new medications in ibd: what’s coming?

11/2/14

Crohn's & Colitis Foundation of America

- For Educational Purposes Only 1

New Medications In IBD: What’s Coming?

Barrett G. Levesque MD

Inflammatory Bowel Disease Center

University of California, San Diego

La Jolla, California

DISCLOSURES

BG Levesque has received consulting fees from Santarus Inc,

Prometheus Labs, Abbvie, Takeda, and Nestle Health Sciences

2

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3

What is our target What is our target What is our target What is our target

if we want to prevent disease progression ?if we want to prevent disease progression ?if we want to prevent disease progression ?if we want to prevent disease progression ?

4

SYMPTOMSSYMPTOMSSYMPTOMSSYMPTOMS

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SYMPTOMS

X-

SECTIONAL/TRANSMURAL

ACTIVITY

HISTOLOGICAL ACTIVITY

BIOLOGIC ACTIVITY

• CRP

• Fecal Calprotectin

ENDOSCOPIC ACTIVITY

What is our target if we want to prevent disease progression ?What is our target if we want to prevent disease progression ?What is our target if we want to prevent disease progression ?What is our target if we want to prevent disease progression ?

Mucosal Healing Relevance ?

6

Normal Mild

Moderate Severe

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Endoscopic healing Endoscopic healing ---- ACCENT IACCENT I

Week 0 Week 10 Week 54

Following induction

regimen (IFX 5 mg/kg)

at weeks 0, 2, and 6

Following infusions (IFX 5 mg/kg)

every 8 weeks after

induction regimen

Baseline

Efficacy

IN04616

Surgery Rates at 10 years by Mucosal Healing Status One Year After Diagnosis

Crohn’’’’s diseaseUlcerative colitis

Pro

po

rtio

n o

f C

D P

ati

en

tsR

esecte

d

Pro

po

rtio

n o

f U

C P

ati

en

ts

Co

lecto

mis

ed

HR 0.34 (0.14-0.86) p<0.02 HR 0.42 (0.20-0.89) p=0.027

Solberg IC, et al. Scand J Gastroenterol. 2009; 44:431-40

Solberg IC, et al. Clin Gastroenterol Hepatol. 2007; 5:1430-8

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PREDEFINED TIMEFRAME PREDEFINED TIMEFRAME

BASELINE ASSESSMENTBASELINE ASSESSMENT

CONTINUE THERAPY

TARGET SURVEILLANCE

TARGET

HIGH

RIS

K O

F

PR

OG

RE

SS

IO

N

LOW

TARGE

T

THERAPY ACCORDING

TO RISK AND TARGET

CONTROL OF

INTESTINAL

INFLAMMATI

ON

AV

OID

AN

CE

OF

LO

NG

-TE

RM

BO

WE

LD

AM

AG

E

AN

DS

UB

SE

QU

EN

TD

ISA

BIL

ITY

ASSESSMENTASSESSMENT ASSESSMENTASSESSMENT

Bouguen G, Levesque BG et al. Clin Gastroenterol Hepatol, 2013.

OPTIMIZEOPTIMIZEOPTIMIZEOPTIMIZE

10

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Time to Initiation of Treatments

perc

ent

perc

ent

perc

ent

perc

ent

P=0.78

ECI 21.0%

CM 21.2%

A Corticosteroids B Antimetabolitesa

ECI 26.7%P<0.001

CM 15.6%

C TNF-Antagonistsb

ECI 27.4%

CM 17.4%

P<0.001

D Combination Therapy with Antimetabolites and TNF-Antagonists

ECI 19.7%

CM 9.6%

P<0.001

HR = 0.97 (0.77, 1.21) HR = 1.84 (1.39, 2.44)

HR = 1.72 (1.34, 2.22)

HR = 2.29 (1.73, 3.04)

