1. The Clinical Relevance of Drug
Immunogenicity
Sandra Garcês
Dissertation to obtain the PhD Degree
in Medicine – Rheumatology
March 16, 2015

2. Prevalent Diseases
Chronic (no cure)
Highly disabling
Affecting young people (in productive age)
- Rheumatoid Arthritis
- Ankylosing Spondylitis
- Psoriasis and Psoriatic Arthritis
- Inflammatory Bowel Diseases…
Immune-Mediated Chronic Inflammatory Diseases:
Introduction
HIGH SOCIAL
AND
ECONOMIC
IMPACT

3. Synthetic DMARDs
1992
Methotrexate
Hydroxychloroquine
Salazopyrin
Corticosteroids
ü Better control of inflammation
ü Improvement in patient’s quality of life
ü Improvement in patient’s functionality
CD20 IL-6B7.1/2
Therapeutic Targets
Paradigm Shift in Treatment:
From small molecules to large proteins
DMARD: disease modifying antirheumatic drug
IL-12/23
Introduction

4. Introduction
Significant Heterogeneity in Therapeutic Responses
~1/3 no response
(Primary non-responders)
~1/3 lose response
(Secondary non-responders)
TNF
Drug
ADAb
• Anti-idiotype antibodies
• Mainly of IgG1 and IgG4
• Prevent the target neutralisation
• Reduce drug bioavailability
Possible reason for failure: DRUG IMMUNOGENICITY
Van
Schie
KA,.
Ann
Rheum
Dis
2015
Hart
M
et
al.
J
Immunol
Methods
2012
Van
Schouwenburg
P
et
al.
Ann
Rheum
Dis
2013
ADAb:
anF-­‐drug
anFbodies

5. Objectives
Clinical
Relevance
of
Drug
Immunogenicity
Formally
document
the
impact
of
ADAb
on
therapeuFc
responses
Impact
of
ADAb
on
drug
safety
profile
To
define
a
convenient
assay
to
assess
ADAb
in
rouFne
To
construct
and
test
an
algorithm
integraFng
immunogenicity
informaFon
I
IIIII
IV

6. Start Point: 2082 studies 17 studies in MA
• Rheumatoid Arthritis, Spondyloarthritis, Psoriasis and Inflammatory Bowel Disease
• Infliximab, Adalimumab and Etanercept
936
Pa)ents
Study Objectives:
1. The impact of ADAb on therapeutic responses
2. The influence of concomitant immunosuppression on ADAb
production
Results I
Systematic Review Literature with Meta-Analysis
ADAb:
anF-­‐drug
anFbodies

7. Results I
Systematic Review Literature with Meta-Analysis
1. ADAb significantly reduce therapeutic responses
ü The presence of ADAb decreased therapeutic response by ~80%, in
studies where low proportion of patients were co-receiving MTX
ADAb:
anF-­‐drug
anFbodies;
MTX:
metothrexate
0%
20%
40%
60%
80%
100%
No
ADAb
ADAb
ADAb
<74%MTX
ADAb
≥74%MTX
68% 77% 51%
%
therapeuFc
response
reducFon

8. Results I
Systematic Review Literature with Meta-Analysis
2. Concomitant immunosuppression reduces ADAb production
0%
20%
40%
60%
80%
100%
No
IS
IS
64%
%
ADAb
frequency
reducFon
ü Concomitant IS (MTX or AZA) decreases ADAb production by 64%
ADAb:
anF-­‐drug
anFbodies;
MTX:
metothrexate;
AZA:
Azathiopryn;
IS:
immunosuppression
3. No anti-etanercept (fusion protein) were detected

9. Results II
Impact of ADAb on drug safety profile
ADAb:
anF-­‐drug
anFbodies;
IrAE:
Infusion-­‐related
adverse
event
• 94 patients (22 RA, 33 AS, 9 PsA, 30 IBD)
• Infliximab 3-5mg/Kg e6-8w
• Mean biologic therapy duration 2.9 (2.0) years
• 2 years follow-up
ADAb
pos
ADAb
neg
27%
1. IrAE occurred in 13% of total patients
• Urticaria
• Flushing
• Hypertention
• Chest pain

10. Results II
Impact of ADAb on drug safety profile
ADAb:
anF-­‐drug
anFbodies;
IrAE:
Infusion-­‐related
adverse
event
• 94 patients (22 RA, 33 AS, 9 PsA, 30 IBD)
• Infliximab 3-5mg/Kg e6-8w
• Mean biologic therapy duration 2.9 (2.0) years
• 2 years follow-up ADAb
pos
ADAb
neg
27%
2. Nearly half of ADAb pos developed an IrAE
0
20
40
60
80
ADAb
pos
ADAb
neg
IrAE
pos
IrAE
neg
No.
paFents
48%
• ADAb detected prior to the
clinically evident IrAE
• All ADAb pos patients had
undetectable drug levels
• None of ADAb pos patients were
able to maintain therapeutic
response

