Marla Dubinsky, MDDirector, Pediatric IBD Center

Associate Professor of PediatricsAbe and Claire Levine Chair in Pediatric IBD

Cedars-Sinai Medical Center

Optimizing the efficacy of immunomodulators and biologics in

pediatric IBD

Objectives• Causes of non response to therapies• Thiopurine drug monitoring• Anti-TNF drug monitoring• Impact of immunogenicity• The future of biologic use

Potential Causes of Drug Response Heterogeneity

pathogenesis and severity of disease drug interactions age nutritional status renal and liver function concomitant illnesses genetic polymorphisms in targets of therapy inherited differences in metabolism and disposition

0%

20%

40%

60%

80%

100%

6-TGN QUARTILES

Freq

uenc

y of

Res

pons

e

41%

78%

n=440-173

n=42174-235

n=43236-367

n=44368-1203

P< 0.001

Target 6-TGN Level to Optimize Efficacy: >235

Dubinsky MC et al. Gastroenterol;118:2000

Odds Ratio 5.0 for treatment response when 6-TGN > 235

Author & Year Patients (Remissi

on)

6TGN Threshold

Proportion Above

Threshold in

Remission

Proportion Below

Threshold in

Remission

Odds Ratio

95% Confidence

Interval

Dubinsky 2000 92 (30) 235 .78 .40 5.07 2.62-9.83Gupta 2001 101 (47) 235 .56 .43 1.65 0.73-3.75Belaiche 2001 28 (19) 230 .75 .65 1.62 0.26-10.2Cuffari 2001 82 (47) 250 .86 .35 11.63 3.78-35.7Goldenberg 2004 74 (15) 235 .24 .18 1.47 0.47-6.42

Achkar 2004 60 (24) 235 .51 .22 3.80 1.17-12.4

Pooled Estimate

0.6295% CI 0.43-0.80

0.3695% CI 0.25-0.48

3.27 1.71-6.27

Meta-Analysis: 6-TGN levels and Clinical Remission

Lewis J et al. Gastroenterology 2006:130;1047-1053

Monitoring Levels of Thiopurines is Useful Because….

1) Standard dosing only 30% effective2) Safe dose escalation to maximize efficacy3) Identify non compliance4) Minimize toxicity5) Identify preferential 6-MMP metabolism6) Explain non response7) Improves patient outcomes

• 150,000 IBD patients are currently on anti-TNFs• 50% of IBD patients will require dose modification or

switch to another treatment1 • Many patients with IBD who have symptoms may not

have active inflammation• Monitoring strategies that identify patients who have

insufficient drug, anti-drug antibodies, or patients whose symptoms are due to causes other than active IBD may help guide treatment outcomes for individual patients

Anti TNFα monitoring is Useful Because….

Alzafiri et al. Clinical and Experimental Gastroenterology 2011; (4):9-17

Effect of Trough Serum Infliximab Concentrations on Clinical Outcome at >52 Weeks

Trough serum infliximab Detectable Undetectable

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

Patients in remission (%) Patients with endoscopic improvement >75% (%)

Patients with complete endoscopic remission (%)Patients with CRP <5 mg/dL (%)

100 100

100 100

0 0

0 0

82

6

88

33

76

32 47

19

p<0.001

p=0.03

p<0.001

p<0.001

ACCENT I: Week 54 Sustained Clinical Outcome and Week 14 Serum Infliximab Level in Crohn’s Disease

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. Presented at the 19th Annual United European Gastroenterology Week (UEGW); October 25, 2011. Stockholm, Sweden. Abstract P0919.

Week 54 Outcome

IFX14 Positive P value

ATI14 *Positive P value

Persistent Remission

70% vs. 36%P < 0.049

50% vs. 60% P = 0.58

Clinical Remission 77% vs. 50%P = 0.09

50% vs. 70%P > 0.99

Deep Remission 67% vs. 37%P = 0.10

50% vs. 58%P > 0.99

Sustained Durable Remission 14

43% vs. 14%P = 0.09

0% vs. 38%P = 0.28

Sustained Durable Remission 22

50% vs. 14%P = 0.04

0% vs. 43%P = 0.15

Detectable week 14 Infliximab Trough levels are associated with week 54 Efficacy Outcomes

