Positioning our recent and future advances in Positioning our recent and future advances in therapies for Crohn’s diseasetherapies for Crohn’s disease

William J. Sandborn, MDWilliam J. Sandborn, MD Professor & Chief, Division of GastroenterologyProfessor & Chief, Division of Gastroenterology Director, UCSD IBD CenterDirector, UCSD IBD Center

Recent and future advancesRecent and future advances

• Azathioprine – new dataAzathioprine – new data• Deep remission and treat to targetDeep remission and treat to target• New agentsNew agents

Mild to moderate diseaseMild to moderate disease

Rifaximin EIRRifaximin EIR

Moderate to severe diseaseModerate to severe disease

Vedolizumab (anti-alpha 4 beta 7)Vedolizumab (anti-alpha 4 beta 7)

Ustekinumab (anti-interleukin 12/23Ustekinumab (anti-interleukin 12/23

Tocilizumab (anti-interleukin 6)Tocilizumab (anti-interleukin 6)

Tofacitinib (Janus Kinase [JAK] inhibitor)Tofacitinib (Janus Kinase [JAK] inhibitor)

Eldelumab (Anti-IP 10)Anti-IP 10)

Top Down Therapy With Azathioprine + Prednisone Versus Top Down Therapy With Azathioprine + Prednisone Versus Step Up Therapy With Prednisone And Then Azathioprine In Step Up Therapy With Prednisone And Then Azathioprine In

Adults With Newly Diagnosed Crohn’s DiseaseAdults With Newly Diagnosed Crohn’s Disease

Cosnes J. Gastroenterology 2013

Top Down Therapy With Azathioprine + Prednisone Top Down Therapy With Azathioprine + Prednisone Versus Prednisone In Adults With Newly Diagnosed Versus Prednisone In Adults With Newly Diagnosed

Crohn’s DiseaseCrohn’s Disease

Panes J. Gastroenterology 2013

Survival free of relapseSustained steroid free remission

Treat-to-Target AlgorithmTreat-to-Target Algorithm

Bouguen G, et al. Clin Gastroenterol Hepatol. 2013 Sep 10. [Epub Ahead of Print]

)

CRP, C-reactive protein.

Rifaximin Extended Intestinal Release for Rifaximin Extended Intestinal Release for Crohn’s Disease: Results at Week 12Crohn’s Disease: Results at Week 12

Prantera C, et al. Gastroenterology 2012

Leucocyte Adhesion

CD 11a/CD18

LEUCOCYTE

CCX282-B

CCR9

CCL-25

ISIS-2302

ICAM-1

NATALIZUMAB

VEDOLIZUMAB

41 (VLA-4)

47

ETROLIZUMAB

VCAM-1MAdCAM-1

MAdCAM mAb (PF-547659)

Therapeutic Targets for Lymphocyte Trafficking

Adapted from Danese S Gut 2011;60:998-1008

ACTIVATED INTESTINAL MICROVASCULAR ENDOTHELIAL CELLS

Vedolizumab: A Humanized, Monoclonal Antibody Vedolizumab: A Humanized, Monoclonal Antibody (mAb) Against (mAb) Against 447 Integrins7 Integrins

• Targets Targets onlyonly a4b7 integrin a4b7 integrin• Created by insertion of ACT-Created by insertion of ACT-

1 CDRs into human IgG1 1 CDRs into human IgG1 framework framework

• Two amino acid substitutions Two amino acid substitutions abrogate Fc-receptor binding abrogate Fc-receptor binding and complement fixation and complement fixation (ADCC)(ADCC)

• IV infusion over 30 – 60 IV infusion over 30 – 60 minutesminutes

N NN N

C C

C C

CH3

CH2

CH1

VH

VL

CL

CDR3

CDR2CDR1

• 185 patients with active Crohn’s disease 185 patients with active Crohn’s disease receiving a stable dose of 5-ASA or receiving a stable dose of 5-ASA or antibiotics or no medical therapyantibiotics or no medical therapy

• Randomized to receive IV doses of Randomized to receive IV doses of placebo, 0.5 mg/kg, or 2.0 mg/kg MLN-placebo, 0.5 mg/kg, or 2.0 mg/kg MLN-02 on days 1 and 2902 on days 1 and 29

• The primary endpoint was % clinical The primary endpoint was % clinical response (decrease in CDAI of response (decrease in CDAI of 770 0 points) at day 57points) at day 57

• Secondary endpoint was % remission Secondary endpoint was % remission (CDAI < 150) at day 57(CDAI < 150) at day 57

• Saturation of Saturation of 447 on peripheral blood 7 on peripheral blood lymphocytes was not consistently lymphocytes was not consistently achievedachieved