Early Combined

Immunosuppression

Conventional

Management

%

Khanna, Levesque, Feagan ECCO 2014

perc

ent

perc

ent

perc

ent

perc

ent

CM 9.5%

ECI 6.6%

P = 0.03

SurgeryA B Serious Complication

P<0.001

CM 30.9%

ECI 24.3%

C Hospitalization

CM 15.6%

ECI 12.9%

P = 0.16

D Hospitalization, Surgery or Serious Disease-Related Complication

CM 34.7%

ECI 27.4%P<0.001

HR = 0.69 (0.50, 0.97)

HR = 0.84 (0.65,1.08)

HR = 0.73 (0.61, 0.87)

HR = 0.73 (0.62, 0.86)

Conventional

Management

Early Combined

Immunosuppression

Proportion of Patients with Major Adverse Outcomes at 24 Months

%

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Early Combined

Immunosuppression

N (%)

Conventional

Management

N (%)

P Value

Worsening Crohn’s disease

Abscess 32 (3.0) 33 (3.7) 0.36

Fistula 29 (2.7) 39 (4.3) 0.03

Stricture/bowel obstruction 67 (6.2) 82 (9.1) 0.01

Serious worsening disease 98 (9.0) 96 (10.7) 0.65

Serious extra-intestinal

manifestations

47 (4.3) 50 (5.6) 0.37

Serious drug-related

complications

10 (0.9) 10 (1.1) 0.84

Deaths

Cardiovascular 2 (0.2) 5 (0.5)

Thromboembolic 1 (0.1) 1 (0.1)

Cancer 3 (0.3) 2 (0.2)

Infection 1 (0.1) 1 (0.1)

Other 0 (0.0) 1 (0.1)

Total Mortality 7 (0.7) 10 (1.1) 0.33b

Serious Disease and Drug-Related Complications and Mortality

Optimizing TNF Antagonist TherapyEmerging Concepts

• Objective evidence of the presence of inflammation should

drive clinical decision making not the presence of symptoms in

isolation

• Combining antimetabolite therapy and a TNF antagonist results

in optimal efficacy and protects the latter against sensitization

• The pharmacokinetics of TNF antagonists are complex and

therapy should be optimized for individual patients

• Therapeutic drug monitoring is a useful guide for clinical

decision making

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The ACT Studies: Proportions of Patients with Clinical Remission by Serum IFX Concentration

Quartiles

Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4

%

26.3

37.0

43.9

43.1

P=0.0504

P<0.0001

Reinisch W. et al DDW 2012

Colectomy Rate According to the Presence and Absence of a Detectable Trough Serum

Infliximab Concentration

% Colectomy

P<0.001

55

7

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

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37

5563

0

25

50

75

100

AZA (N=76) IFX (N=77) IFX/AZA (N=78)

Fra

cti

on

of

pts

(%

)

UC SUCCESS: Mucosal Healing Week 16

n=38 n=53 n=60

**

* p<0.05 vs. AZA alone

†Mayo endoscopy sub-score 0 or 1

Panaccione et al. ECCO 2011. Abstract OP13

ULTRA 1: Clinical Remission at Week 8

ITT-A3 analysis set (NRI)

Clinical remission: Mayo score ≤2 with no individual subscore >1

0

5

10

15

20

25

30

35

Ma

yo

sc

ore

re

mis

sio

n (

%)

Placebo

N=130

9.2%

ADA 80/40 mg

N=130

10.0%

ADA 160/80 mg

N=130

18.5%

N=390

*p=0.031, ADA 160/80 vs placebo

Reinisch W, et al. Gut, 2011; 60:780-787

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Cyclosporine vs Infliximab in UC

Laharie D. et al. Gastroenterology 2011;140(5;Suppl 1):S112

ULTRA 2: Remission- Weeks 8 and 52

0

5

10

15

20

Cli

nic

al re

mis

sio

n (

%)

Week 8

n=246

9.3%

25

n=248

16.5%

p=0.019

Week 52

n=246

8.5%

n=248

17.3%

p=0.004

Placebo

ADA 160/80/40 mg

ITT analysis set (NRI)