11. Results II
Impact of ADAb on drug safety profile
ADAb:
anF-­‐drug
anFbodies;
IrAE:
Infusion-­‐related
adverse
event
4 IBD patients ADAb pos with IrAE + 1 IBD patient ADAb neg
0 1 2 3 4 5 6 7 8
0
5
10
10
20
30
40
50
60
70
Time (Weeks)
Drugconcentration(µg/ml)

12. Results III
Define a practical assay for ADAb assessment
RIA:
radioimmunoassay;
ABT:
anFgen
binding
assay
RIA-ABT Bridging
ELISA
No.
ADAb
pos
paFents
110 patients
• 12 PsA, 43 RA, 22 IBD, 33 AS
• 82 infliximab, 13 adalimumab,
15 etanercept
0
20
40
60
80
100
RIA-­‐ABT
Br
ELISA
2626 • 21 anti-infliximab
• 5 anti-adalimumab
• 0 anti-etanercept
ADAb

13. Results IV
How to integrate immunogenicity in clinical practice
Current clinical approach to patients receiving biologic therapies
Primary
Non-Responders
Secondary
Non-Responders
Responders
MANTAIN THERAPY
(DRUG AND DOSAGE)
SWITCH TO ANY OF THE APPROVED
BIOLOGICS
IFX
ABT
ETA
TNF
CD20
IL-­‐6
B7.1/2
GOL
ADA
RTX
TCZ
UST
IL-­‐12/23
CTZ

14. Drug
Levels
(every
3
M)
Detect
Response
Maintain/Decreased
Therapy
Non-­‐
response
Sw
to
another
MOA
Not
Detect
ADAb
ADAb
pos
Response
Re-­‐evaluate
pa)ent
Ac)ve
synovi)s?
Consider
stop
therapy
Non-­‐
response
Sw
to
less
immunogenic
drug
ADAb
neg
Assess
compliance/
Weight
adjust
Response
Re-­‐evaluate
pa)ent
Ac)ve
synovi)s?
Consider
stop
therapy
Non-­‐
Response
Repeat
Tests
Assisted
Drug
Admin
Results IV
New Algorithm Integrating Immunogenicity

15. Non-­‐Responders
Drug + Wrong target
(ex TNF vs. IL-6)
Switch to ≠ MOA
Drug -
ADAb -
ADAb +
Switch to a less
immunogenic drug
Assess patient’s compliance
Responders
Drug +
Drug -
Consider Progressive Dose Reduction
If remission, consider therapy discontinuation
Results IV
≠ subgroup of patients ≠ therapeutic strategies

16. Results IV
Algorithm’s performance in clinical practice
• 105 Rheumatoid Arthritis patients
• Median (IQR) biologic duration: 2.6 (0.6-5.3) years
• Follow-Up: 2 years (Feb 2010-Jan 2012)
• Drug levels and ADAb systematically assessed
• Clinicians blind for the tests’ results
Objectives:
1) Concordance grade between current approach and our proposed
algorithm
2) Clinical outcomes between concordant and non-concordant therapeutic
strategies
Infliximab
Adalimumab
Etanercept
48 pts
24 pts
33 pts

17. Results IV
Algorithm’s performance in clinical practice
1. Concordance grade with new algorithm
Concordant
Decision
Non-concordant
Decision
51,4% 48,6%
DELAY
~ 8 months
2. New algorithm: 10x higher probability of low disease activity
Group A Group B
Over the following
year after
therapeutic
decision

18. Results IV
ADAb-positive patients had higher disease activity
0%
20%
40%
60%
80%
100%
Inflix Etaner Adalim
ADAb pos
ADAb neg
37,5 27,3
0%
20%
40%
60%
80%
ADAb neg ADAb pos
Response
ΔDAS≥1.2
Low Dis Activity
DAS≤3.2
62,1
22,2
34,5
5,6
%
ADAb
pos
%
PaFents
**
*
0
4
8
12
16
20
ADAb neg ADAb pos
C-­‐reacFve
protein
(mg/L)
*

19. ConclusionS
1. ADAb may reduce therapeutic responses by as much of 80%
2. ADAb may also increase the risk of IrAE
3. Classic immunosuppression (MTX or AZA) may modulate
ADAb responses
4. Bridging ELISA is a practical method to use on a routine
basis, to assess ADAb for clinical purposes
5. Therapeutic drug monitoring should be implemented in the
clinical practice: it provides faster, better and safer therapeutic
strategies, at lower cost

20.
Marília Antunes
Jocelyne Demengeot
PATIENTS
Lucien Aarden
Elizabeth Benito-Garcia
PGFMA
Leonor Parreira
João Ferreira
António Coutinho
Acknowledgments