Newer Therapies in IBD: When, What and How

Stephen B. Hanauer, MDClifford Joseph Barborka Professor of Medicine

Northwestern University Feinberg School of Medicine

Treatment Goals c.2015

• Induce and maintain remission

- Mucosal healing

• Prevent complications

- Disease Related

- Therapy Related

• Improve quality of life

• Limit surgery?

Evolving Approach to Treating UC

Near Future Approach• Newer therapies with favorable

safety and side effect profiles • Individualized therapy based on

genetics and physiology

• Treatment to hard endpoints such as mucosal healing or surrogates of it

• Disease monitoring to prevent relapse

Current Approach• Assessment of prognosis• “Optimization” of

azathioprine/6-MP (dose or metabolites)

• Adopt biologic therapy earlier in disease

• Appreciation for the implications of a healed mucosa

Predictors of Poor Response or Colectomy

• Low serum albumin• ESR >30 mm/h• Bandemia• Prolonged flare• Active infection• Hospitalization setting• Severe endoscopic lesions• Disease duration

• Stool frequency • Percentage of bloody stools• Body temperature >37.5• Heart rate >90 bpm• Increased CRP• Toxic megacolon• Low hemoglobin

<10.5 g/dL

CRP=C-reactive protein.Lindgren SC, et al. Eur J Gastroenterol Hepatol. 1998;10:831-835.; Gonzalez-Lama Y, et al. Hepatogastroenterology. 2008;55:1609-1614.Suzuki Y, et al. Dig Dis Sci. 2006;51:2031-2038.; Cacheux W, et al. Am J Gastroenterol. 2008;103:637-642.Ananthakrishnan AN, et al. Am J Gastroenterol. 2008;103:2789-2798.

High-Risk Patients

• Oxford Index identifies patients with a high risk for colectomy- Evaluate CRP concentration- Evaluate number of bloody bowel movements

• Biomarkers to identify high-risk patients- Serum albumin concentration- Fecal calprotectin concentration

• Endoscopic disease severity is predictive• Residual histopathologic inflammation

Oxford Index: >8 stools/day or 3-8/day and CRP >45mg.dL on third day of corticosteroid. Travis SP, et al. Gut. 1996;38:905-910; Ho GT, et al. Aliment Pharmacol Ther. 2004;19:1079-1087; Carbonnel F, et al. Dig Dis Sci. 1994;39:1550-1557; Sandborn W, et al. 2010;105(Suppl 1):S438.

Mucosal Healing as a Surrogate for Longer Term Outcomes

Associated with:

• Better quality of life

• Fewer hospitalizations

• Fewer surgeries

• Longer time to clinical relapse

• Reduction in dysplasia/cancer

Sands, B. ACG-FDA Workshop 2012

Therapy is stepped up according to severity at presentation or failure at prior step

AminosalicylateOral/Topical/Combo

Corticosteroid

Anti-TNF +/ISCyclosporine (UC)

