Induction and Maintenance Therapies: Lessons from PROTECT Joel R. Rosh, MD Director, Pediatric Gastroenterology Goryeb Children's Hospital/Atlantic Health

Induction and Maintenance Therapies: Lessons from PROTECT

Joel R. Rosh, MDDirector, Pediatric Gastroenterology

Goryeb Children's Hospital/Atlantic Health Professor of Pediatrics

Icahn School of Medicine at Mount Sinai

Disclosures

• Grant Support: – Abbvie, Astra-Zeneca, Janssen

• Consultant:– Abbvie, Given, Janssen, Soligenix

• Honoraria/Speakers’ Bureau– Abbott Nutrition, Abbvie, Prometheus

Incidence of IBD is Increasing Dramatically WorldwideSartor, Nature Clin Prac, 2006

Key Point 1:

IBD is a Complex Disorder that May Require a Genetically Susceptible Host with an Appropriate Environmental Trigger(s)

Key Point 2:

IBD Results from an Exaggerated Mucosal Immune Response to Commensal Microorganisms

Pathogenesis of IBD

GWAS Studies Have Identified over 180 Inflammatory Bowel Disease Susceptibility Loci

Lees C W et al. Gut doi:10.1136/gut.2009.

EVOLVING CLASSIFICATION(Diabetes as the Model)

ULCERATIVE COLITIS• Mucosal• Continuous

CROHNS DISEASE• Transmural• Discontinuous• OralPeri-anal

Inde

term

inat

e Co

litis

IBD 1 IBD 2 IBD 3 IBD 4 IBD5

IMM

UNE

RESPONSE

ENVIRONMENTAL

FACTORS TREATMENT

GENET

IC

SUSC

EPTIB

ILITY

HOST GENETICS

GENE EXPRESSION

MICROBIOMESMOKING

DIET

INNATE RESPONSE

PHARMACOGENOMICS

SURGERY

BIOLOGICS

STRESSNSAIDS

ADHERENCE

ADAPTIVE RESPONSE

IBD patients may have unique signatures that predict complicated or treatment refractory disease

FAMILY HISTORY

Large bowel Small bowelIBD

SEROLOGICAL RESPONSE

Clinical features: age, location, endoscopy, histology, etc.

MONITORING

IBD: Therapeutic Themes

• Correct diagnosis!• Induction therapies• Maintenance therapies• “Step in” is better than “step up”• Optimization of therapy• Treat the whole patient







28%21%

39%

51%

0%

20%

40%

60%

80%

100%

Week 30 Response Week 30 Remission

28%

17%

54%

40%

0%

20%

40%

60%

80%

100%


29%36%

48%

63%

0%

20%

40%

60%

80%

100%


30%37%

55%

67%

0%

20%

40%

60%

80%

100%


Infliximab Week 2 RespondersACCENT 1

Adalimumab Week 4 RespondersCHARM

Certolizumab Week 6 RespondersPRECiSE 2

Natalizumab Week 10 RespondersENACT-2

Placebo

Infliximab Adalimumab

Placebo eow

Placebo

Certolizumab

Placebo

Natalizumab

Pa

tien

ts (

%)

Pa

tien

ts (

%)

Pa

tien

ts (

%)

Pa

tien

ts (

%)

Adapted from Hanauer SB et al. Lancet. 2002;359(9317):1541-1549 (ACCENT 1), Colombel J-F et al. Gastroenterology. 2007;132(1):52-65 (CHARM), Schreiber S et al. N Engl J Med. 2007;357(3):239-250 (PRECiSE 2), and Sandborn WJ et al. N Engl J Med 2005;353:1912-1925 (ENACT-2)..