*Only 4 patients ATI14 positive Rosenthal C et al 2013

IFX14< 3

IFX14> 3

Fisher P

value

IFX14< 5.5

IFX14> 5.5

Fisher P

value

IFX14< 6.8

IFX14> 6.8*

Fisher P

value

Persistent Remission

(N = 26)45% 65% 0.54 48% 85% 0.043 50% 100% 0.01

Results: Optimal IFX14 Trough Level

* Regression Tree analysis identified optimal cut point

Serum Infliximab Trough Levels and Steroid-free Remission at Week 30 Sonic Study

Steroid-free Clinical Remission at Week 26 by IFX Trough Level at

Week 30

Median IFX Concentration

N=97 N=10919/32 13/23 43/59 36/49 31/43

Web figures 5a and 5b. http://www.nejm.org/doi/suppl/10.1056/NEJMoa0904492/suppl_file/nejm_colombel_1383sa1.pdf;Accessed on October 12, 2012.

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 8 26.3%(<21.3μg/mL)

37.9%(≥21.3-<33μg/mL)

43.9%(≥33-<47.9μg/mL)

43.1%(>47.9μg/mL) P=0.0504

Week 30 14.6%(<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 54 21.1%(<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

ACT1 and ACT 2 cont’d

Detectable Serum Trough IFX Concentration is Associated with Higher Remission Rate and

Endoscopic Improvement in UC Patients

Undetectable serum IFX predicted an increased risk for colectomy (55% vs 7%; p<0.001)

% o

f pat

ient

s

P<0.001

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

Rapid IFX clearance: Mechanism of Non Response in UC

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

Effect of Patient Factors on MAb Pharmacokinetics

• Patient factors identified with changes in IFX clearance– Weight– Albumin– ADA

• Impact on IFX clearance is substantial and should be considered for dose selection

ADA, antidrug antibody ; IFX, infliximabFasanmade AA, et al. Eur J Clin Pharmacol. 2009;65(12):1211. Xu Z, et al. A Population-based Pharmacokinetic Pooled Analysis of Infliximab in Pediatrics. Presented at the 41st Annual Meeting of the American College of Clinical Pharmacology; September 23-25, 2012; San Diego, CA.

0.40

100

Cle

aran

ce (L

/day

)

Weight (kg)

0.28

0.209040 80706050

0.90

5.5

Clea

ranc

e (L

/day

)

Albumin (g/dL)

0.30

0.205.01.5 4.03.02.52.0

0.60

0.40

0.80

0.70

0.50

4.53.5

0.34

0.24

0.30

0.22

0.38

0.26

0.32

0.36

ADA Trough Above 0.33 µg/mL Predicts Clinical Response

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

1.0

0.8

0.6

0.4

0.2

0.0

Patie

nts

with

Sus

tain

ed

Clin

ical

Res

pons

e (%

)

0 30 60 90 120 150 180 210 240Sustained Clinical Response (weeks)

Log Rank: P=0.01

ADA TR>0.33 µg/mL, n=104

ADA TR<0.33 µg/mL, n=16

PURSUIT – Golimumab for the Induction and Maintenance of UC

Sandborn WJ, et al. Presented at DDW; May 22, 2012. Abstract 943d.

Phase 2: Clinical Endpoints by Serum Golimumab ConcentrationQuartile at Week 6

No exposure< 1st Quartile1st and < 2nd Quartile2nd and < 3rd Quartile3rd Quartile

-0.82

0.294

-0.1

-0.48 -0.394

-0.74

-1.5

-1

-0.5

0

0.5

1

SerumAlbumin

ATI Con. IS Body Weight(total

clearance)

Body Weight(central

clearance)

Body Weight(peripheralclearance)

Rela

tive

Stre

ngth

of E

ffec

tFactors Affecting Infliximab

Clearance in CD

Con. IS, concomitant immunosuppressantFasanmade AA, et al. Clin Ther. 2011;33(7):946.

Scheduled & Episodic Therapy ACCENT I (n=580)

Immunogenicity

• Immunogenicity is usually dependent on antibody construct, route of administration, target of the antibody, disease, and other factors– Therapeutic antibodies that

deplete B-cells are less immunogenic than other MAbs

Murine Chimeric Hyper-Chimeric Human

Immunogenicity

Half-Life

Complement and ADCC

Route of Administration: SC > IM > IV

Infliximab (chimeric) should be more immunogenic than adalimumab (human), but immunogenicity is

similar.

