-FORWARD T06 Active RA despite MTX 444
Arthritis GO-AFTER T11 Active RA w/previous anti-TNF(s) 461

GO-LIVE T12 Active RA despite MTX / IV inj. 643

Psoriatic Active PsA
GO-REVEAL T08 356
Arthritis

Ankylosing GO-RAISE T09 Active AS 405
Spondylitis

Golimumab, a human antibody to TNF-α α
given 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 College
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

GO-FORWARD: Study Design
GO-
Early escape if
<20% Subjects with active RA despite MTX therapy (n=444)
improvement in
TJC and SJC Placebo GLM 100 mg GLM 50 mg GLM 100 mg
(ethical reasons)
+ MTX + Placebo + MTX + MTX
SQ injection n=133 n=133 n=89 n=89
Week 0
Week 4
Week 8 Blinded Blinded
Blinded Blinded
Week 12 Early Escape Early Escape Early Escape Early Escape
Week 14* (Golimumab 50 mg) (MTX, baseline dose) (Golimumab 100 mg) (No Change)
Week 16
Week 20
Week 24**

Week 48:
Co-primary Endpoints:
Active, Blind
*ACR 20 response at Week 14
Treatment
**Change from baseline in HAQ at Week 24

GO-FORWARD: ACR Responses at
GO-
Week 14

Co-primary * * p< 0.001
* p< 0.01
end point # p< 0.05
**
* **

** **
**
#

* *


GO-FORWARD: ACR Responses at
GO-
Week 24
* * p< 0.001
* p< 0.01
# p< 0.05
**

** **

** **
**

** **
*


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

* * *
* * *

**

Placebo + MTX (N=133)
Golimumab 100 mg + Placebo (N=133)
Golimumab 50 mg + MTX (N=89)
*p<0.001 Golimumab 100 mg + MTX (N=89)
** p=0.01 Golimumab + MTX Combined (N=178)

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

*
* *
* * *

Placebo + MTX (N=133)
Golimumab 100 mg + Placebo (N=133)
Golimumab + MTX Combined (N=178)
*p<0.001

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

GO-AFTER: Study Design
GO-
Early escape if
<20% α
Patients with active RA and previously treated with TNFα inhibitor(s)
improvement in
TJC and SJC
(n=461)
(ethical reasons)
Placebo q4 Golimumab 50 mg q4 Golimumab 100 mg q4
SQ injection n=155 n=153 n=153
Week 0
Week 4
Week 8
Double-blinded Double-blinded Double-blinded
Week 12 Early Escape Early Escape Early Escape
Week 14* (Golimumab 50 mg) (Golimumab 100 mg) (No change)
Week 16
Week 20
Week 24
Primary Endpoint:
*ACR 20 response at Week 14
Stratification by investigational site and baseline MTX use

GLM is efficacious in anti-TNF Experienced Pts
anti-
Regardless of Type, No. of anti-TNFs and Reason for
anti-
Discontinuation: GO-AFTER
GO-
Number of previous anti-TNFs Type of 1st anti-TNF: ADA, IFX, ETA
ACR 20 at wk 14 wk 14 wk 24
Percent of Patients

p=0.002 p=0.014

Reason for discontinuation
ACR 20 at wk 14 Pts previously treated with ADA,
Percent of Patients

p<0.001 p=0.027 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


CNTO 148 T11
Proportion of ACR20
Responders at Week 14 by Sub-Groups
Sub-
Proportion of ACR20 Responders at Week 14

Odds Ratio and 95% CI Golimumab Odds
Golimumab Combined vs. Placebo Placebo Combined Ratio (95% CI) p-value
n (%) n (%)
DMARD

Yes 107 17.8 215 40 3 (1.8, 5.4) <0.0001

No 48 18.8 89 29.2 1.8 (0.8, 4.2) 0.1836

No. of prior TNF inhibitor

1 90 -20 213 -38.5 2.5 (1.4, 4.5) 0.0021

2 44 -15.9 71 -38 3.2 (1.3, 8.3) 0.0141

3
21 -14.3 22 -13.6 0.9 (0.2, 5.3) 0.951
Reason for discontinuation
of prior TNF inhibitor
96 17.7 173 39.3 3 (1.6, 5.5) 0.0004
Lack of efficacy
Non-efficacy related reasons 84 20.2 162 34 2 (1.1, 3.8) 0.0265

Placebo Golimumab Combined
Better Better

GO-AFTER: Conclusion
GO-

• In patients with active RA who had received
α
anti-TNFα therapy
– GLM significantly reduced RA signs and
symptoms and improved physical function
• Well-tolerated
• First randomized study of a switch from a previous
anti TNF alpha to second anti TNF alpha

Golimumab,
Golimumab, a New, Human, TNF Alpha
Antibody Administered Subcutaneously
Every 4 Weeks, in Ankylosing Spondylitis
(AS): 24 Week Efficacy and Safety Results
of Randomized, Placebo Controlled
GO-RAISE Study
GO-
Inman et al.
Arthritis Rheum 2008; 58(11): 3402-12

Golimumab, A New, Human, TNF-alpha
TNF-
antibody administered as a monthly
subcutaneous injection in psoriatic arthritis:
24-week efficacy and safety results of the
24-
randomized,placebo-
randomized,placebo-controlled
GO-REVEAL study
GO-
Kavanaugh A et al.
Arthritis & Rheum 2009; 60: 976-986

Can we compare with other
anti TNFα trials?
TNFα

ACR20 Response at Week 24 Compared
with Other anti-TNFs
anti- No head-to-head trials

Golimumab Infliximab Etanercept Adalimumab
(GO-BEFORE) (ASPIRE) (ERA) (PREMIER)
Week 24 Week 221 6 months2 1 Year 3
100
∆=13 ∆=11 ∆=7 ∆=10
80 73.0
Percent of Patients

72.0
62.0 65.0 63.0
61.0 58.0
60
49.0

40

20

p=0.011 p=0.001 p=NS p=0.022
0
Pbo GLM Pbo IFX MTX ETN MTX ADA 40 mg
+MTX Combo + MTX Combo (n=217) 25 mg (n=257) eow + MTX
(n=160) + MTX (n=245) + MTX 2x wk (n=268)
(n=318) (n=648) (n=207)
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.

CNTO 148 T05
Limitation of comparing studies :
substantial and variable placebo effect
MTX mono in MTX naive patients : no head to head comparison
100 This control panel show the
90 heterogeneous responsiveness of
different patients’ populations
80 (J Smolen Lancet 2007; 370 : 1861-74) 75
70 63
60 53.6
49.4
50 46
43
40 32.1
29.4 28
30 21.2 19
20 15.6
10
0
T05 (24w) ASPIRE (54w) PREMIER (1y) TEMPO (52w)

ACR20 ACR50 ACR70

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

This is consistent with ETN and ADA

Intended for training purposes only / Requires local regulatory review prior to external use Anti TNFα monotherapies versus
TNFα
combination with MTX
ACR response at 52 weeks in TEMPO study -
100 *†
85
Percentage of Patients

76
*‡
80 75
69

60 48
*‡
43 43
40
24
19
20

0
ACR 20 ACR 50 ACR 70

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

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

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