Clinical remission: Mayo score ≤2 with no individual subscore >1

Sandborn WJ, et al. Gastroenterology 10.1053/j.gastro.2011.10.032

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PURSUIT-SC Induction: Clinical Response† at Week 6

Pro

po

rtio

n o

f p

atie

nts

(%

)

Placebo(n=256)

200 mg → 100 mg(n=257)

400 mg → 200 mg(n=258)

**

* p<0.0001 vs. placebo

Randomized Patients in Phase 3 After the Dose Selection

Sandborn WJ et al. DDW 2012

PURSUIT-SC Induction: Secondary Endpoints at Week 6

Pro

po

rtio

n o

f p

atie

nts

(%

)

p<0.0001

‡†

→→

Randomized Patients in Phase 3 After the Dose Selection

Normal/Inactive Mucosal Disease

p<0.0001

p<0.0005

p<0.0001

*p=0.043 vs. placebo

**p<0.001 vs. placebo

* **

†

‡Sandborn WJ et al. DDW 2012

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Recruitment of Neutrophils Into Inflamed Tissue

Van Deventer. Gut. 2002

Endothelial and Leukocyte Adhesion: αααα4 Integrins

ββ11/β/β77α4α4• Leukocyte membrane

glycoproteins

• β1 and β7 subunits

• Interact with endothelial ligands VCAM-1, fibronectin, and MAdCAM-1

• Mediate leukocyte adhesion and trafficking

Springer TA. Cell. 1994;76:301–314. Butcher EC, et al. Science. 1996;272:60-66.

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Clinical Efficacy: 3 Point Improvement in UCSS Score

0

10

20

30

40

50

60

70

Week 6

Placebo 0.5 mg/kg 2.0 mg/kg

33%

57%66%

Overall p=.001

p=.001 p=.010

Feagan et al New Eng J Med 2005

Vedolizumab & Mucosal Healing Through 52 Weeks, ITT Population

%

∆26.1 ∆29.1 ∆32.8 ∆28.5 ∆32.0 ∆36.3 ∆11.8 ∆15.3 ∆17.6 ∆31.4

***

***

**

**

***

*** ***

***

*

***

*P<0.05. **P<0.01. ***P<0.0001

n: 72 70 73

Feagan BG et al New Engl J Med 2013

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Primary and Secondary Outcomes Through 52 Weeks

%

***

***

***

*** ***

***

***

****

*

∆26.1 ∆29.1 ∆32.8 ∆28.5 ∆32.0 ∆36.3 ∆11.8 ∆15.3 ∆17.6 ∆31.4

72 70 73n:

*P<0.05 **P<0.01 ***P<0.0001

Maintenance ITT Population

27 Feagan, NEJM 2013

22.324.8

22.7 24.2

39.2*

46.8†

39.2‡

47.8†

0

10

20

30

40

50

60

Week 6 Week 10 Week 6 Week 10

Vedolizumab Phase 3 Induction Trial in CD CDAI-100 Response

Pati

en

ts, %

*P=0.0011 vs placebo; †P<0.0001 vs placebo; ‡P=0.0002 vs placebo

PBO

VDZ

Overall Population(n=416)

ITT Population

Anti-TNFα Failure Population(n=315)

CDAI-100 Response

Sandborn, NEJM 2014

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Budesonide MMX for Active Ulcerative ColitisClinical and Endoscopic Remission at Week 8

Sandborn WJ, et al. Gastroenterology. 2012;143(5):1218-1226.

