1. Anti-Integrin Therapy in IBD: When to use, how to choose
David T. Rubin, MD, FACG, AGAF, FACP
The Joseph B. Kirsner Professor of Medicine
Chief, Section of Gastroenterology, Hepatology and Nutrition
@IBDMD

2. Objectives
Be aware of the different anti-integrin (and other adhesion molecule) therapeutics.
Know the risks associated with different anti-integrins.
Implement the newly approved vedolizumab into your IBD treatment algorithms.
Know when to refer for treatment with natalizumab and/or clinical trials with newer (β7) agents such as etrolizumab.

3. Overview of (Anti-)Integrins NOT ANTI-TNF!
Integrins (leukocyte cell-surface adhesion molecules) allow leucocytes to: 1. Stop rolling and 2. start migrating/extravasation through the vascular wall.
Action of Adhesion molecules (eg. Integrins) in the intestinal endothelium
Lobatón T, et al. Aliment Pharmacol Ther 2014; 39:

4. Tissue specific adhesion molecules
Integrins (4 families)
Tissue specific adhesion molecules
Involves CNS
α2β2 (expressed on neutrophils)
ICAM -1 (intercellular)
N/A
α4β1 (on leucocytes)
VCAM-1 (vascular)
Yes
α4β7 (on gut lymphocytes and gut-assoc lymphoid tissues)
MAdCAM-1 (mucosal addressin) No
αE4b7 (intraepithelial T lymphocytes)
E-cadherin (epithelial cells. ?
Lobatón T, et al. Aliment Pharmacol Ther 2014; 39:

5. Tissue specific adhesion molecules
Integrins (4 families)
Tissue specific adhesion molecules
Involves CNS
α2β2 (expressed on neutrophils)
ICAM -1 (intercellular)
N/A
α4β1 (on leucocytes)
VCAM-1 (vascular)
Yes
α4β7 (on gut lymphocytes and gut-assoc lymphoid tissues)
MAdCAM-1 (mucosal addressin) No
αE4b7 (intraepithelial T lymphocytes)
E-cadherin (epithelial cells. ?
Natalizumab
Lobatón T, et al. Aliment Pharmacol Ther 2014; 39:

6. Tissue specific adhesion molecules
Integrins (4 families)
Tissue specific adhesion molecules
Involves CNS
α2β2 (expressed on neutrophils)
ICAM -1 (intercellular)
N/A
α4β1 (on leucocytes)
VCAM-1 (vascular)
Yes
α4β7 (on gut lymphocytes and gut-assoc lymphoid tissues)
MAdCAM-1 (mucosal addressin) No
αE4b7 (intraepithelial T lymphocytes)
E-cadherin (epithelial cells. ?
Natalizumab
Vedolizumab
AMG181
Lobatón T, et al. Aliment Pharmacol Ther 2014; 39:

7. Tissue specific adhesion molecules
Integrins (4 families)
Tissue specific adhesion molecules
Involves CNS
α2β2 (expressed on neutrophils)
ICAM -1 (intercellular)
N/A
α4β1 (on leucocytes)
VCAM-1 (vascular)
Yes
α4β7 (on gut lymphocytes and gut-assoc lymphoid tissues)
MAdCAM-1 (mucosal addressin) No
αE4b7 (intraepithelial T lymphocytes)
E-cadherin (epithelial cells. ?
Natalizumab
Vedolizumab
AMG181
Etrolizumab
Lobatón T, et al. Aliment Pharmacol Ther 2014; 39:

8. Anti-Adhesion Molecule Treatment
Drug
Target
Administr CD UC
Anti-integrins
Natalizumab α4 IV
Approved in USA
Pilot (+/-)a
Vedolizumab
α4β7
Approved in USA, EU
AMG181
IV/SC
Phase 1 & 2b
Etrolizumab (rhuMAb β7) β7 -
Phase 2 (+)
Phase 3b
AJM300
Oral
Phase 3(+/-)c
Phase 1 & 2 (+/-)
Other adhesion molecules PF
MAdCAM-1
Phase 1 (+)
Alicaforsen
ICAM-1
Phase 3 (+/-)
CCX282-B
CCR9
Phase 3 (disc)d
aNo clear benefit; bOngoing; cpositive in 1 small RCT , but potential PML risk; dDiscontinued after negative study.
Lobatón T, et al. Aliment Pharmacol Ther 2014; 39:

9. Anti-Integrin Treatment
Drug
Target
Administr CD UC
Anti-integrins
Natalizumab α4 IV
Approved in USA
Pilot (+/-)a
Vedolizumab
α4β7
Approved in USA, EU
AMG181
IV/SC
Phase 1 & 2b
Etrolizumab (rhuMAb β7) β7 -
Phase 2 (+)
Phase 3b
AJM300
Oral
Phase 3(+/-)c
Phase 1 & 2 (+/-)
Other adhesion molecules PF
MAdCAM-1
Phase 1 (+)
Alicaforsen
ICAM-1
Phase 3 (+/-)
CCX282-B
CCR9
Phase 3 (disc)d
aNo clear benefit; bOngoing; cpositive in 1 small RCT , but potential PML risk; dDiscontinued after negative study.
Lobatón T, et al. Aliment Pharmacol Ther 2014; 39:

10. Anti-a4 Integrins and Their Ligands Block Tissue-tropic Lymphocyte Migration
MAdCAM-1
47
Gut-tropic T cell
Gut Endothelium
41
VCAM-1
CNS Endothelium
CNS-tropic T cell
von Andrian & Mackay, NEJM (2000); von Andrian & Engelhardt, NEJM (2003).

11. Anti-a4 Integrins and Their Ligands Block Tissue-tropic Lymphocyte Migration
MAdCAM-1
47
Gut-tropic T cell
Gut Endothelium
41
VCAM-1
CNS Endothelium
CNS-tropic T cell
Natalizumab
Targets
von Andrian & Mackay, NEJM (2000); von Andrian & Engelhardt, NEJM (2003).

12. Anti-a4 Integrins and Their Ligands Block Tissue-tropic Lymphocyte Migration
MAdCAM-1
47
Gut-tropic T cell
Gut Endothelium
41
VCAM-1
CNS Endothelium
CNS-tropic T cell
Natalizumab
Targets
Vedolizumab
Target
von Andrian & Mackay, NEJM (2000); von Andrian & Engelhardt, NEJM (2003).

13. Natalizumab: Subset Analysis from ENACT Remission in Anti-TNF Failures
P < .001
P < .001
P = .005
P = .005
(171)
(168)
(33)
(24)
(171)
(168)
(33)
(24)
ITT
Failed TNF
ITT
Failed TNF
Month 6
Month 12
Sandborn et al. N Engl J Med. 2005;353(18):1912.
David T. Rubin, MD 2014

14. What happens to the patients who receive natalizumab in the current post-TNF paradigm? Chicago Experience
Sakuraba et al. Inflamm Bowel Dis 2013;19(3):621-6.
Sakuraba et al. Inflamm Bowel Dis 2013;19(12):

15. Updated Utilization and Safety Results of Natalizumab in CD and MS (TOUCH, CD INFORM, TYGRIS & Pregnancy Registry Studies)
125,800 patients have received globally (post-marketing) as of 3/31/2014
Predominantly MS patients
(accessed 12-Dec-2013); PML Incidence according to Biogen Idec at 19-jun-2014.

16. Updated Utilization and Safety Results of Natalizumab in CD and MS (TOUCH, CD INFORM, TYGRIS & Pregnancy Registry Studies)
125,800 patients have received globally (post-marketing) as of 3/31/2014
Predominantly MS patients
PML (Progressive Multifocal Leukoencephalopathy)
Overall incidence of PML 3.64 (95%CI ) per 1000 patients and 23% have died. As of June 4, 2014.
Longer duration and prior immunosuppressant use increases risk
Risk for patients treated months similar to rates seen in clinical trials
Limited safety data beyond 4 yrs of treatment
No known treatment or prevention interventions for PML
(accessed 12-Dec-2013); PML Incidence according to Biogen Idec at 19-jun-2014.

