What do we do when the patient loses their response to an anti-TNF: Minor tweaks or

major treatment changes?

Robert N. Baldassano, MD

Colman Professor of PediatricsUniversity of Pennsylvania, Perelman School of Medicine

Director, Center for Pediatric IBDThe Children's Hospital of Philadelphia

What is secondary loss of response ?

Symptoms only“(1) an increase in the PCDAI of >15 points from the reference PCDAI at week 10 at 2 consecutive visits at least 7 days apart, or (2) the PCDAI was higher than 30 points at any scheduled or unscheduled visit” (Hyams J, Gastro 2007) “Patients who initially respond to anti-TNF therapy and

subsequently lost clinical response…with a rise of >70 points of CDAI” (Allez M, ECCO Workshop, J Crohn Colitis 2010)

“Symptoms plus evidence of inflammation” (Regueiro M, Inflam Bowel Dis 2007)

Symptoms +inflammation

“Withdrawal of infliximab and switch of medical therapy or need for surgery” (de Ridder, Inflam Bowel Dis 2008)“Recurrent symptoms necessitating

adalimumab dose escalation”Karmiris K, Gastro 2009

Symptoms +Treatment change

Intensification & Discontinuationof anti-TNF at 12 months

0

10

20

30

40

50

60

CZP (W

ELCOME)*

CZP (PRECIS

E II)*

IFX (

ACCENT I)

IFX (

REACH)

IFX (

PIBDCRG

)

IFX (

Pittsb

urgh)

IFX (

London)

ADA (CHARM

)

ADA (Rotte

rdam

)

ADA (New

-York

)

Dose escalation

Drug discontinuation

Ben-Horin S, Aliment Pharmacol Ther 2011

At 12 months:Dose escalation - 23-46% Drug discontinuation - 5-13%

Cumulative rate of loss of responseover time to anti-TNF treatment

(adalimumab)

Alimentary Pharmacology & TherapeuticsVolume 33, Issue 9, pages 987-995, 2011

2/3 of patients who lose response to anti-TNF do so within the first 12 months of therapy

Managing loss of response:

Verify the cause of LOR

Is it really inflammatory IBD activity ?

Uncontrolled IBD inflammation : (Low drug level) Loss of anti-TNF activity due to anti-drug antibodies Relentless TNF-mediated flare ‘consuming’ all anti-TNF Ab Loss of anti-TNF activity due to non-immune drug clearance Non-adherence to therapy

Uncontrolled IBD inflammation: (Adequate drug level) Shift of disease pathway away from TNF to other mediators

Non-IBD related inflammation: (Adequate drug level, High CRP) Infection ! Other (vasculitis, ischemia)

Non-inflammatory mechanisms (Adequate drug level, Normal CRP) Fibrostenotic strictures Cancer IBS Miscellaneous (Amyloidosis, BOG, Bile salt diarrhea, etc)

Possible mechanisms of worsening on anti-TNFs

Adapted from Allez M, J Crohn Colitis 2010

Possible mechanisms of worsening on anti-TNFs

Adapted from Allez M, J Crohn Colitis 2010

Scope, Scope and Scope…

Managing loss of response:

Start with prevention…

Scheduled vs. Episodic IFX Matters

Maser, EA, et al. Clin Gastroenterol Hepatol 2006;4:124854.

Maser, EA, et al. Clin Gastroenterol Hepatol 2006;4:124854.

Clinical Remission CRP < 5 mg/dlEndoscopic

Improvement >75%

P<0.001 P<0.001 P<0.001

% o

f pati

ents

IFX Trough Levels are Important

Outcomes at 1 year on scheduled infliximab therapy

**

*

Trough Trough Trough

Higher trough levels associated with better response

1.0

3.8

0

2

4

6

8

10

IFX + Placebo (n=73) IFX + AZA (n=76)

Colombel JF, et al. N Engl J Med. 2010;362:1383-1395

HYPOTHESIS: Optimizing levels with anti-TNF monotherapy could be an alternate to dual therapy

SONIC Trial

Effect of Infliximab Antibody Concentration on Duration of Response

0

20

40

60

80

100

120

140

Negative 1.8–8.0 µg/mL 8.0–20.0 µg/mL >20.0 µg/mL

Concentration of Antibodies to Infliximab

Day

s U

nti

l S

ub

seq

uen

t In

fusi

on P < 0.001

Baert F et al. N Engl J Med. 2003;348:601.

28 days

61 days

Relationship Between ATI Concentration and Infusion Reactions

No Infusion Reaction Infusion Reaction

AT

I L

evel

(µ

g/m

L)

2

0

4

6

8

10

12

14

16

1820

2224

26

28

30

ATI levels 8.0 µg/mLMore likely to experience infusion reactions (relative risk, 3.9; 95% CI 1.3 to 11.7; P = 0.04)

Miele E et al. J Pediatr Gastroenterol Nutr. 2004;38:502.

