Brian G. Feagan Professor of Medicine, Epidemiology and Biostatistics, Western University, Senior Scientific Officer, Robarts Clinical Trials Inc.

A Practical Approach to Anti-Integrins in IBD 2020

Disclosures

Grant/Research Support AbbVie Inc., Amgen Inc., AstraZeneca/MedImmune Ltd., Atlantic Pharmaceuticals Ltd., Boehringer-Ingelheim, Celgene Corporation, Celltech, Genentech Inc/Hoffmann-La Roche Ltd., Gilead Sciences Inc., GlaxoSmithKline (GSK), Janssen Research & Development LLC., Pfizer Inc., Receptos Inc. / Celgene International, Sanofi, Santarus Inc., Takeda Development Center Americas Inc., Tillotts Pharma AG, UCB,

Consultant Abbott/AbbVie, Akebia Therapeutics, Allergan, Amgen, Applied Molecular Transport Inc., Aptevo Therapeutics, Astra Zeneca, Atlantic Pharma, Avir Pharma, Biogen Idec, BioMxIsrael, Boehringer-Ingelheim, Bristol-Myers Squibb, Calypso Biotech, Celgene, Elan/Biogen, EnGene, Ferring Pharma, Roche/Genentech, Galapagos, GiCare Pharma, Gilead, Gossamer Pharma, GSK, Inception IBD Inc, JnJ/Janssen, Kyowa Kakko Kirin Co Ltd., Lexicon, Lilly, Lycera BioTech, Merck, Mesoblast Pharma, Millennium, Nestles, Nextbiotix, Novonordisk, Pfizer, Prometheus Therapeutics and Diagnostics, Progenity, Protagonist, Receptos, Salix Pharma, Shire, Sienna Biologics, Sigmoid Pharma, Sterna Biologicals, Synergy Pharma Inc., Takeda, Teva Pharma, TiGenix, Tillotts, UCB Pharma, Vertex Pharma, Vivelix Pharma, VHsquared Ltd., Zyngenia

Speakers Bureau Abbott/AbbVie, JnJ/Janssen, Lilly, Takeda, Tillotts, UCB PharmaPatent HolderMember, Scientific Advisory Board

Abbott/AbbVie, Allergan, Amgen, Astra Zeneca, Atlantic Pharma, Avaxia Biologics Inc., Boehringer-Ingelheim, Bristol-Myers Squibb, Celgene, Centocor Inc., Elan/Biogen, Galapagos, Genentech/Roche, JnJ/Janssen, Merck, Nestles, Novartis, Novonordisk, Pfizer, Prometheus Laboratories, Protagonist, Salix Pharma, Sterna Biologicals, Takeda, Teva, TiGenix, Tillotts Pharma AG, UCB Pharma

Member, Board of Directors Senior Scientific Officer – Robarts Clinical Trials Inc, LondonStock ShareholderOther Financial SupportOther Relationship/Affiliation

Anti-Integrins Mechanism of Action

Mosli M et al, Drugs 2014; 74: 297-311

Topic to Be Covered

• Efficacy of anti-integrins

• Safety

• Comparative effectiveness

• Practical considerations

• Current Guidelines\Agent Sequencing

• Future Directions

• Conclusions

Lancet Case Report 1994

Efficacy -TNF antagonists for CD was a gamechanger- but we are a long way from perfect……

.Colombel JF. et al. Gastroenterology 2007

Clinical remissionClinical response

% o

f Pat

ient

s 60

40

20

0

p < 0.001

p < 0.001

60

40

20

0

p < 0.001

p < 0.001

60

40

20

0

p < 0.001

p < 0.001

60

40

20

0

p < 0.001

p < 0.001

Week 26

Week 56

Placebo

Adalimumab40 mg weekly

Adalimumab40 mg EOW

% o

f Pat

ient

s17

4047

12

3641

p =NS

p = NS

p = NS

27

52 52

17

4148

p =NS

SONIC Remission Rates

30

45

57

0

20

40

60

80

100

Prop

ortio

n of

Pat

ient

s (%

)

AZA + placebo IFX + placebo IFX+ AZA

p<0.001

p=0.009 p=0.022

52/170 75/169 96/169

Colombel JF. et al. N Engl J Med. 2010 Apr 15;362(15):1383-95.