P=NSP=0.04

Feagan Clinical Gastroenterology & Hepatology 2008

Vedolizumab For Active Crohn’s DiseaseVedolizumab For Active Crohn’s DiseaseResponse and Remission at Week 8Response and Remission at Week 8

Res

pon

se o

rR

emis

sion

(%

)

Vedolizumab For Active Crohn’s DiseaseVedolizumab For Active Crohn’s DiseaseRemission at Week 8Remission at Week 8

* p-value < 0.05

ITT population

**

*

MLN0002 induced a significantly greater clinical remission rate in patients with Crohn’s disease compared to placebo (2 mg/kg group) at days 15, 29, and 57.Feagan Clinical Gastroenterology & Hepatology 2008

Vedolizumab (Anti-Alpha 4 Beta 7 Integrin) For Moderately-to-Severely Active Crohn’s Disease: Results at Week 6 in 368 Patients

P=0.02

P=0.23

Δ 7.81.2, 14.3

Δ 5.7–3.6, 15.0

95% CI:

Induction ITT Population

Patie

nts,

%

Sandborn W.N Engl J Med 2013

Vedolizumab (Anti- 47 Integrin) For Maintenance of Response in Moderately-to-Severely Active Crohn’s Disease: Results at Week 52 in 461 Patients

Patie

nts,

%

*

*

Δ17.4 Δ14.7 Δ13.4 Δ15.3 Δ7.2 Δ2.0Δ15.9 Δ12.9

*P<0.05 **P<0.01 †CS tapering began in responders at 6 weeks; for others, as soon as a clinical response was achieved.

Maintenance ITT Population

*

**

****

Sandborn W.N Engl J Med 2013

Other Drugs in this ClassOther Drugs in this Class

• Anti-MAdCAM1 (PF-00547,659)Anti-MAdCAM1 (PF-00547,659)• Etrolizumab (anti-Etrolizumab (anti-7, rhumab beta 7)7, rhumab beta 7)• Anti-Anti-7 (AMG181)7 (AMG181)

CD4+

TCR

AntigenPresenting Cell

MHCII

Ag

StimulusTLR?

IFNg(Th1)

p40p35

Biology of Interleukins 12 and 23Biology of Interleukins 12 and 23

IL-12

IL-12R1

2

IL-23

p40p19

IL-17(Th17)IL-23R

IL-12R1

Anti-IL-12/23

Anti-IL-12/23

X

• Ustekinumab and Ustekinumab and briakinumab are fully briakinumab are fully human IgG1 monoclonal human IgG1 monoclonal antibodiesantibodies

• Bind the p40 subunit of Bind the p40 subunit of human IL-12/23human IL-12/23

• Prevent IL-12 and IL-23 Prevent IL-12 and IL-23 from binding IL-12Rb1from binding IL-12Rb1

• Normalize IL-12 and IL-Normalize IL-12 and IL-23 mediated signaling, 23 mediated signaling, cellular activation, and cellular activation, and cytokine productioncytokine production

• In development in In development in Crohn’s disease and Crohn’s disease and psoriasispsoriasis

Anti-IL-12/23Anti-IL-12/23

Ustekinumab (anti-IL 12/23p40) for Induction of Clinical Response in Moderate to Severe Crohn’s Disease

Sandborn WJ. Gastroenterology 2008;135:1130-1141.

UstekinumabPlacebo

2 4 6 80

20

40

60

80

100

Weeks

Pat

ient

s (%

)

2 4 6 80

20

40

60

80

100

Weeks

Infli

xim

ab-E

xper

ienc

edP

atie

nts

(%)

P=.046 P=.001 P=.004 P=.022

0

0.2

0.4

0.6

0.8

1.2

1.0

IntravenousSubcutaneous Intravenous Subcutaneous

Placebo

Med

ian

CR

P (

mg/

dL)

Ustekinumab

P=.335P=.02 P=.019 P=.337

Week 8Week 0

All Patients Previously Treated with Infliximab

CRP in All Patients

Ustekinumab (Anti-IL-12/23p40) for Induction of Moderate to Severe Crohn’s Disease

+p<0.05 vs. PBO by CMH test

+

+

+

++

+

+

Sandborn WJ. N Engl J Med 2012; 367:1519-1528

+

+

+

Clinical Response Clinical Remission

Ustekinumab (Anti-IL-12/23p40) for Maintenance of Moderate to Severe Crohn’s Disease

p=0.029

p<0.001

Sandborn WJ. N Engl J Med 2012; 367:1519-1528

Tofacitinib an Oral Janus Kinase (JK) Inhibitor

Tofacitinib blocks phosphorylation of STAT and downstream activation

JAK

α

STAT

STAT

mRNA

JAKPP

STAT

STAT

P

P

P

β γCytokine

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 Th2Induce 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

