Management of Biologic Therapies in IBD

Stephen B. Hanauer, MDClifford Joseph Barborka Professor of Medicine

Northwestern University Feinberg School of Medicine

Defining Maintenance Treatment

• Simply: A maintenance therapy prevents “relapse”- In contrast to episodic therapy or re-treatment

• Levels of Maintenance- Maintenance of Response- Maintenance of Clinical (or Post-operative) Remission

• Maintenance of Steroid-free remission

- Maintenance of Mucosal Healing- Prevention of Hospitalizations/Surgery- Disease Modification

Clinical Trial Data

Re-Treatment Benefit With Infliximab

Clinical response defined as a ³ 70-point decrease in CDAI score from baseline.* Patients responding to an initial infusion.

Resp

onse

(%)

WeekInfusion

Rutgeerts et al. (1999). Gastroenterology 117(4): 761-769.

CD: Comparing ACCENT I, CHARM, and PRECiSE 2 Remission Results

30.747.9

64.1

020406080

Week 6Response

Week 26Remission

OverallRemission

Week 26

PRECiSE 2(certolizumab pegol)

ACCENT I*(infliximab)

CHARM**(adalimumab)

*5 mg/kg dose.**Maintenance trial with 80/40 mg induction dosing. Randomized responders = CR-70 at week 4. Week 26 remission among randomized responders on 40 mg every other week dosing. 

24

60

40

0

20

40

60

80

100

Week 4

Response

Week 26

Remission

Overall

Remission

Week 26

Pat

ien

ts (

%)

Pat

ien

ts (

%)

Pat

ien

ts (

%)

Health Claims Data

Loss of Response to Infliximab in Crohn’s Disease: Health-Care Claims Data

0 50 100 150 200 250 300 350 400 450 500 550 600 650 700 750 8000%

20%

40%

60%

80%

100%

Days from Index Date

Loss

of-

Resp

onse

Rat

e

2 years, 77%

– Loss of response

• Health-care claims database (1999–2005)

• Selected patients with CD receiving infliximab maintenance therapy with an initial response

• Loss of response inferred from:

– Upward dose adjustment

– New drug therapy for CD

– CD-related emergency room or inpatient visits

• Annual total health-care and CD-related costs estimated and adjusted for inflation to 2005 US dollars

Wu EQ et al. Value Health. 2008;11:820-829.

1 year, ~50%

Comparative Effectiveness of Infliximab and Adalimumab for Crohn's Disease

• Retrospective cohort study by using U.S. Medicare data from 2006 through 2010. • Patients with CD who were new users of infliximab (n = 1459) or adalimumab (n = 871)

after January 31, 2007. • Primary outcome measures were disease persistence on therapy at week 26

Osterman, M. CGH 2014;12:811-17

After 26 weeks of treatment, 49% of patients receiving infliximab remained on drug,compared with 47% of those receiving adalimumab

Kane Svet al. Adv Ther. 2009;26(10):936-946; Fasanmade AA, et al. Eur J Clin Pharmacol.2009;65(12):1211-1228; Ben-Horin S, et al. Autoimmun Rev. 2014;13(1):24-30; Farrell RJ, et al. Gastroenterology. 2003;124(4):917-924.

Causes of Treatment Failure With Anti-TNF Agents

• Poor adherence reported in one-third of patients

• Suboptimal drug concentrations result from pharmacokinetic (PK) differences- Weight-based dosing- Measure serum concentrations

• Antidrug antibodies (ADAs) production

• Concomitant Infection (C. Diff & CMV)

Therapeutic Windows with Biologics

0 2 6 14 22 wks.

1

10

100

µg/mL

AUC

Sub-treshold trough levels associated with:• Loss of response • Immunogenicity

Peak

Trough

0

20

40

60

80

100

Trough Levels of Infliximab Are Predictor of Continued Response

0

10

20

30

Undetectable 2.0 ug/ml

* P < 0.001

0

20

40

60

80

100

Undetectable 2.0 ug/mlUndetectable 2.0 ug/ml

* P < 0.001 * P < 0.001

CLINICAL REMISSION C- REACTIVE PROTEIN ENDOSCOPIC CHANGE

**

*

Maser EA et al. Clin Gastroenterol Hepatol. 2006;4:1248-54

Prospective cohort study of relationship between serum infliximab level and efficacy in luminal CD

Levesque BG, et al. Aliment Pharmacol Ther. 2014;39:1126-35.