Travis S, et al. Gut. 2013;

*Statistically significant (P<0.025)

+Statistically significant (P<0.05)

Remission (%)* *

+

n=103n=109n=89n=124n=123n=121

Cytokine Signaling of Janus Kinase (JAK)

30

Tofacitinib blocks phosphorylation of STAT and downstream activationJAK

α

STA

T

STA

T

mRNA

JAKPP

STA

T

STA

T

P

P

P

β γCytokine

Abstract: 1029156

Cytokine Effects on the immune system

IL-2Stimulate the proliferation and differentiation of Th,

Tc, B, and natural killer (NK) cells

IL-4Induce the differentiation of Th0 to Th2

Induce immunoglobulin switching

IL-7Promote the development, proliferation and survival

of T, B, and NK cells

IL-9 Stimulate intrathymic T cell development

IL-15Promote the proliferation, cytotoxicity and cytokine

production of NK cells

IL-21 Enhance T and B cell function

Ig, immunoglobulin; IL, interleukin; JAK, Janus kinase; NK, natural killer; STAT, signal transducer and activator of transcription; Th, T helper; Tc, cytotoxic T cell

1ADIS. Drugs 2010; 10(4): 271-274; 2Coombs J et al. Ann Rheum Dis 2007; 66: 257; 3Li X et al. Presented at the 15th IIRA Conference, Chantilly, Virginia, September 21-24, 2008; 4Rochman Y et al. Nat Rev Immunol 2009; 9(7): 480-490

� Tofacitinib (CP-690,550) is a novel, small-molecule, oral JAK inhibitor that is being investigated as a targeted immunomodulator for several inflammatory diseases including ulcerative colitis (UC) and Crohn’s disease1,2

� Tofacitinib inhibits JAK1, JAK2, and JAK3 in vitro with functional cellular specificity for JAK1 and JAK3 over JAK2.3 Importantly, tofacitinib directly or indirectly modulates signaling for an important subset of pro-inflammatory cytokines including IL-2, -4, -7, -9, -15, and -214

Courtesy of Dr. William Sandborn

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Rates of Primary and Major Secondary Endpoints at 8 Weeks in the

Modified Intention-to-Treat Population According to Study Group

Sandborn WJ. et al. New Eng J Med. 2012 Aug. In Press

Ustekinumab (Anti-Interleukin 12/23 p40) for Active

Crohn’s Disease: Clinical Response at Week 6

Sandborn W. Gastroenterology 2011 Abstract

Number of Subjects in Clinical Remissiona,b at Week 22; Subjects Randomized as Responders to UST Induction

Pro

po

rtio

n o

f S

ub

jects

(%

)

Ustekinumab

p=0.021p=0.057

p=0.005p=0.005

N=132 N=131 N=131N=132 N=394

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Ustekinumab (Anti-Interleukin 12/23 p40) for Active

Crohn’s Disease: Clinical Remission at Week 22

p=0.029

20/73Pro

po

rtio

n o

f S

ub

jects

(%

)Number of Subjects in Clinical Remissiona,b at

Week 22; Subjects Randomized as Responders to UST

Induction

30/72

Sandborn W. Gastroenterology 2011 Abstract

Etrolizumab vs Placebo – Eucalyptus Phase II Randomized Induction Study in Active UC –

Clinical Remission at Wk 10

100 mg 300 mg + LD

PlaceboEtrolizumab

20.5%

10.3%

0%

%

P=0.004

P=0.049

• Humanized monoclonal

antibody to the B7 subunit

of the heterodimeric

integrins α4β7 and αEβ7

in patients with mod-sev

active UC

• N=124

• Randomized to 2 dose

groups vs placebo

Vermiere S. et al. Lancet 2014

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• S1P1R agonism induces receptor

internalization lymphocytes lose

response to S1P gradient

• Become trapped in lymph nodes

causing peripheral lymphopenia

• Upon drug withdrawal receptor

expression is restored and

lymphocytes leave nodes reversing

lymphopenia

Sphingosine 1‐‐‐‐Phosphate Receptor 1 Modulation:Mechanism of Action

Courtesy Dr. Alan Olsen

Anti Smad 7GED-0301

Marafini,

Monteleone,JCCI

2014

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On the Horizon?

• Bacterial Release Oral Anti-TNF Therapy?

• Cow’s Milk Clostrum Oral Anti-TNF therapy?

• Phosphatidyl Choline (oral Therapy) for UC?

• Andrographis Paniculata (oral therapy) For UC?

• Nutritional Therapies?

Conclusions

new medications in ibd: what’s coming?

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