Tofacitinib (CP-690,550) is a novel, small-molecule, oral JAK inhibitor Tofacitinib inhibits JAK1, JAK2, and JAK3 in vitro with functional cellular specificity for JAK1 and JAK3

over JAK2. Importantly, tofacitinib directly or indirectly modulates signaling for an important subset of pro-inflammatory cytokines including IL-2, -4, -7, -9, -15, and -21

Sandborn W. New England Journal of Medicine 2012

Estimated clinical responserate (80% CIs)

Clinical Response-70

Clinical Response-100

0

10

20

30

40

50

60

Placebo 1 mgBID

5 mgBID

15 mgBID

Tofacitinib

N=34 N=36 N=34 N=35

44.8%48.0%

49.9%

42.9%

0

10

20

30

40

50

60

Placebo 1 mgBID

5 mgBID

15 mgBID

Tofacitinib

N=34 N=36 N=34 N=35

28.1%33.7%

38.8%40.8%

Tofacitinib for Induction in Moderate to Severe Crohn’s Disease: Clinical Response and Remission at Week 4

Sandborn W. Gastroenterology 2011 Abstract

Mean percentage change from baseline in log transformed CRP (mg/L) in those patients with baseline CRP ≥5 mg/L (B)

Sandborn W. Gastroenterology 2011 Abstract

Tocilizumab (Humanized Monoclonal Antibody Interleukin-6 Receptor – Previously Atlizumab or MRA) For Active Crohn’s Disease Active Crohn’s Disease

• 36 patients with active Crohn’s 36 patients with active Crohn’s disease (CDAI > 150, disease (CDAI > 150, ↑ CRP↑ CRP))

• Randomized to receive IV placebo, Randomized to receive IV placebo, tocilizumab (previously atlizumab, tocilizumab (previously atlizumab, MRA) 8 mg/kg every 2 weeks, or MRA) 8 mg/kg every 2 weeks, or atlizumab 8 mg/kg every 4 weeks for atlizumab 8 mg/kg every 4 weeks for 12 weeks12 weeks

• The endpoints were % response The endpoints were % response (decrease in CDAI (decrease in CDAI 70) and 70) and remission (CDAI remission (CDAI 150) at week 12 150) at week 12

• Frequency of adverse events similar Frequency of adverse events similar in all groupsin all groups

P=0.019

P=NS

Ito Gastroenterology 2004

Other Drugs in this ClassOther Drugs in this Class

• BMS-945429 (fully human antibody to interleukin-6)BMS-945429 (fully human antibody to interleukin-6)• PF-04236921 (fully human IgG2 antibody to interleukin-6)PF-04236921 (fully human IgG2 antibody to interleukin-6)

Belongs to CXC family of chemokine ligands Induced by IFN- and produced by various cell types including hematopoietic & stromal cells Mechanism of action

CXCR3-mediated recruitment of T cells to inflamed tissues CXCR3-independent (or dependent) modulation of functions of other cells including

epithelial, endothelial and islet cells

IP-10

CXCR3

Unidentified receptorHeparansulfateTLR4 (?)

T cell

Epithelial

Islet cell

Endothelial

↑ Trafficking

↓ Proliferation & Migration1,2

↓ Proliferation3

↑ Apoptosis4

Interferon Gamma Inducible Protein 10 Interferon Gamma Inducible Protein 10 (IP-10 or CXCL-10)(IP-10 or CXCL-10)

1 Suzuki et al. Pathology International 2007; 57(7):413-420; 2. Soejima et al, J Immun 2001; 167:6576-6582; 3. Luster et al. J Exp Med 1995; 182:219-231; 4. Schulthess et al. Cell Metabolism 2009;9(2):125-139

Drug in this ClassDrug in this Class

• Eldelumab (fully human antibody to IP-10)

ConclusionsConclusions

• Top down therapy with steroids and azathioprine Top down therapy with steroids and azathioprine is not effective in adults with newly diagnosed is not effective in adults with newly diagnosed Crohn’s diseaseCrohn’s disease

• Treatment goals in Crohn’s disease are evolving Treatment goals in Crohn’s disease are evolving towards deep remission achieved via a treat to towards deep remission achieved via a treat to target strategytarget strategy

• Agents targeted against multiple targets including Agents targeted against multiple targets including beta 7 integrin, MAdCAM-1, and the p40 subunit beta 7 integrin, MAdCAM-1, and the p40 subunit of interleukin 12/23, and possibly JAK, IP-10, and of interleukin 12/23, and possibly JAK, IP-10, and interleukin-6, hold great promise for the futureinterleukin-6, hold great promise for the future