Higher Serum Infliximab Concentration is Associated with a Higher Response Rate in CD

• Study design: prospective, cohort study

• N=125, 30% Rx for fistula • Median follow-up: 36 months• Efficacy

- Infliximab concentrations ≥12 μg/mL were associated with greater median duration of response

- Immunosuppressant use was associated with IFX concentrations ≥12 μg/mL

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

Duration of Response Based onIFX Concentrations

≥12.0 μg/mL <12.0 μg/mL0

20

40

60

80

100

81.5

68.5

Du

rati

on

of

Re

sp

on

se

(d

ay

s)

P<0.01

·Pr

opor

tion

of P

atien

ts (%

)

IFX Concentration (mcg/ml) at Wk 30

Clinical Remission Without Corticosteroids by Trough IFX Concentration at Week 26: SONIC

Primary Endpoint

·*IFX and IFX+AZA patients who had 1 or more PK samples obtained after their first study agent administration were included in the analysis

0 >0-1 >1-3 >3-6 >60

102030405060708090

100

59 57

73 74 72

31/4336/4943/5913/2319/32

·Colombel JF, et al. N Engl J Med. 2010.

Higher Serum Infliximab Level is Associated with Longer Remission and Better Endoscopy Score in CD

• Study design: prospective cohort in moderate-severe CD

• N=105• Median follow-up: 88 weeks• Efficacy

- Infliximab concentrations were positively correlated with the interval of clinical remission and change in endoscopic score

Maser EA, et al. Clin Gastroenterol Hepatol. 2006;4:1248.

40

50

60

70

80

90

100

Rem

issi

on (%

)

Serum Infliximab (µg/ml)

R2= 0.61P<0.001

0 2 4 6 8 10 12

-100

50

0

50

100

Endo

scop

ic Im

prov

emen

t (%

)

Serum Infliximab (µg/ml)

R2= 0.46P<0.001

0 2 4 6 8 10 12

High Infliximab Levels are Associated with Mucosal Healing in Crohn’s Disease

• Serum samples in 210 CD patients undergoing treatment with infliximab were collected

• Infliximab trough levels were correlated with endoscopic healing (complete, partial or none)

Complete Partial None0

1

2

3

4

5

6

7

5.77

3.89

0.950000000000001

Tro

ug

h l

ev

el

(mc

g/m

L)

· Van Moerkercke W. et al. DDW 2010. Abs #405

Implications of Low Trough Levels

•Disease Recurs- No longer maintenance but re-treatment

•Development of anti-drug antibodies- Eventual loss of response

•Do Not Administer Intermittently!

Factors that Influence the PK of TNF Antagonists

Impact on TNF antagonist PK

Presence of ADAs Decreases drug concentration Increases clearanceWorse clinical outcomes

Concomitant use of immunosuppressives Reduces ADA formationIncreases drug concentrationDecreases drug clearanceBetter clinical outcomes

Low serum albumin concentration Increases drug clearanceWorse clinical outcome

High baseline CRP concentration Increase drug clearance

High baseline TNF concentration May decrease drug concentration by increasing clearance

High body size May increase drug clearance

Sex Males have higher clearance

Ordas I et. al. Clin Gastroenterol Hepatol. 2012; 10:1079-1087. 18

Therapeutic drug monitoring with biologic therapy

• Relationship of exposure to response?• Define a minimum effective concentration?• Define a maximum therapeutic concentration above which

- no additional benefit?- increased risk of toxicity?

• Relationship between drug concentration and anti-drug antibodies, and treatment strategy?

• Is TDM cost-effective?• In what clinical situations should TDM be used?

- Induction?- Maintenance?- Loss of response?- Toxicity?

ACCENT I: Week 54 Sustained Clinical Outcome and Week 14 Serum Infliximab Level in CD

Sustained Clinical Outcome<3.5 μg/mL Week 14

Serum IFX Level≥3.5 μg/mL Week 14

Serum IFX Level P-value*

Subjects included in analysis 96 51

Subjects with sustained response 17 (17.7%) 20 (39.2%) 0.0042

Subjects without sustained response 79 (82.3%) 31 (60.8%)

*Chi-square test

.Cornillie F, et al., Gut. 2014;63: 1721-7

Infliximab Trough Between Weeks 14 and 22 May Predict Sustained Response in Crohn’s 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 2013;7:736-743.