ADCC, antibody-dependent cell cytotoxicity; 1. http://www.medversation.com/medversation/hcp/section/PRE/SED733445-07DB-4A2D-F2BC-

A717D20C0E0E.html

Immunogenicity of TNF Antagonists:Patients With Detectable Antibodies to a TNF

Antagonist

IMS, immunosuppressant; RA, rheumatoid arthritis; UC, ulcerative colitis

1. Hanauer et al. Clin Gastroenterol Hepatol. 2004;2(7):542. 2. Sandborn WJ, et al. Presented at DDW; May 19-24, 2007. Abstract T1273. 3. Sandborn WJ, et al. N Engl J Med. 2007;357:228. 4. Schreiber S, et al. N Engl J Med. 2007;357:239. 5. Summary of Product

Characteristics for adalimumab. Abbott Laboratories. July 2007. 6. Sandborn WJ, et al. Gut. 2007;56:1232.

Patients, %

Episodic Maintenance Scheduled Maintenance

IMS- IMS+ IMS- IMS+

Infliximab1 (CD 5 mg/kg)(CD 10 mg/kg) 38% 16% 11%

8%7%4%

Infliximab2 (UC 5 mg/kg)(UC 10 mg/kg) No data

19%9%

2%4%

Certolizumab3 (PRECiSE I) 10% 4%

Certolizumab4 (PRECiSE II) 24% 8% 12% 2%

Adalimumab5 (RA, all doses)No data

12% 1%

Adalimumab6 (CLASSIC II) 4% 0%

Presence of ATI is Associated with a Higher Non-response Rate and Shorter Duration of Response

Farrell RJ, et al. Gastroenterology 2003;124:917-24

ATI (+)N=19

ATI (-)N=33 P-value

Rate of Non-response to subsequent infusions

52% 14% 0.0005

Median Duration of Response 28 days 61 days 0.007

Incidence of subsequent infusion reactions

40% 5% 0.0001

Incidence of serious infusion reactions 28% 0% 0.0001

22

SONIC: Immunogenicity Results at Week 30*

*Patients who had 1 or more PK samples obtained after their first study agent administration were included in the analysis. PK data at week 30 was not available for 1 patient treated with AZA + placebo, 3 patients treated with IFX + placebo, and 4 patients treated with AZA + IFX.

AZA, azathioprine; IFX, infliximab; PK, pharmacokinetic; SONIC, Study of Biologic and Immunomodulator Naive Patients in Crohn’s Disease

Colombel JF, et al. N Engl J Med. 2010;362(15):1383.

Perc

ent o

f Pati

ents

(%)

10

20

40

60

80

100

AZA + placebo IFX + placebo AZA + IFX

1/89

87/89 15/106 16/106 72/106 113/120

Positive Negative Inconclusive

98

0/89

0

14 15

68

11/120

22/120

94

• 92% of the patients with a trough serum concentration measured below the threshold for detection were positive for AAA

AAA Formation Lowers Adalimumab Trough Serum Levels in Patients with Crohn’s Disease

AAA, antibodies against adalimumab; ADA, adalimumab; TR, trough serum concentration

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

• “an IFX level of <4 μg/mL measured 4 weeks after the first infusion had a PPV of 81% to detect the development of high ATIs during the later course of treatment”

• “an IFX level of >15 μg/mL measured 4 weeks after the first infusion was 80% predictive for the absence of ATIs during later follow-up”

Serum IFX at Week 4 After an Infusion Predicts Eventual Appearance of ATI’s in Episodic Dosing

ATI, antibodies to infliximab; IFX, infliximab; PPV, positive predictive valueVermeire S et al. Gut. 2007;56(9);1226.

Week 4 Serum Level and Subsequent ATI Titre

P<0.001P<0.001

P=NS

ATI <8

ATI >8

ATI ??

100

10

1

Ser

um IF

X L

evel

(µ

g/m

l)

• N=57, Patients were selected based on ATIs detected on at least one time point during follow-up • 788 serum samples were analyzed for IFX trough levels (ITL) and ATIs • Treatment decisions to optimize and stop therapy were made on clinical grounds and CRP and not on

ATI or ITL.

Transient versus Sustained Antibodies to Infliximab: Possibility to Overcome Low Titer Antibody Responses

by Dose Optimization

Before the second infusion 20% of pts who had “late persisting ATIs“ had an undetectable ITL

Concomitant immunomodulator use was associated with less ATI formation

Van de Casteele N, et al. Presented at the 7th Congress of ECCO; February 16-18, 2012. Barcelona, Spain. Abstract P253.

ATIs may be transient and can disappear after dose optimization. Sustained high levels of ATIs lead however to permanent loss of response. When low or undetectable ITL are detected measuring ATIs is necessary. Low titer ATIs can be overcome by treatment optimization. High ATIs necessitate treatment stop.

