OCTOBER 23-28

Tailored Therapy for Patients with Refractory IBD

Marla Dubinsky, MDProfessor of Pediatrics and Medicine

Chief Pediatric GI and NutritionMount Sinai Kravis Children’s Hospital

Co-Director, Susan and Leonard Feinstein IBD Clinical CenterIcahn School of Medicine, Mount Sinai New York

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Disclosures

• Consulting Fees: Abbvie, Arena, BMS, Boehringer Ingelheim, Celgene, Genentech Roche, Gilead, Janssen, Lilly, Pfizer, Prometheus Biosciences, Takeda, Target PharmaSolutions

• Research Funding: Abbvie, Janssen, Pfizer, Prometheus Biosciences

• Co-Founder: Cornerstones Health, Mi-Test Health LLC, Trellus Health

• MiTest Health, LLC has a patent pending for a “System and Method of Communicating Predicted Medical Outcomes”, filed 3/34/10.

• Shareholder: Trellus Health

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How will we break through the efficacy plateau?

• Predictive biomarkers to select the right drug for the right patient (personalized medicine)

• Sequencing strategies

• Combinations of therapies that are at least additive in effect, or preferably synergistic

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Find the Right Drug for the Right Person

Current Paradigm: One Treatment Fits All

Personalized Paradigm: Using Biomarkers to Guide Diagnosis and Therapy

Therapy

Effect No Effect Adverse Effects Effect

Therapy

Biomarkers

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No association of IL23R in rheumatoid arthritis

Cho and Feldmann, Nature Medicine 2015; 730

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Biomarker Predictors of Anti-TNF Response

• OSM is cytokine in IL-6 family increased in IBD patients

• OSM and OMS receptor (OSMR) expression increased in colon biopsies of patients who did not respond to anti-TNF

• Used 5 datasets, overall n =22

• Combination of endoscopic and clinical definitions

West N et al Nat Med 2017

ROC curves for mucosal healing

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IBD CD UC

30

20

10

0RNR

% o

f α

4β7

po

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ve c

ells

/HP

F

30

20

10

0RNR

% o

f α

4β7

po

siti

ve c

ells

/HP

F

Intestinal α4β7 expression predicts therapeutic response to VDZ

CD, Crohn’s disease; HPF, high power field; IBD, inflammatory bowel disease; NR, non-remitters; R, remitters; UC, ulcerative colitis

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OCTOBER 23-28

Fundamental Principles in Choosing the Right Therapy

• Disease activity vs Disease Severity

• Risk stratification based on prognostic factors

• Match therapy with prognosis/severity not only activity

• Treat to target the mucosa and PRO (urgency and emotional well being)

• Maintain tight control with biomarkers

• Special populations need to be considered (EIM, elderly, pregnancy)

• Proactive care is superior to reactive care

• Need for speed: rapidity of response

• Sequence does matter http

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THE CD Story

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Comparative Efficacy of CD TherapiesNguyen et al. Clin Gastroenterol Hepatol 2020;18:1268–1279

Singh S et al. Aliment Pharmacol Ther 2018;48:394–409..

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SERENE-CD study design

*Stratification factors for randomization: hs-CRP at BL (300). †Mandatory corticosteroids taper at Week 4. aSES-CD excluding the narrowing component. ADA, adalimumab; BL, baseline; CDAI, Clinical Disease Activity Index; hs-CRP, high sensitivity C-reactive protein; Pts, patients; IFX, infliximab; SES-CD, Simplified Endoscopic Score for Crohn’s Disease; TDM, therapeutic drug monitoring

Main Inclusion Criteria:

• Adult patients: 18–75 years

• Moderate to severe CD:

• CDAI 220–450

• Centrally read endoscopic evidence of mucosal inflammation; SES-CDa ≥6 (≥4 for pts with isolated ileal disease)

• Bio-naïve, or IFX failure/intolerant (≤25%)

SCREENING

44 weeks

Week 2 12

Clinically adjusted regimen

4† 56

ADA TDMHigher (n=308)

Standard (n=206)

1 48

Double-blindinduction study

Double-blindmaintenance study

PBO

3 5 6

160mg

80mg

40mg

40mg

160mg

160mg

160mg

160mg

40mg

40mg

ADA

-4

RA

ND

OM

IZA

TIO

N (

2:3

)

RE-

RA

ND

OM

IZA

TIO

N

Co-primary endpointsClinical remission at Week 4

Endoscopic response at Week 12

0*

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Co-primary efficacy endpoints

ITT analysis set. aAdjusted by stratification factors. Non-responder imputation (NRI).Central reviewer scoring of endoscopy results was used for all efficacy assessments

43.739.3

43.5 42.9

0

10

20

30

40

50

60

70

80

90

100

90/206 134/308

Pati

ents

(%

)

81/206 132/308

p=1.000

∆ = –0.3a

p=0.509

∆ = 3.2a

Clinical remission at Week 4CDAI 50% SES-CD from BL

(or if BL SES-CD =4, ≥2-point reduction from BL)

Standard induction

dosing

Higher induction

dosing

Standard induction

dosing

Higher induction

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Vedolizumab Efficacy is Decreased in Anti-TNFα Exposed CD Patients

Sands BE, et al. Inflamm Bowel Dis. 2017;1:97-106. Adapted from Figure 1.