Detectable Serum Trough Infliximab Associated with Higher Remission Rate and Endoscopic Improvement in UC

• Study design: cohort study• N=115 patients with moderate to

severe UC• Follow-up time: median 13.9

months• Efficacy

- Detectable serum IFX was associated with• Higher remission rates (69% vs. 15%;

P<0.001)• Endoscopic improvement

(76% vs. 28%; P<0.001)

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

Undetectable Detectable0

10

20

30

40

50

60

70

80

15

69

Re

mis

sio

n (

% o

f P

ati

en

ts)

P<0.001

Presence of Detectable Trough Infliximab Levels Reduces Colectomy Rates in Ulcerative Colitis

Seow CH, et al. Gut. 2010;59:49.

Undetectable Detectable0

20

40

60

80

100

55

7

Cole

ctom

y (%

of P

atien

ts) P < 0.001

Proportion of Patients Achieving Clinical Remission by Serum IFX Concentration: ACT 1 and 2

IFX Conc.(% patients)

1stQuartile

2nd Quartile

3rd Quartile

4thQuartile P-values

Week 826.3%

(<21.3μg/mL)37.9%

(≥21.3-<33μg/mL)43.9%

(≥33-<47.9μg/mL)43.1%

(>47.9μg/mL)P=0.0504

Week 3014.6%

(<0.11μg/mL)25.5%

(≥0.11-<2.4μg/mL)59.6%

(≥2.4-<6.8μg/mL)52.1%

(>6.8μg/mL)P<0.0001

Week 5421.1%

(<1.4μg/mL)55.0%

(≥1.4-<3.6μg/mL)79.0%

(≥3.6-<8.1μg/mL)60.0%

(>8.1μg/mL)P=0.0066

At wks 8, 30 and 54, the proportion of patients achieving clinical remission increased with increasing quartiles of IFX concentrations.

Reinisch W et al., Gastro Vol 142, Issue 5, suppl-1, May 2012, page S-114

Week 54 Outcome IFX14 median level (μg/ml) P-value*

Persistent Remission (Y vs. N) 4.7 vs. 2.6P = 0.03

Clinical Remission (Y vs. N) 3.2 vs. 2.2P = 0.07

Deep Remission (Y vs. N) 4.2 vs. 3.0P = 0.07

Sustained Durable Remission 14 (Y vs. N) 5.5 vs. 3.1P = 0.05

Sustained Durable Remission 22 (Y vs. N) 5.1 vs. 3.0P = 0.04

Week 14 IFX levels predict week 54 outcomes

Singh N, et al. Inflamm Bowel Dis 2014;10:1708-13

* 6 discontinued IFX, 3 continued same dose 3, 3 proceeded to surgery, 5 patients could not be assessed

Clinical outcomes in patients with detectable HACA (n=35)*

* 10 continued same dose, 9 discontinued IFX, 8 proceeded to surgery and 7 patients could not be assessed

Clinical outcomes in patients with sub-therapeutic concentrations (n=69)*

Increasing dose of infliximab in the presence of ATI formation is inferior to changing anti-TNF

Com

plet

e / p

artia

l res

pons

e (%

)

P<0.004

Com

plet

e / p

artia

l res

pons

e (%

) P<0.016

Afif W, et al. Am J Gastroenterol 2010;105:1133-9.

Adalimumab & ATA Levels at LOR correlate with response to dose intensification

(A) ROC analysis of adalimumab level and active inflammation.

(B) Adalimumab levels at the time of LOR in patients who subsequently responded to dose intensification compared with those who did not.

(D) ATA levels at the time of LOR in patients who subsequently responded to dose intensification compared with those who did not.

(C) ROC analysis of adalimumab level and failure of early response to dose intensification.

Yanai, CGH 2015;13:522–530

Combined analysis for patients with a suspected LOR to either infliximab or adalimumab

Survival curve of regained response to dose intensification according to ADA titer status.

Survival curve for regained response among patients with high-titer ADA.

Yanai, CGH 2015;13:522–530

Combined analysis for patients with a suspected LOR to either infliximab or adalimumab

Survival curve for regained response among patients with no/low-titer ADA.

Anti-TNF drug level before and after dose intensification

Yanai, CGH 2015;13:522–530

Combined analysis for patients with a suspected LOR to either infliximab or adalimumab with adequate drug

levels

Survival curve for regained response among patients who received anti-TNF optimization (dose intensification or a switch within the anti-TNF class) vs expectant management

survival curve for regained response among patients who received anti-TNF optimization vs out-of-class intervention

Yanai, CGH 2015;13:522–530

Survival curves of regained response to adalimumab or infliximab dose intensification according to ATA/ATI titer status at the time of LOR.