17. Recommendations for JCV Antibody Testing
Testing prior to treatment with natalizumab
If positive, consider retesting.
If confirmed, option is treatment with natalizumab for 9-12 months
If negative, may treat with natalizumab, retest every 6 months
If converts to positive, stop therapy
The benefit and safety of a drug holiday and restarting after “resetting” the exposure has not been tested in Crohn’s disease

18. Vedolizumab during Induction phase for UC at 6 weeks (Gemini I)
Vedolizumab (n=225)
Placebo (n=149)
=22%
p<0.0001
=16%
P=0.0012
Patients %
(95% CI)
=12%
P=0.0009
Primary
Secondary
Feagan et al. N Engl J Med. 2013;369(8):

19. GEMINI I: Vedolizumab in UC Percent change from week 6 in prednisone-equivalent dose
Feagan et al, N Engl J Med 2013;369:

20. GEMINI I: Vedolizumab for the treatment of UC (induction) and prior anti-TNF use
exposure
No prior anti-TNF
exposure
Placebo
Vedolizumab
Feagan et al, Presented at DDW; May 22, Abstract 943b
*P< 0.005

21. Vedolizumab during maintenance phase for UC: week 52 (Gemini I)
=29%
=36%
VDZ / VDZ Q8w (n=122)
VDZ / Placebo (n=126)
VDZ / VDZ Q4w (n=125)
p<0.0001
p<0.0001
=33%
=32%
p<0.0001
p<0.0001
=31%
p<0.0001
=18%
=15%
p<0.05
p<0.001
Patients %
(95% CI)
=12%
p<0.01
N=72
N=70
N=73
Feagan et al. N Engl J Med. 2013;369(8):

22. Vedolizumab during maintenance phase for UC: week 52 (Gemini I)
=29%
=36%
VDZ / VDZ Q8w (n=122)
VDZ / Placebo (n=126)
VDZ / VDZ Q4w (n=125)
p<0.0001
p<0.0001
=33%
=32%
p<0.0001
p<0.0001
=31%
p<0.0001
=18%
=15%
p<0.05
p<0.001
Patients %
(95% CI)
=12%
p<0.01
N=72
N=70
N=73
Feagan et al. N Engl J Med. 2013;369(8):

23. Vedolizumab - Primary endpoints during Induction phase for CD at week 6 (Gemini II)
Vedolizumab (n=220)
Placebo (n=148)
p=0.021
=8%
p=0.23
=6%
Patients %
(95% CI)
Sandborn et al. N Engl J Med. 2013;369(8):

24. Vedolizumab - Primary endpoint during Induction phase for CD at week 52 (Gemini II)
=15%
VDZ / VDZ Q8w (n=154)
VDZ / VDZ Q4w (n=154)
VDZ / Placebo (n=153)
p<0.01
=17%
p<0.001
Patients %
(95% CI)
Sandborn et al. N Engl J Med. 2013;369(8):

25. Vedolizumab during maintenance phase for CD Secondary endpoints (Gemini II)
VDZ / VDZ Q8w (n=154)
VDZ / VDZ Q4w (n=154)
VDZ / Placebo (n=153)
=15%
p<0.01
=13%
p<0.05
=13%
p<0.05
=2%
p=0.641
=16%
p<0.05
=7%
p=0.104
Patients %
(95% CI)
n=82
n=82
n=80
Sandborn et al. N Engl J Med. 2013;369(8):

26. Vedolizumab during maintenance phase for CD Secondary endpoints (Gemini II)
VDZ / VDZ Q8w (n=154)
VDZ / VDZ Q4w (n=154)
VDZ / Placebo (n=153)
=15%
p<0.01
=13%
p<0.05
=13%
p<0.05
=2%
p=0.641
=16%
p<0.05
=7%
p=0.104
Patients %
(95% CI)
n=82
n=82
n=80
Sandborn et al. N Engl J Med. 2013;369(8):