Rapid IFX Clearance: Mechanism of Non-response in UC

Kevans D, et al. DDW 2012

Undetectable Serum IFX Trough Predictiveof Colectomy in UC

55%

17%

P<0.001

Cole

ctom

y(%

pati

ents

)

Seow CH et al, Gut 2010;59:49-54

Managing loss of response:

Dose intensification

Dose escalation results in ~60% (short-term??) response

Managing loss of response – Dose intensification

0

20

40

60

80

100

% re

gain

ed re

spon

se

Ben-Horin S, Aliment Pharmacol Ther 2011

At 12 months:Regained response - 50-70%

Diverse Protocols Abound

Infliximab Adalimumab5mg/kg/6weeks 40mg/EW

7.5mg/kg/8weeks 80mg/EOW

10mg/kg/8weeks 40mg/10 days

5mg/kg/4weeks

Re-induction followed by de-escalation

How to intensify ?

Month

Number at risk 168 119 110 93 86 75 62

Res

po

nse

ra

te t

o e

scal

ati

on

(%

)

Combined sustained response: 47% at 12 months

Month

Number at risk 168 119 110 93 86 75 62

Res

po

nse

ra

te t

o e

scal

ati

on

(%

)

Month

Number at risk 168 119 110 93 86 75 62

Res

po

nse

ra

te t

o e

scal

ati

on

(%

)

Combined sustained response: 47% at 12 months

10mg/kg/8w

5mg/kg/4wP=0.2

Katz L, Inflamm Bowel Dis, 2012

Double dose (10mg/kg/8w) is at least as effective as interval halving (5mg/kg/4w) in loss of response to Infliximab

0 2 6 14 22 wks.0

3

10

µg/mL increased toxicity?

The therapeutic window concept

Nesterov I. J Rheumatol 2005

loss of efficacy

Antibody to IFX Can Be Transient

• 90 adult IBD patients– 1,232 serum samples

• 59% developed ATI– By study design

• ATI was transient in 28%

Vande Casteele N et al. Am J Gastroenterol 2013

Vande Casteele N, Am J Gastroenterol 2013

Patients with sustained ATI developed significantly higher ATI levels over time compared with patients with transient ATI.

Vande Casteele N, Am J Gastroenterol 2013

Trou

gh le

vel o

f Infl

ixim

ab (μ

g/m

l)

Dose-intensification must increaseIFX trough level to regain response

Managing loss of response:

Add an immunomodulator (6MP, AZA, MTX)

02468

101214161820

0 10 20 30 40

0

1

2

3

4

5

6

7

Infliximab anti-infliximab antibodies (ATI)

Conc

entr

ation

(mcg

/ml)

Start MTX

10 20 30 40 50

Patient 1

Weeks

0

5

10

15

20

25

Infliximab anti-infliximab antibodies (ATI) 0 10 20 30 40 50 60

Start AZA

Patient 3

Start 6-MP

Patient 2

0

5

10

15

20

25

Start AZA

0 10 20 30 40 50

Patient 4

Conc

entr

ation

(mcg

/ml)

Weeks

Ben Horin S, Clin Gastroenterol Hepatol 2013

Adding immunomodulator to revert immunogenicity

Weeks

Weeks

Weeks Weeks

Conc

entr

ation

(mcg

/ml)

Conc

entr

ation

(mcg

/ml)

Predictive Value

Infliximab Trough May Predict Sustained Response in Crohn Disease

• Retrospective adult cohort 84 patients

– IFX trough level measured at 14 or 22 wks

• Sustained clinical response• IFX Trough level > 3 μg/ml

• Increase in ATI• IFX Trough level < 3 μg/ml

Bortlik M et al. J Crohns Colitis 2012

IFX Trough Levels• Greatest predictor of IFX failure

– Any IFX trough < 0.91 μg/ml

• IFX trough <2.2 μg/ml at week 14 predicts– Develop ATI (p<0.0001)– Discontinue IFX for LOR/hypersensitivity (p=0.003)

• When escalating therapy– ATI > 9.1 U/mL risk of failure (LR 3.6)– Patients with success had increase in IFX levels

Vande Casteele N et al. Am J Gastroenterol 2013; epub ahead of print

Authors suggest:dose escalation if IFX trough <2.2 at week 14dose escalation can be attempted with low level ATI

Proposed Treatment Algorithm

Positive ATI (detectable antibody) > 9

≤ 9

Change to another anti-TNF

Increase infliximabor add IM no

success

If persistent disease,change to Rx with different mechanism of action (non- anti-TNF agent)

Therapeutic IFX conc(>3 mcg/ml trough level)

Active disease onEndoscopy/radiology

Inactive disease onEndoscopy/radiology

Change to Rx with different mechanism of action (non- anti-TNF agent)

Investigate for alternate etiology of symptoms

Sub-therapeutic IFX(<3 mcg/ml trough level)

Increase infliximaband/or add IM

If persistent disease, change to another anti-TNF

Adapted from Afif W et al. Am J Gastroenterol 2010; 105:1133-1139