Adalimumab Infliximab

Yanai, CGH 2015;13:522–530

Potential yield of drug/ADA tests as illustrated by cohort subgroups of PK measurements

Yanai, CGH 2015;13:522–530

Proposed algorithm for patients with loss of response to infliximab

Positive HACA

Change to another anti-TNF agent

Change to non–anti-TNF agent

persistent disease

Increase infliximab

dose or frequency

Change to non–

anti-TNF agent

Change to different anti-TNF

agent

Change to different anti-TNF

agent

Subtherapeutic IFX concentration

Therapeutic IFX concentration

Active disease on endoscopy/radiology?

Change to different anti-TNF

agent

Investigate alternate etiologies

yes no

Afif W et al. Am J Gastroenterol 2010;105:1133.

What About ADA in the Presence of Drug?

Therapeutic IFX Concentration had no effect on CRP in presence of ADA

• 66 patients: 27% with detectable ATA 59 (89%) CD, 7 (11%) UC

• Mean ADA levels were higher in patients with Undetectable ATA Mucosal healing Concomitant use of immunosuppressants

• ADA level ≥ 5 µg/ml is associated with lower CRP and healed mucosa

• Variables associated with positive ATA (≥ 1.7 µg/ml) ADA < 5µg/ml: OR 8.6, 95%CI (2.3-31) Mucosal inflammation: OR 3.8, 95% CI (1.1-13) Steroid use: OR 3.7, 95% CI (1.1-13)

Serum Adalimumab (ADA) Levels and Anti-Adalimumab Antibodies (ATA) Correlate with Endoscopic Inflammation

and Inflammatory Markers

Yarur, AJ, et al. Presented at DDW; May 21, 2013. Abstract Tu1147.

Endoscopic Inflammation

ad

alim

um

ab

[g

/mL

]

0

10

20

30

40

p=0.016

adal

imu

mab

[ g

/mL]

0

10

20

30

40

p=0.002

Immunosuppresant Use

adal

imum

ab [

g/m

L]

0

10

20

30

40

p=0.028

Cross-sectional study of ADA drug level as predictor of clinical response and CRP in CD

• ADA level of 5.85 μg/mL was optimal- Sensitivity 68%- Specificity 71%- Positive LR 2.3

• AAA were inversely related to ADA drug levels

Mazor Y, et al. Aliment Pharmcol Ther 2014;40:620-8.

Higher trough levels of adalimumab are associated with higher rates of mucosal healing

Roblin X, et al. Clin Gastroenterol Hepatol 2014;12:80-84.

Trough adalimumab levels are higher in patients with mucosal healing

6.5 μg/mL

4.2 μg/mL

P<0.005

Roblin X, et al. Clin Gastroenterol Hepatol 2014;12:80-84.

Adalimumab Trough Serum Levels < 0.33 µg/mL Predicts a Lower Rate of Sustained Complete Response in Patients with Crohn’s Disease

Karmiris K, et al. Gastroenterology. 2009;137:1628.

Patie

nts

with

Sus

tain

edCl

inic

al R

espo

nse

(%)

0.0

0.2

0.4

0.6

0.8

1.0

0 210 240

LogRank: P=.01

Sustained Clinical Response (weeks)90 12030 15060 180

ADA TR>0.33 µg/mL, n=104

ADA TR<0.33 µg/mL, n=16

Proposed algorithm incorporating pharmacokinetics of adalimumab in IBD

AAA: antibodies against adalimumabADA: adalimumabTRA: trough levels of adalimumab

Low TRA: <4.9 μg/ml AAA present: >10 ng/ml

Roblin X, et al. Am J Gastroenterol 2014;109:1250-6.

• Single-center cohort of 125 steroid-refractory acute UC patients

• Standard infliximab induction/maintenance

• Fluid-phase assay for [IFX] and ATI

Trough Infliximab >2 µg/ml is Associated with Clinical Remission in Steroid-Refractory UC

Remission aOR [95%CI]

Colectomy aOR [95%CI]

Trough IFX > 2 µg/ml (vs. ≤ 2 µg/ml)

10 [3,35] 0.18 [0.07,0.44]

ATI (vs. no ATI) 0.64 [0.2,2.4] 1.0 [0.5,2.1]

IFX, infliximab Murthy S, et al. Presented at DDW; May 19, 2012. Abstract Sa2047.