27. Vedolizumab during maintenance phase for CD Secondary endpoints (Gemini II)
VDZ / VDZ Q8w (n=154)
VDZ / VDZ Q4w (n=154)
VDZ / Placebo (n=153)
=15%
p<0.01
=13%
p<0.05
=13%
p<0.05
=2%
p=0.641
=16%
p<0.05
=7%
p=0.104
Patients %
(95% CI)
n=82
n=82
n=80
Sandborn et al. N Engl J Med. 2013;369(8):

28. Maintenance Follow-up with Vedolizumab: Crohn’s disease
VDZ / VDZ Q8w (n=122)
VDZ / Placebo (n=126)
VDZ / VDZ Q4w (n=125)
Maintenance Study
Clinical Remission
(%)
Weeks (All patients had 2 doses in Induction Phase)

29. Pooled Analysis of GEMINI 2 and 3 Summary of Adverse Events
GEMINI 2 and 3: Pooled Safety and Efficacy of Vedolizumab in Anti-TNF-Naïve CD Patients
Pooled Analysis of GEMINI 2 and 3
Clinical Remission*
Summary of Adverse Events
*CDAI ≤150 with ≥100-point decrease from baseline
Sands B, et al. Presented at DDW; May 6, 2014 Abstract 864.

30. Safety of Vedolizumab
Adverse reactions in ≥3% of Entyvio-treated patients and ≥1% higher than in placebo (UC Trials I & IIa and CD Trials I & IIIa)
Vedolizumab (N=1434)
Placeboc (N=297)
Nasopharyngitis
13% 7%
Headache
12%
11%
Arthralgia
10%
Nausea 9% 8%
Pyrexia
Upper respiratory tract infection 6%
Fatigue 3%
Cough 5%
Bronchitis 4%
Influenza 2%
Back pain
Rash
Pruritus 1%
Sinusitis
Oropharyngeal pain
Pain in extremities
Entyvio [package insert]. Deerfield, IL: Takeda Pharmaceuticals America, Inc; May 2014.

31. Scheduled Maintenance
Immunogenicity of Biologics with and without Concomitant Immune Modulators (IMS)
Patients, %
Episodic Maintenance
Scheduled Maintenance
IMS-
IMS+
Infliximab1
(CD 5 mg/kg)
(CD 10 mg/kg)
38%
16%
11% 8% 7% 4%
Infliximab2
(UC 5 mg/kg)
(UC 10 mg/kg)
No data
19% 9% 2%
Certolizumab3
(PRECiSE I)
10%
Certolizumab4
(PRECiSE II)
24%
12% 1%
Adalimumab5
(RA, all doses)
Adalimumab6
(CLASSIC II) 0%
Golimumab7
(PURSUIT)
Natalizumab8a,b
(ENACT-1a & 2b)
11%8a ; 8%8b
3%8a ; 0%8b
Vedolizumab9,10
(GEMINI)
v/p:* 18%
v/v:* 3.0%
v/p: 3%
v/v: 3%
Ustekinumab11
(CERTIFI)
0.7%
N/A
1Hanauer et al. Clin Gastroenterol Hepatol. 2004; 2Sandborn et al. DDW 2007 Poster and abstract T1273;
3Sandborn WJ, et al. N Engl J Med. 2007; 4Schreiber S, et al. N Engl J Med. 2007; 5Summary of Product Characteristics for adalimumab. Abbott Laboratories. July 2007; 6Sandborn WJ, et al. Gut. 2007; 7Golimumab package insert. Janssen Biotech Inc., Horsham PA. 2012; 8Sandborn WJ, et al. N Engl J Med ; 9Sandborn WJ, et al. N Engl J Med. 2013; 10Feagan B, et al. N Engl J Med Sandborn WJ, et al. N Engl J Med. 2012 31 31