28%21%

39%

51%

0%

20%

40%

60%

80%

100%


28%

17%

54%

40%

0%

20%

40%

60%

80%

100%


29%36%

48%

63%

0%

20%

40%

60%

80%

100%


30%37%

55%

67%

0%

20%

40%

60%

80%

100%


Infliximab Week 2 RespondersACCENT 1

Adalimumab Week 4 RespondersCHARM

Certolizumab Week 6 RespondersPRECiSE 2

Natalizumab Week 10 RespondersENACT-2

Placebo

Infliximab Adalimumab

Placebo eow

Placebo

Certolizumab

Placebo

Natalizumab

Pa

tien

ts (

%)

Pa

tien

ts (

%)

Pa

tien

ts (

%)

Pa

tien

ts (

%)

Adapted from Hanauer SB et al. Lancet. 2002;359(9317):1541-1549 (ACCENT 1), Colombel J-F et al. Gastroenterology. 2007;132(1):52-65 (CHARM), Schreiber S et al. N Engl J Med. 2007;357(3):239-250 (PRECiSE 2), and Sandborn WJ et al. N Engl J Med 2005;353:1912-1925 (ENACT-2)..


• Correct diagnosis!• Induction therapies• Maintenance therapies• “Step in” is better than “step up”• Optimization of therapy• Treat the whole patient:

– The best combination therapy!


• Correct diagnosis!• Induction therapies• Maintenance therapies• “Step in” is better than “step up”• Optimization of therapy• Treat the whole patient:

– The best combination therapy!– Start with how we speak

Predicting Response tO

STandardized PEdiatric Colitis Therapy

1U01 DK 095745-01

Disease Location at BaselineN=379 Enrolled with UC

LocationAssessed

Out of N=379

MacroscopicDisease

Microscopic Disease

onlyCecum 343(90.5%) 232(67.6%) 26(7.6%)Ascending Colon 347(91.6%) 233(67.1%) 35 (10.1%)Transverse Colon 354(93.4%) 287(81.1%) 17(4.8%)Descending Colon 371(97.9%) 343(92.5%) 8(2.2%)Sigmoid 376(99.2%) 372(98.9%) 1(0.3%)Rectum 376(99.2%) 373(99.2%) 3(0.8%)

Non-Classical Features at Diagnosis N=379 Enrolled with UC

Non-classical Feature %Relative rectal sparing 33(8.7%)Macroscopic patchiness 35(9.2%)Periappendiceal inflammation 27(7.1%)Backwash ileitis 28(7.4%)Microscopic gastritis 212(55.9%)Non-spec macro gastritis 102(26.9%)

Diagnosis of UC

MildPUCAI 10-34

Moderate/SeverePUCAI 35-64

Severe/Fulminant ≥65

Pathway A: Mesalamine

Response No Response

Remission Flare

Pathway B: PO Steroids

Response No Response

Pathway CAdd Mesalamine

WeanPrednisone

Remission

MaintainanceMesalamine

C.I. Anti-TNF

Flare: Early (<6 mon)Late (≥ 6 mon)

IM/Anti-TNF

Hospital

Pathway D: IV Steroids

Response≤14 days

No Response

C.I. Anti-TNF

S

Flare5-ASA intolerance1

StopMesalamine

C.I. = calcineurin inhibitorAnti-TNF = anti-TNFαIM = ImmunomodulatorS= Surgery(1) Paradoxical worsening with mesalamine

IM/Anti-TNFMaintenance

MaintainanceMesalamine

Early

Late

Pathway F

Pathway G

Pathway E

Initial Therapy By PUCAI:Need to “Right Fit”

2 patients with UC did not receive medical therapy. One had a colectomy and one decided to treat UC with diet.2 patients had missing data2 received both Pentasa and steroids at time 0

Baseline PUCAI Pentasa Oral Steroids

IV Steroids

Mild (n=90) 78 (87%) 9 (10%) 2 (2.0%)

Moderate (n=164) 48 (29%) 81 (49%) 30 (18%)

Severe (n=119) 2 (2%) 33 (28%) 81 (68%)

n=379




IV Steroids

Mild (n=90) 78 (87%) 9 (10%) 2 (2.0%)