Clinical remission: CDAI score of ≤150.Δ, difference; CD, Crohn’s disease; PBO, placebo; TNFα, tumor necrosis factor alpha; VDZ, vedolizumab.

CD (GEMINI 2)

10.6

26.8

9.717.1

22.7

51.5

13.3

29.5

0

25

50

75

100

Clinical RemissionWeek 6

Clinical RemissionWeek 52

Clinical RemissionWeek 6

Clinical RemissionWeek 52

Pro

po

rtio

n o

f p

ati

en

ts (

%)

PBO VDZ

Δ=24.7

Clinical remission outcomes for VDZ therapy (week 6 and 52)

Anti-TNFα naïve Anti-TNFα exposed

Δ=12.1 Δ=3.6 Δ=12.4

Confidential – Slides Available Upon Unsolicited Request

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Ustekinumab Clinical Efficacy is Decreased in Anti-TNFαExposed CD Patients

Feagan BG et al. N Engl J Med. 2016 Nov 17;375(20):1946-1960.

Clinical remission: CDAI score of ≤150. CDAI-100 response: ≥100-point decrease from baseline in the CDAI score.CD, Crohn’s disease; CDAI, Crohn’s Disease Activity Index; PBO, placebo; TNFα, tumor necrosis factor alpha; UST, ustekinumab.

CD (UNITI 1 & 2)

19.6

28.7

7.3

21.5

40.2

55.5

20.9

33.7

0

20

40

60

80

100

Clinical Remission Clinical Response Clinical Remission Clinical Response

Pro

po

rtio

n o

f p

ati

en

ts (

%)

PBO UST (6 mg/kg)

Δ=26.8Δ=20.6 Δ=13.6 Δ=12.2

Efficacy outcomes for UST induction therapy (week 6 & 8)

UNITI-2(Predominantly anti-TNFα naïve population)

UNITI-1(anti-TNFα refractory population)

Confidential – Slides Available Upon Unsolicited Request

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Nguyen et al. Clin Gastroenterol Hepatol 2020;18:1268–1279.

Positioning therapies in Crohn’s disease

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Figure 1

Gastroenterology 2018 155687-695.e10DOI: (10.1053/j.gastro.2018.05.039)

Predicting Vedolizumab Responsiveness in CD

Dulai P et al Gastroenterol 2018 155 687-695

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THE UC STORY

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Adalimumab’s Efficacy is Decreased in Infliximab Exposed Patients

Sandborn et al. Gastroenterology. 2012;142:257-65

21.3

59.3

22.0

36.7

9.2

36.7

10.2

20.4

0

20

40

60

80

100

Clinical Remission Clinical Response Clinical Remission Clinical Response

Pro

po

rtio

n o

f p

ati

en

ts (

%)

Anti-TNF Naïve Anti-TNF Exposed

Week 8 Week 52

UC (ULTRA II)

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SERENE-UC: High Dose induction and Weekly Adalimumab Maintenance

ADA, adalimumab; TDM, therapeutic drug monitoring; EW, every week; EOW, every other week

Randomized, Double-Blind, Multicenter Study

Safety: No significant difference in safety profiles between 40mg EW and 40mg EOW

Clinical remission at week 52 among week 8 responders (Main study + Japan study)

8 Week Induction Phase

Higher (N=512)160mg W0,W1,2&3, then 40mg W4&6

Standard (N=340)

ADA 40mg EW (N=175)

ADA 40mg EOW (N=163)

ADA with TDM (N=74)

Re-Randomized2:2:1

Primary Endpoint44 Week Maintenance Study, ITT N=412

(including Japan study)

Clinical remission

(Mayo≤2, no subscore>1)

Colombel JF, et al. Presented at DDW. May 2020. Abstract 945.

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Vedolizumab Efficacy is Decreased in Anti-TNFα Exposed Patients

Feagan B, et al. Clin Gastroenterol Hepatol. 2018 May 29. pii: S1542-3565(18)30558-5

a % Diff from PBO=adjusted mean % change from baseline for VDZ – adjusted mean % change from baseline for PBO. *Lower limits of 95% CI >0 indicate statistical significance at a nominal significance level of 0.05 and are shown in bold.Abbreviations: CI, confidence interval; diff; nominal difference; PBO, placebo; RBS, rectal bleeding subscore; SFS, stool frequency subscore; TNF, tumor necrosis factor antagonist; UC, VDZ, vedolizumab.