32. Scheduled Maintenance
Immunogenicity of Biologics with and without Concomitant Immune Modulators (IMS)
Patients, %
Episodic Maintenance
Scheduled Maintenance
IMS-
IMS+
Infliximab1
(CD 5 mg/kg)
(CD 10 mg/kg)
38%
16%
11% 8% 7% 4%
Infliximab2
(UC 5 mg/kg)
(UC 10 mg/kg)
No data
19% 9% 2%
Certolizumab3
(PRECiSE I)
10%
Certolizumab4
(PRECiSE II)
24%
12% 1%
Adalimumab5
(RA, all doses)
Adalimumab6
(CLASSIC II) 0%
Golimumab7
(PURSUIT)
Natalizumab8a,b
(ENACT-1a & 2b)
11%8a ; 8%8b
3%8a ; 0%8b
Vedolizumab9,10
(GEMINI)
v/p:* 18%
v/v:* 3.0%
v/p: 3%
v/v: 3%
Ustekinumab11
(CERTIFI)
0.7%
N/A
1Hanauer et al. Clin Gastroenterol Hepatol. 2004; 2Sandborn et al. DDW 2007 Poster and abstract T1273;
3Sandborn WJ, et al. N Engl J Med. 2007; 4Schreiber S, et al. N Engl J Med. 2007; 5Summary of Product Characteristics for adalimumab. Abbott Laboratories. July 2007; 6Sandborn WJ, et al. Gut. 2007; 7Golimumab package insert. Janssen Biotech Inc., Horsham PA. 2012; 8Sandborn WJ, et al. N Engl J Med ; 9Sandborn WJ, et al. N Engl J Med. 2013; 10Feagan B, et al. N Engl J Med Sandborn WJ, et al. N Engl J Med. 2012 32 32

33. Sequential Therapies for IBD: how should this be updated?
Curatio PowerPoint Template
6/23/ :02 PM
Sequential Therapies for IBD: how should this be updated?
Disease severity
at presentation?
Natalizumab
Anti-TNF (UC)/
Thiopurine/MTX (CD)
Anti-TNF
Severe
Moderate
Mild
Aminosalicylate (UC)/
Thiopurine/MTX (CD)
Budesonide (CD, UC)
Corticosteroids
Aminosalicylate
Aminosalicylate
Induction
Maintenance
Step-up according to severity at presentation or failure at prior step
time

34. Sequential Therapies for IBD: how should this be updated?
Curatio PowerPoint Template
6/23/ :02 PM
Sequential Therapies for IBD: how should this be updated?
Disease severity
at presentation?
Vedolizumab?
Natalizumab
Anti-TNF (UC)/
Thiopurine/MTX (CD)
Anti-TNF
Severe
Moderate
Mild
Aminosalicylate (UC)/
Thiopurine/MTX (CD)
Budesonide (CD, UC)
Corticosteroids
Aminosalicylate
Aminosalicylate
Induction
Maintenance
Step-up according to severity at presentation or failure at prior step
time

35. AJM300, an Oral α4 Integrin Antagonist, for Active UC Shows Efficacy in a Phase 2A Randomized, Placebo-Controlled Trial
Response to AJM300 at 8 Weeks
AJM300 is an orally bioavailable small molecule that selectively inhibits α4 integrin
8-week, multicenter RCT in patients with active UC (N=102)
Primary end-point: Response (reduction in Mayo score >2)
Conclusions
AJM300 appears effective in 5-ASA- refractory UC
Safety data was limited to 8 weeks and this agent is not gut selective (JC virus risk)
No data provided on concomitant immunomodulator use
Watanabe M, et al. Presented at ASGE/AGA Joint Presidential Plenary, DDW; May 4, Abstract 370

36. Conclusion - Anti-Integrin Therapy in IBD: When to use, How to choose
Patient failing anti-TNF therapy as a mechanism
Primary failure (and confirmation of active inflammation)
High drug levels, no antibodies
Secondary loss of response, failure of two anti-TNFs?
Positioning earlier in the algorithm?
Before steroids?
Before anti-TNF therapy?
Select patient populations?
CNS complications of anti-TNF (optic neuritis, transverse myelitis)
Elderly patients?
Psoriasiform patients?