Moderate (n=164) 48 (29%) 81 (49%) 30 (18%)

Severe (n=119) 2 (2%) 33 (28%) 81 (68%)

n=379




IV Steroids

Mild (n=90) 78 (87%) 9 (10%) 2 (2.0%)

Moderate (n=164) 48 (29%) 81 (49%) 30 (18%)

Severe (n=119) 2 (2%) 33 (28%) 81 (68%)

n=379

24022821620419218016815614413212010896847260483624120

0

10

20

30

40

50

60

70

80

90

100

Cu

mu

lati

ve P

rob

abil

ity

(%)

Patients at risk: Months2002 552 229 95 37N =

Penetrating

Cosnes J et al. Inflamm Bowel Dis. 2002;8:244-250.

High Potential Low Potential

InflammatoryStructuring

Impact of Therapy Depends on Degree of Structural Damage and Velocity of Progression

Slide Courtesy of the GI Health Foundation

Consensus Predictors of Poor Outcome*

• Deep colonic ulcerations on endoscopy • Persistent severe disease despite adequate induction

therapy • Extensive (pan-enteric) disease • Marked growth retardation (> -2.5 height Z scores), • Severe osteoporosis • Stricturing or penetrating disease (B2 and/or B3

disease behavior) at onset • Severe perianal disease

*Ruemmele et al. J Crohn’s Colitis ECCO/ESPGHAN Working Group 2014;8:1179

Optimizing Outcomes:TREAT TO TARGET:

• Regular assessment of disease activity using objective clinical and biologic outcome measures

• Adjust treatment if not accomplishing the goal

• Enables better outcomes in RA, hypertension, diabetes, hypercholesterolemia

Bouguen, Clin Gastroenterol Hepatol ePub 2013 Sep 10, PMID 24036054

LOSS OF RESPONSE TO ANTI-TNF THERAPIES: “GIST”

Ben-Horin, Aliment Pharmacol Ther 2011;33:987

Strategies to Optimize Durable Biologic Response

• Regularly scheduled maintenance• Concomitant immunomodulator

– ?duration

• Monitoring drug/antibody levels– “treat to trough”

Proactive Testing in Pediatric IBD:Week 14 IFX Levels and Outcomes

Week 54 Outcome (Yes v. No) Median IFX Level (ug/mL)

Persistent Remission 4.7 versus 2.6*

Clinical Remission 3.2 versus 2.2

Clinical & Laboratory Remission 4.2 versus 3.0

Sustained Durable RemissionWeek 14 to 54

5.5 versus 3.1*

Sustained Durable RemissionWeek 22 to 54

5.1 versus 3.0*

(n=58)

* p<0.05 Singh et al. Inflamm Bowl Disease 2014;20:1708

IS MUCOSAL HEALING ACHIEVABLE?

Bouguen, Clin Gastroenterol Hepatol 2014;12:978-85.



67 CD patients underwent 161 endoscopies

Summary:Inflammatory Bowel Diseases

• Chronic intestinal inflammation from a dysregulated immune response to the enteric microbiome in a genetically predisposed host

• A family of diseases currently simplified to two umbrella terms: Crohn’s disease and ulcerative colitis

• Accurate diagnosis and staging requires clinical suspicion and appropriate confirmatory testing.

Summary:Inflammatory Bowel Diseases

• Pyramid approach does not change the natural history and disabling outcomes of surgery, hospitalization, lowered QOL.

• Personalized approach of Risk stratification and “treat to target” are emerging as best practices.

• Therapeutic drug monitoring and optimization of therapy are critically important goals in the biologic era.

• Treatment of the whole patient will result in best overall outcomes.