Proportion of patients who achieved Stool Frequency Subscore ≤1 and Rectal Bleeding Subscore =0

UC (GEMINI 1)http

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CI, confidence interval; IV, intravenous; SC, subcutaneous; TNF, tumour necrosis factor; UC, ulcerative colitis.

Clinical remission: Complete Mayo score of ≤2 and no individual subscore >1.

Data from full analysis set, which includes all randomised patients who received at least 1 dose of study drug.

*Anti-TNF subgroup analysis was prespecified and produced nominal p values.

Sands BE, et al. N Engl J Med 2019;381:1215-26.725.

VARSITY: Vedolizumab superior to adalimumab in achieving clinical remission in overall and anti-TNF-naïve UC populations at Week 52

31.334.2

20.322.524.3

16.0

0

20

40

60

p=0.006

Overall

Primary Endpoint

Anti-TNF Naïve Anti-TNF Exposure/Failure

383 305304 8179386

Pat

ien

ts, %

Subgroup Analysis*

Adalimumab SC 40 mg Q2WVedolizumab IV 300 mg Q8W

N=

∆ = 8.8%(95% CI: 2.5%, 15.0%)

∆ = 9.9%(95% CI: 2.8%, 17.1%)

∆ = 4.2%(95% CI: −7.8%, 16.2%)

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Tofacitinib Efficacy is not Decreased in Anti-TNFα Exposed Patients

Sandborn WJ, et al. N Engl J Med 2017; 376:1723–1736 (supplement)

Clinical remission: a total Mayo score of ≤2, with no subscore >1 and a rectal bleeding subscore of 0. Mucosal healing: a Mayo endoscopic subscore of ≤1.PBO, placebo; TNFα, tumor necrosis factor alpha; TOF, tofacitinib.

UC (OCTAVE 1 & 2)

12.5

23.1

0.86.2

23.7

38.1

11.4

23.0

0

20

40

60

80

100

Clinical Remission Mucosal Healing Clinical Remission Mucosal Healing

Pro

po

rtio

n o

f p

ati

en

ts (

%)

Δ=15.0Δ=11.2 Δ=10.6 Δ=16.8

Efficacy outcomes for TOF induction therapy (week 6) ITT population

Anti-TNFα naïve Anti-TNFα exposed

TOFPlacebo TOFPlacebo

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Ustekinumab Efficacy is not Decreased in Biologic-Failure Patients

Clinical remission: Mayo score ≤ 2 points with no individual subscore > 1. Clinical response: Decrease from baseline in the Mayo score by ≥30% and ≥3 points with either a decrease from baseline rectal bleeding subscore ≥1 or a rectal bleeding subscore of 0 or 1. Endoscopic Improvement: Mayo endoscopic subscore of 0 or 1 (by central review).

UC (UNIFI)

9.9

35.8

21.2

1.2

27.3

6.8

18.4

66.7

33.3

12.7

57.2

21.1

0

25

50

75

100

ClinicalRemission

ClinicalResponse

EndoscopicImprovement

ClinicalRemission

ClinicalResponse

EndoscopicImprovement

Pro

po

rtio

n o

f p

ati

en

ts (

%)

PBO

UST (6 mg/kg)Δ=30.9Δ=8.5 Δ=11.5 Δ=14.3

Efficacy outcomes for UST induction therapy (week 8)

Biologic-Naive Biologic-Failure

Δ=12.1 Δ=29.9

Sands B et al NEJM 2019 Sep 26;381(13):1201-1214

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0.49

0.56

0.76

0.41

0.32

0.95

0.42

0.47

0.63

0.68

0.35

0.95

Ustekinumab

Tofacitinib

Vedolizumab

Golimumab

Adalimumab

Infliximab

0.83

0.91

0.34

0.26

0.87

0.87

0.48

0.15

Ustekinumab

Tofacitinib

Vedolizumab

Adalimumab

Endoscopic Remission Clinical Remission

Sequencing of Induction Therapy for Patients with Moderately-to-Severely Active UC

Singh S et al. Clin Gastroenterol Hepatol. 2020;18(10):2179-2191.e6.

Biologic-naïve Prior Anti-TNF exposure

-

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Cumulative rates of Tx persistence, clinical response and clinical remission in the 2L cohort were similar to rates observed in the 1L anti-TNFα cohort

76.6

57.1

19.6

90.0

43.536.2

79.5

61.1

14.7

92.2

74.8 74.6

0

20

40

60

80

100

Tx Persistence Tx ClinicalResponse

Tx ClinicalRemission

Tx Persistence Tx ClinicalResponse

Tx ClinicalRemission

Cu

mu

lati

ve R

ate

(%)

1L 2L

UC CD

Second-Line Anti-TNFα: Efficacy at 6 Months

Unadjusted p-values compare the 2L and 1L cohorts using the log-rank test.