Disease Severity at Presentation

Anti-Integrin

Aminosalicylate/Thiopurine

Anti-TNF/Thiopurine

Induction

Maintenance

Severe

Moderate

MildAminosalicylateOral/Topical/Combo

Sequential Therapies for Ulcerative Colitis

Anti-TNF agents in Ulcerative colitis

Infliximab AdalimumabGolimumab

IgG1Fc

Fab

Etanercept

IgG1Fc

Receptor

Monoclonal antibody

Human

Human recombinant

receptor/Fc fusion protein

Chimeric

Fab′

Certolizumab pegol

PEG

PEGylated humanized

Fab′ fragment

2 × 20 kDa PEG

Anti-TNF Agents Evaluated in Ulcerative Colitis

Clinical Remission in UC: ACT (Infliximab), ULTRA-2 (Adalimumab) and PURSUIT

(Golimumab)Patients failing 5-ASA/Steroids/IS

Infliximab 10 mg/kg

Infliximab 5 mg/kg

Placebo0%

10%

20%

30%

40%

Infliximab 8 Weeks

Adalimumab Placebo0%

10%

20%

30%

40%

Adalimumab 8 Weeks

Golimumab 400/200 mg

Golimumab 200/100 mg

Placebo0%

10%

20%

30%

40%

Golimumab 6 Weeks

Infliximab 10 mg/kg

Infliximab 5 mg/kg

Placebo0%

10%

20%

30%

40%

Infliximab 54 Weeks

Adalimumab Placebo0%

10%

20%

30%

40%

Adalimumab 52 Weeks

Golimumab 100 mg

Golimumab 50 mg

Placebo0%5%

10%15%20%25%30%35%40%

Golimumab 54 Weeks

**

** ***

**

****

** **

*P<0.05 versus placebo; **P<0.01 versus placeboSandborn WJ, et al. Gastroenterology. 2014;146(1):96-109; Sandborn WJ, et al. Gastroenterology. 2014;146(1):85-95; Sandborn WJ, et al. Gastroenterology. 2012;142(2):257-265; Rutgeerts P, et al. N Engl J Med. 2005;353(23):2462-2476; Panaccione R, et al. Can J Gastroenterol. 2008;22(3):261-272.

Is Combination Therapy Superior?

AZA Infliximab Combination0%

5%

10%

15%

20%

25%

30%

35%

40%

45%

P=0.017

P=0.813

P=0.032

Panaccione R, et al. Gastroenterology. 2014;146(2):392-400.

UC SUCCESS:Corticosteroid-free Remission in Early UC

AZA Infliximab Combination0%

10%

20%

30%

40%

50%

60%

70%P=0.028

P=0.001

P=0.295

Panaccione R, et al. Gastroenterology. 2014;146(2):392-400.

UC SUCCESS: Mucosal Healing in Early UC

Therapeutic Monitoring for Anti-TNF

Congestive heart failure

Autoimmunity,immunogenicity Demyelinating disease,

PML*

Infection

Malignancy/lymphoma

Infusion reactions,injection-site reactions

Hepatotoxicity Bone marrow suppression

*Reported with natalizumab.

• Use combination therapy with thiopurines?

• Check anti-TNF levels? • Check for antibodies?

• Vaccinations: flu, pneumonia

• TB testing• Hepatitis screening

• Switch to another anti-TNF agent?• Switch to agent with different mechanism of action?

A New Mechanism of Action

α4β7 Integrin–MAdCAM-1 Is One of the Interactions that Contributes to Chronic Inflammation in UC and CD

MAdCAM-1=mucosal addressin cell adhesion molecule-1Briskin M, et al. Am J Pathol. 1997;151:97-110.

α4β7−MAdCAM-1 interaction has been implicated as an important contributor to

the chronic inflammation that is a hallmark of UC and CD

MAdCAM-1

α4β7 integrin

Memory T lymphocyte

MAdCAM-1

β7subunit

α4subunit

Artist’s rendition

Vedolizumab Binds to α4β7 Integrin and Blocks Its Interaction With MAdCAM-1

Memory T lymphocyte

Vedolizumab:A humanized monoclonal antibody (mAb) that binds to the α4β7 integrin Vedolizumab blocks the

interaction of α4β7 integrin with MAdCAM-

1

Endothelial cell

β7subunit

α4subunit

MAdCAM-1

β7subunit

α4subunit

vedolizumab

Artist’s rendition

Vedolizumab Phase III Trial in UC: Clinical Response, Clinical Remission, and Mucosal Healing at 6 weeks†

D 21.711.6, 31.7

D 11.54.7, 18.3

D 16.16.4, 25.9

95% CI:

Clinical Response Clinical Remission Mucosal Healing0%

5%

10%

15%

20%

25%

30%

35%

40%

45%

50%

Placebo

Vedolizumab

**

*

*

*P = 0.001**P<0.0001

† ITT population, 6 weeks

Feagan BG, et al. New Engl J Med. 2013;369(8):699-710.

19

Please see Important Safety Information contained on slides 33-34.

Corticosteroid-Free Clinical Remission at Week 52 in UC II

CS-free remission: Week 520%

20%

40%

60%

80%

100%

14%

31%

Patie

nts

P=0.012

Secondary endpoint

CS-free clinical remission was assessed in the subgroup of patients who were receiving CS at baseline and who were in clinical response at Week 6. CS-free clinical remission was defined as the proportion of patients in this subgroup that discontinued CS by

Week 52 and were in clinical remission at Week 52.

Placebo (n=72)

Entyvio 300 mg Q8 weeks (n=70)

a

a Patients must have achieved clinical response at Week 6 to continue into UC Trial II. This group includes patients that were not in clinical remission at Week 6.

Feagan BG et al. New Engl J Med. 2013;369:699-710.