Steroid-free Remission by IFX/ATI Status100

0

60

20

Pat

ien

ts i

n R

emis

sio

n (

%)

80

40

IFX+ATI-

70.0

16.6

28.5

13.0

IFX+ATI+

IFX-ATI-

IFX-ATI+

P=0.84

P=0.073

P<0.001

Steroid-free Remission by IFX Trough Status100

0

60

20

Pat

ien

ts i

nR

emis

sio

n (

%)

80

40

Serum IFX≤ 2µg/ml

17.5

69.4

Serum IFX> 2µg/ml

P<0.001

Colectomy by IFX Trough Status100

0

60

20Co

lect

om

y (%

)

80

40

Serum IFX≤ 2µg/ml

55.5

17.7

Serum IFX> 2µg/ml

P<0.001

Rapid IFX Clearance: Mechanism of Non-Response in UC

Kevans D, et al. Presented at DDW; May 19, 2012.

• Multicenter, propspective observational study in anti-TNF-naïve patients (N=19) with moderate-to-severe UC (Endoscopic Mayo 2/3)1

- IFX measured at 10 time points during first 6 weeks of induction therapy- Nonlinear mixed-effects modelling

• No difference in IFX concentration area under the curve (AUC) between endoscopic responders and endoscopic non-responders at week 8 (P=0.65 )

• Patients with CRP>50 µg/mL had lower IFX concentration (P=0.001)• 7/19 had positive ATI (homogeneous mobility shift assay)

- 6 of 8 endoscopic non-responders were ATI +- 2 of 8 endoscopic non-responders were ATI –

• Concomitant immunomodulator = 12/19 (P=NS)• IFX presumed to be lost in stool in severe IBD colitis2

Pharmacokinetics of Infliximab Induction Therapy in Patients With Moderate to Severe UC

1. Brandse JF, et al. Presented at DDW; May 5, 2014 A786. 2. Brandse JF, et al. Presented at DDW; May 18, 2013. A157.

Factors Affecting the Pharmacokinetics of Monoclonal Antibodies

Impact on Pharmacokinetics

Presence of ADAs • Decreases serum mAbs• Threefold-increased clearance• Worse clinical outcomes

Concomitant use of IS• Reduces formation• Increases serum mAbs• Decreases mAb clearance• Better clinical outcomes

High baseline TNF-α • May decrease mAbs by increasing clearance

Low albumin • Increases clearance• Worse clinical outcomes

High baseline CRP • Increases clearance

Body size • High BMI may increase clearance

Gender • Males have higher clearance

Ordas I et al. Clin Pharmacol Ther. 2012;91:635.

mAB, monoclonal antibody; ADA, antidrug antibody

Do early serial trough and antidrug antibody level measurements predict clinical outcome of infliximab and adalimumab treatment?

Vande Casteele N, et al. Gut 2012;61:321

ADA=anti-drug antibodyAfif W et al. Am J Gastroenterol. 2010;105:1133-1139.

Monitoring Biologics To Guide Treatment Decisions

•Neutralizing antibodies/low trough levels•Other immune pathways drive inflammation•Patient has no residual inflammation

Options•Increase dose, switch to other anti-TNF•Biological with other MOA, immunosuppress.•Surgery

What drives loss of response to monoclonalanti TNF Abs?

Utility of IFX and ATI assays

Afif, Am J Gastoenterol 2010

Detectable HACA Subtherapeutic concentration0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Increase infliximab

Change anti-TNF

Co

mp

lete

/par

tial

Res

po

nse

***

**P < 0.004*P < 0.016

Afif W, et al. Am J Gastroenterol. 2010;105(5):1133-1139.

Measuring Infliximab and HACA Concentrations in Patients With IBD: Clinical Outcomes

BRIDGe “anti-TNF optimizer”

www.BRIDGeIBD.com

BRIDGe “anti-TNF optimizer”

www.BRIDGeIBD.com

BRIDGe “anti-TNF optimizer”

www.BRIDGeIBD.com

BRIDGe “anti-TNF optimizer”

www.BRIDGeIBD.com

BRIDGe “anti-TNF optimizer”

www.BRIDGeIBD.com

Can you make antibodies go away?

Ben-Horin S, et al. Clin Gastroenterol Hepatol. 2013; 11:444-447.

IFX levels closed squaresATI open squares