Bressler et al. Am J Gastroenterol. 2019;114:S373

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Entyvio pre and post TNF in Children

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Ustekinumab Remission Rates in Pediatric IBD

Dayan J et al JPGN 2019;69:61-67

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Durability of Ustekinumab

Dayan J et al JPGN 2019;69:61-67

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Tofacitinib Experience in Treatment Pediatric IBD

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Is Combination Therapy the Solution for Refractory Pediatric IBD

PatientPrevious Biologic

Exposures

Biologic or JAK Inhibitor Immediately Prior to

DT

Days on Previous Biologic or JAK Inhibitor Prior to

DTReason for initiation of DT DT

CD1 IFX TOFA 53 Partial Response TOFA/VDZ

CD2 ADA, IFX, UST VDZ 329 Worsening Enthesitis VDZ/TOFA

CD3 IFX UST 588 Partial Response UST/VDZ

CD4 IFX UST 498 Partial Response UST/VDZ

CD5 IFX, ADA, UST, GOL VDZ 142 Partial Response VDZ/TOFA

CD6 ADA, IFX, UST TOFA 263 Partial Response TOFA/VDZ

CD7 IFX UST 334 Persistent endoscopic inflammation UST/VDZ

UC1 IFX, VDZ UST 151 Partial Response UST/TOFA

UC2 VDZ, IFX IFX N/A No Response VDZ/TOFA

UC3 IFX, VDZ TOFA 347 Partial Response TOFA/UST

UC4 IFX, VDZ TOFA 193 Partial Response TOFA/VDZ

UC5 IFX VDZ 1016 Persistent Endoscopic Inflammation VDZ/TOFA

UC6 IFX VDZ 641 Partial Response VDZ/TOFA

UC7 IFX, VDZ, TOFA UST 272 Partial Response UST/TOFA

UC8 IFX UST 355 Persistent Endoscopic Inflammation UST/VDZ

IBD-U1 IFX (twice), UST TOFA 92 Partial Response TOFA/VDZ

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Outcomes of Combination Therapy In Pediatric IBD

Diagnosis Number of Patients Dual TherapySteroid-Free Clinical

Remission, n (%)

CD 3 Vedolizumab/Ustekinumab 2 (66.7)

4 Vedolizumab/Tofacitinib 3 (50)

UC/IBD-U 3 Ustekinumab/Tofacitinib 2 (66.7)

5 Vedolizumab/Tofacitinib 3 (60)

1 Vedolizumab/Ustekinumab 1 (100)

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Specific Scenarios for Choice of First IBD Therapy

Modifier First drug consideration Reason

Psoriasis Ustekinumab or anti-TNF On label

>60 yo VedolizumabOlder patients have higher risk of

infections

SynovitisArthritis

Anti-TNF or Tofacitinib On label

Low albumin, high BMI, High CRPTofacitinib

Cyclosporine, TacrolimusNon-protein-based therapies (not a

biologic)

Need for speedInfliximabtofacitinib

Rapidity of onset

PreconceptionAnti-TNF, vedolizumab,

ustekinumabEstablished safety and not cross placenta

in 1st trimester

Combination therapy contraindicated

Vedolizumab, Ustekinumabtofacitinib

No benefit for combination therapy over monotherapyht

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Reasons to Switch Therapies and What to Choose

Modifier First drug consideration Reason

1st Anti-TNF failure Ustekinumab and tofacitinibResponse less impacted by

anti-TNF failure

Anti-TNF-induced lupoid reaction Non-anti-TNFNot reported with non-anti-

TNF drugs

Anti-drug antibody to first anti-TNFWithin class or out of class

(vedolizumab, ustekinumab)High likelihood of ADA to

second anti-TNF

Joint pain+ vedolizumabAnti-TNF

TofacitinibOn label

Anti-TNF-induced psoriasis or palmar plantar pustulosis

UstekinumabTofacitinib

Vedolizumab

On labelNot reportedCase Reports1

Cancer (solid tumor)None during Chemo

VedolizumabUstekinumab

Safetyht

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OCTOBER 23-28

Summary of Tailoring and Positioning IBD Therapies

• Patients prioritize symptom control and safety

• Symptom control not the preferred target

• Patient segmentation can help with positioning

• Sequencing does matter especially if failed anti-TNF

• Combination or Dual Biologics may be the key

• Future targets will need to establish their position based on anti-TNF failure data as well as safety

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