Vedolizumab Phase III Clinical Trial in UC:Clinical Remission and Durable Clinical

Response at 52 Weeks

25.4 (5.1, 43.8)29.7 (10.3, 47.7)

24.9 (7.1, 42.6)27.0 (9.4, 44.6)

26.8 (12.4, 41.2)29.0 (14.6, 43.3)

38.7 (24.0, 53.4)29.6 (14.6, 44.6)

Mean % vs VDZ/PBO (95% CI)VDZ/VDZ Q8W:VDZ/VDZ Q4W:

Clinical Response Durable Clinical Response0%

10%

20%

30%

40%

50%

60%

70%

Prior Anti-TNF Antagonist Exposure(n=149)

Clinical Response Durable Clinical Response

0%

10%

20%

30%

40%

50%

60%

70%

Patients Without TNF Antag-onist Exposure

(n=224)

VDZ/PBO

VDZ/VDZ Q8W

VDZ/VDZ Q4W

PBO = placebo; VDZ = vedolizumabFeagan BG, et al. New Engl J Med. 2013;369(8):699-710.

Positioning New Therapies

What Is the Optimal Positioning for Golimumab in UC?

Therapy is stepped up according to severity at presentation or failure at prior step

Corticosteroid

Anti-TNF +/ISCyclosporine (UC)

Anti-Integrin

Aminosalicylate/Thiopurine

Anti-TNF/Thiopurine

Induction

Maintenance

Severe

Moderate

Mild

Golimumab

Tested

Possible

Unlikely in Severe/Fulminant

With/Without IS?

What Is the Optimal Positioning for Vedolizumab in UC?

Corticosteroid

Anti-TNF +/ISCyclosporine (UC)

Anti-Integrin

Aminosalicylate/Thiopurine

Anti-TNF/Thiopurine

Induction

Maintenance

Severe

Moderate

Mild

Vedolizumab

Before Steroids?

BeforeAnti-TNFs?

Vedolizumab in Crohn’s Disease

Clinical Remission CDAI-100 Response0

20

40

60

80

100

6.8

25.7

14.5

31.4

Placebo

VedolizumabP

atie

nts

(%

)

PBO=placebo; VDZ=vedolizumabSandborn WJ et al. New Engl J Med. 2013;369:711-721.

Clinical Remission and CDAI-100Response at Week 6

P=.02

7.8 (1.2, 14.3) 5.7 (–3.6, 15.0)Mean % vs PBO (95% CI)

P=.23

Primary and Secondary Outcomesat 52 Weeks

†P<.01 vs placebo; ‡P<.05 vs placeboCS=corticosteroid; VDZ=vedolizumabSandborn WJ et al. New Engl J Med. 2013;369:711-721.

Clinical Remission CDAI-100 Response CS-Free Remission Durable Remission0

20

40

60

80

100

21.630.1

15.9 14.4

39.0†43.5‡

31.7‡

21.4

36.4†45.5†

28.8‡

16.2

VDZ/PBOVDZ/VDZ Q8WVDZ/VDZ Q4W

Pat

ien

ts (

%)

Primary Outcome

SecondaryOutcomes

17.4 14.7 13.4 15.3 7.2 2.015.9 12.9Mean % vsVDZ/PBO

0

20

40

60

80

100

17.123.2 26.8

38.029.5 30.7

51.560.6

27.7

38.646.5

53.5

Maintenance ITT Population*

VDZ/PBOVDZ/VDZ Q8WVDZ/VDZ Q4W

Pati

en

ts (

%)Patients With Prior

Anti-TNFα Exposure(n=253)

Patients Without PriorAnti-TNFα Exposure

(n=208)

Clinical Remission, CDAI-100 Response at 52 Weeks by Prior TNF Antagonist Exposure

VDZ=vedolizumabSandborn WJ et al. New Engl J Med. 2013;369:711-721.

12.5 (–0.1, 25.0)10.6 (–2.0, 23.2)

7.5 (–5.8, 20.8)15.4 (1.5, 29.3)

24.8 (8.9, 40.6)19.7 (4.2, 35.2)

22.6 (6.3, 38.9)15.5 (–0.7, 31.7)

Mean % vs VDZ/PBO (95% CI)VDZ/VDZ Q8W:VDZ/VDZ Q4W:

*P=.0011 vs placebo; †P<.0001 vs placebo; ‡P=.0002 vs placeboPBO=placebo; VDZ=vedolizumabSands B et al. Presented at ECCO 2013.

