The Clinical Relevance of Drug Immunogenicity

Sandra Garcês

Dissertation to obtain the PhD Degree

in Medicine – Rheumatology

March 16, 2015

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

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-6 B7.1/2

Therapeutic Targets

Paradigm Shift in Treatment: From small molecules to large proteins

DMARD: disease modifying antirheumatic drug

IL-12/23

Introduction

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  

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

II III

IV

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  

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%

%    the

rape

uFc  respon

se  

redu

cFon

 

Results I Systematic Review Literature with Meta-Analysis

2. Concomitant immunosuppression reduces ADAb production

0%  

20%  

40%  

60%  

80%  

100%  

No  IS   IS  

64%

%    A

DAb  freq

uency    

redu

cFon

 

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

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

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.  paF

ents  

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

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

1010203040506070

Time (Weeks)

Dru

g co

ncen

trat

ion

(µg/

ml)

Results III Define a practical assay for ADAb assessment

RIA:  radioimmunoassay;  ABT:  anFgen  binding  assay  

RIA-ABT Bridging ELISA

No.  ADA

b  po

s  paF

ents  

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  

26 26 •  21 anti-infliximab •  5 anti-adalimumab •  0 anti-etanercept

ADAb

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  

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

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

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

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

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

%    A

DAb  po

s    

%    PaF

ents  

**

*

0  

4  

8  

12  

16  

20  

ADAb neg ADAb pos

C-­‐reacFve  protein  

(mg/L)  

*

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

   

Marília Antunes

 Jocelyne Demengeot

PATIENTS  

Lucien Aarden

Elizabeth Benito-Garcia

PGFMA  

Leonor Parreira João Ferreira

António Coutinho

Acknowledgments