Early ATI Formation Treatment Discontinuation after Dose Optimization

n=19 n=38

• Goal: Find objective IFX cutoff using CRP

• High CRP should predict low IFX & vice versa

Results: IFX Liquid Phase ROC Analysis

AUC, area under the curve; CRP, c-reactive protein; FPR, false positive rate; IFX, infliximab; ROC, receiver operating characteristic; TPR, true positive rateFeagan B, et al. Gastroenterology. 2012;142(5) Suppl 1: S-114. Abstract 565.

Cutoff(μg/ml)

ROCAUC 95% C.I

0.1 0.697 0.666, 0.728

3.0 0.735 0.711, 0.760

5.0 0.702 0.677, 0.728

0.0 1.0

TPR

0.0

0.6

0.8

1.0

FPR0.4 0.80.60.2

0.6

0.8

AUC=0.735

IFX assay LLOQ 0.1 μg/ml ATI+ serum samples

significantly lower odds of having detectable IFX– Odds ratio = 0.040, P<0.0001

154/353 (44%) ATI+ serum samples had detectable IFX

ATI− ATI+IFX− 3.7% 13.4%

IFX+ 72.6% 10.4%

55199

1,079

154

0

200

400

600

800

1,000

1,200

ATI- ATI+

Cou

nt

Serum IFX Concentration* (mg/ml)

IFX-IFX+

IFX & ATI Counts

LLOQ, lower limit of quantification

1,487 serum samples from 483 participants in 4 CD RCTs/cohortsDisease activity measured by CRP

1,205 pairs of samples taken over sequential time points (trough infliximab/ATI in first sample, CRP in second sample)

Predictors of higher CRP: ATI+, infliximab < 3mcg/mL

Novel Infliximab and Antibody-to-Infliximab Assays Are Predictive of Disease Activity in

Patients with CD

Feagan B, et al. Presented at DDW; May 20, 2012. Abstract 565.

CR

P m

g/L

ATI- ATI+

50.0

0.5

5.010.0

25.0

1.0

2.5

244

890

294 59

5.98 11.921.98 11.57

IFX < 3 µg/mlIFX ≥ 3 µg/ml

Median CRP (mg/L)

******

Sample size

Clinical Outcomes of Patients with Detectable Antibodies to Infliximab or Sub-therapeutic Infliximab Concentrations

Response to testComplete/partial

response (%) P valueDetectable HACA Increase infliximab

Change anti-TNF1/6 (17)

11/12 (92)P<0.004

Subtherapeutic concentration

Increase infliximabChange anti-TNF

25/29 (86)2/6 (33)

P<0.016

Elevating Infliximab Concentration from Sub-Therapeutic Levels is Effective in Regaining Response in HACA (-)

Patients

HACA, Human anti-chimeric antibodies

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

Treatment Paradigms in Symptomatic Patients that Lose Response to IFX

ATI - ATI+

IFX < threshold Increase dose Switch (high ATI) or

Dose optimize (low ATI)

IFX ≥ threshold Check endoscopy Switch (high activity) or Switch or

Monitor (low activity)

Only 43% have optimal ITL. In the others dose adjustment was carried out. 9% of the patients have undetectable ITL despite staying in remission. The current controlled study will show whether long term adjustment of treatment based on IFX levels is a superior strategy.

• 270 IBD patients on IFX maintenance therapy. All pts had their IFX trough levels adjusted to 3-7 ug/ml.

• They were then randomized to dosing based on IFX trough levels (ITL) – Group 1: ITL kept between 3 and 7 μg/ml– Group 2: dosing and optimization based on clinical symptoms

Individualized IFX Treatment Using Therapeutic Drug Monitoring: A Prospective Controlled Trough Level

Adapted InfliXImab Treatment (TAXIT) Trial

Infliximab EMEA SPC: 5 mg/kg IV infusion over a 2-hour period

Van de Casteele N, et al. Presented at the 7th Congress of ECCO; February 16-18, 2012. Barcelona, Spain. Abstract OP11.

Decreased dose Increased dose

(77%) were ATI positive

Therapeutic Drug Monitoring for Anti-TNFα

• Measurable drug level associated with improved response outcomes

• Anti-infliximab antibodies associated with decreased efficacy

• ATI and drug levels can help guide treatment decisions

• Dose ranges should be studied during drug development given pharmacokinetic variability