Vedolizumab Phase 3 Induction Trial in CD CDAI-100 Response

Week 6 Week 10 Week 6 Week 100

20

40

60

80

100

22.3 24.8 22.7 24.2

39.2*46.8†

39.2‡47.8†

ITT Population

Placebo Vedolizumab

CDAI-100 Response

Pat

ien

ts (

%)

Anti-TNFα Failure Population(n=315)

Overall Population(n=416)

Vedolizumab TroughConcentration (μg/mL):

Vedolizumab Trough Levels Also Correlate with Response to Therapy: UC Week 6

n=54 n=53

First Second Third FourthQuartile:

Vedolizumab TroughConcentration (μg/mL):

0 to<16.7

16.7 to<24.8

24.8 to<33.3

33.3 to65.6

n=53 n=54

Feagan B et al. N Engl J Med. 2013;369:699-710.

Vedolizumab Indications

Adult Crohn’s Disease (CD)Adult patients with moderately to severely active CD who have had an inadequate response with, lost response to, or were intolerant to a TNF blocker or immunomodulator; or had an inadequate response with, were intolerant to, or demonstrated dependence on corticosteroids:

• achieving clinical response• achieving clinical remission• achieving corticosteroid-free remission

Entyvio [package insert]. Deerfield, IL: Takeda Pharmaceuticals America, Inc; May 2014.

Positioning Vedolizumab in Crohn’s?

Therapy is stepped up according to severity at presentation or failure at prior step

AminosalicylateOral/Topical/Combo

Corticosteroid

Anti-TNF +/IS

Disease Severity at Presentation Natalizumab (CD)

Aminosalicylate/Thiopurine

Anti-TNF/Thiopurine

InductionMaintenance

Severe

Moderate

Mild

AminosalicylateOral/Topical/Combo

Vedolizumab?

Positioning Vedolizuma for Crohn’s Disease

• Vedolizumab- Before (?)/After (?) anti-TNF- Maintenance benefits>Induction

•Earlier disease?•Steroid induction?

IL-12 and IL-23 Cytokines and Receptors Are First Cousins

• IL-23R polymorphisms are found in Crohn’s disease and ulcerative colitis • Targeting p19 (blocking IL-23 signaling) is therapeutic in mouse colitis models• Now shown to be effective in Crohn’s disease

Adapted from Trinchieri G. Nat Rev Immunol. 2003;3:133-145.

IL-12R1 IL-12R2

Anti-p40 AbIL-12

p35p40

IL-12R1 IL-23R

Anti-p40 AbIL-23

p19p40

Anti-p19 Ab

Initial Evaluation of MEDI2070 (specific anti-IL-23 antibody) in patients with active Crohn’s disease who have failed anti-TNF antibody therapy: A randomized, double-blind placebo-controlled phase 2a induction study Bruce Sands et al. Abstract #830 Tuesday 8a

IL-23Oppmann B et al. Immunity. 2000;13:715.IL-12 Presky DH et al. Proc Natl Acad Sci U S A. 1996;93:14002.

p40p19p40 p35

Anti-p40 Mechanism of Action

IL-12Rb1IL-23R

IL-12Rb1 IL-12Rb2

NK or T cell membrane

No Signal

UstekinumabBriakinumab

Parham C et al. J Immunol. 2002;168:5699.

Chua AO et al. J Immunol. 1995;155:4286.

Ustekinumab for Crohn’s disease: blocks IL-12/IL-23

Clinical Response Week 6 (primary end point)

Clinical Response Week 8 Clinical Remission Week 6 Clinical Remission Week 80

10

20

30

40

50

Placebo

UST 1 mg/kg

UST 3 mg/kg

UST 6 mg/kg

UST combined

*P<.05

23.5

36.6

*34

.139

.7*

36.8

*

17.4

32.1

*31

.8*

43.5

*35

.8*

10.6

15.9

12.2 14

.7

10.6

17.4

18.3

17.8

16

17.6

Clinical Response and Remission at Weeks 6 and 8

Sandborn W, et al. N Engl J Med. 2012 Oct 18;367(16):1519-28.

• What and When?- Now

• Golimumab for UC• Vedolizumab for UC and CD

- 12 Months• Ustekinemab for CD

• How?- Earlier the better- Combine with Immunosuppressive?

• Safety vs Efficacy- Therapeutic Drug Monitoring Likely

Summary: Newer Biologic Therapies in IBD