Backup Slides

RISK Study: The Microbiome shifts in pediatric Crohn’s disease: Decreased diversity, losses and gains

Microbiome was profiled in 800 RISK subjects

enrolled at 28 pediatric centers in US/CAN

500 cases + 300 controls

Gevers et al. Cell Host Micro 2014;15:382

The relative goodness of fit of the models, P <0.0043 Clinical variables only Clinical, expression and microbialC statistics (AUC) 0.705 0.760

A multi’omic model is superior in predicting surgery and steroid free remission in comparison to clinical factors alone.

Multiple regression analysis including clinical, gene expression, and microbial variables. p-value OR CIAge≥10 vs. <10 0.8868 0.944 0.430, 2.075Ileal DU vs. no DU

PCDAI>30 0.6244 0.771 0.271, 2.188PCDAI≤30 0.0029 4.713 1.701, 13.057

Anti-TNF therapy 0.0020 5.181 1.828, 14.706APOA1 expression level > 80th percentile 0.0152 3.058 1.241, 7.576

Blautia Abundant (>70th percentile) vs non-abundant

Veillonella abundant 0.5183 1.634 0.368, 7.25Veillonella non-abundant 0.0028 0.231 0.089,0.604

Haberman et al JCI 2014PRO-KIIDS RISK Study

0

20

40

60

80

100

Perc

ent o

f pati

ents

(%)

AZA + placebo IFX + placebo IFX+ AZA

p<0.001

p=0.025 p=0.002

SONIC: Steroid Free Remission

48/170 67/169 94/169

28.2

39.6

55.6

All Randomized Patients (N=508)*

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

Vedolizumab: Primary Maintenance Endpoint For Adult Crohn’s Disease

Clinical Remission0%

5%

10%

15%

20%

25%

30%

35%

40%

22%

39%

36%

VDZ / VDZ Q8w (n=154)VDZ / VDZ Q4w (n=154)

VDZ / Placebo (n=153)p<0.01

=17%

=15%

Patients %

(95% CI)

p<0.001

Predictors of Disabling Crohn’s

• Initial requirement for steroidsOR: 3.1 [95% CI: 2.2 – 4.4]

• Age at diagnosis below 40OR: 2.1 [95% CI: 1.3 – 3.6]

• Perianal disease at diagnosisOR: 1.8 [95% CI: 1.2 – 2.8]

Referred cohort of 1128 CD patients 3 factors independently predictive

disabling CD course within 5-year

Beaugerie L et al. Gastroenterology 2006;130:650-6

Progressive Bowel Damage in CD

Pariente et al. Inflamm Bowel Dis 2011

ProactiveEffective Medical Therapy

Reactive Maximal Medical Therapy

Early Surgery

Physical & Psychosocial Growth & Development

What you see onthe outside does not always indicatewhat is going oninside

Months

No

lo

ss o

f re

sp

on

se

100

80

60

40

20

00 12 24 36 48

Loss of Response After Immunomodulator Withdrawal

TL=trough levelsDrobne D et al. DDW 2011; Abstract 279

Loss of Response after Immunomodulator Withdrawal

TL detectable & CRP <5 mg/L

TL detectable & CRP >5 mg/L

TL undetectable & CRP >5 mg/L

Slide Courtesy of the GI Health Foundation


HR 2.35 (95%CI 1.15-4.97) HR 4.28 (95%CI 1.9-11.5)


SUGGESTED ALGORITHM

Bouguen, Clin Gastroenterol Hepatol ePub 2013 Sep 10, PMID 24036054

IBD:Management Goals

Relievesymptoms

Treat inflammation

Treatcomplications

Address psychosocial

issues

Identify dysplasiaand detect

cancerImprove daily

functioning

Replenish nutritional

deficits

Minimize treatment toxicity

Maintain remission

EstablishDiagnosisEstablishDiagnosis

Documents

Induction and Maintenance Therapies: Lessons from PROTECT Joel R. Rosh, MD Director, Pediatric Gastroenterology Goryeb Children's Hospital/Atlantic Health