34.7%

27.4%

10

20

30

40

Time (months)

Hos

pita

lisat

ion,

sur

gery

or c

ompl

icat

ions

(%)

HR (95% CI) = 0.73 (0.62, 0.86), p <0.001

00 3 6 9 12 15 18 21 24

Conventional managementEarly combined immunosuppression

REACT: Time to First Hospitalization, Surgery or Complication

Khanna R. et al. The Lancet. 2015 Nov 7;386(10006):1825-34

REACT: Serious Disease and Drug-Related Complications and Mortality

Early combinedimmunosuppression 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) 0.33

Khanna R. et al. The Lancet. 2015 Nov 7;386(10006):1825-34

TREAT: Risk Factors for Serious Infections

1.69

0.69

0

1

2

3

IFX treated Non-IFXtreatedSe

rious

infe

ctio

ns p

er 1

00 p

tyrs

IFX use was independently associated with an increased incidence of serious infections

Lichtenstein, et al. DDW 2010: Abstract #T1040

Univariate

1.481.97 2.33 2.44

0.1

1

10

IFX Prednisone Narcotics CD severity

Haz

ard

ratio

(95%

CI)

Multivariate predictors of serious infection

p < 0.001

p = 0.011 p < 0.001 p < 0.001p < 0.001

What are the Specific Risks with TNF Antagonists? Perception vs. Reality

Perception! Reality !

# 1

# 2

# 3

Risk Factors for Serious Infections: Effects of Combining Therapies in the TREAT Registry

Lichtenstein, DDW 2010. Abstract T1039.

Demographic and disease characteristic predictors to time to first serious infection*: Multivariate model**

1.19

2.37 2.12

4.73

2.12 2.24

0.1

1

10

IS IS+CS IFX IFX+CS IFX IFX+IS

Haza

rd ra

tio (9

5% C

I)

Immunological Risks

• Hypersensitivity reactions• Drug induced lupus (1/500)• Psoriasis-like lesions

– 3-5% of patients– chronic exposure– hands, feet, scalp– high cross-reactivity– TH17 cells(ustekinumab

therapy)

TREAT Registry Risk of Malignancy

• Infliximab exposure was not an independent risk factor for development of malignancy in IBD

• Independent risk factors included: advanced age, disease duration and cigarette smoking

• Multivariate analysis of 6273 Crohn’sdisease patients managed at community and academic sites

Lichtenstein et al Am J Gastro 2014;109:212-223

Infliximab and Risk of Lymphoma

• Infliximab was associated with a more than two-fold increase in the incidence of lymphoma

• A six-fold increased risk was noted in patients on combination therapy with an immunosuppressive

• Retrospective analysis utilizing French national health insurance data

• 189,289 IBD patients with median follow up of 6.7 years

Lemaire et al JAMA 2017;318:1679-1686

Mosli M et al, Drugs 2014; 74: 297-311Feagan et al New Eng J Med 2013;396(8):699-710

Vedolizumab Therapy for UC and CD

25.5

5.4

24.8

47.1

16.9

40.9

0

5

10

15

20

25

30

35

40

45

50

Clinical Response Clinical Remission Mucosal Healing

PlaceboVedolizumab

UC Induction-Week 6

Primary and Secondary Outcomes Through 52 Weeks, ITT Population

15.9

23.819.8

8.7

13.9

41.8

56.651.6

20.5

31.4

44.8

52.056.0

24.0

45.2

0

10

20

30

40

50

60

Clinical Remission Durable ClinicalResponse

Mucosal Healing Durable ClinicalRemission

CS-Free Remission

PlaceboVDZ Q8WksVDZ Q4Wks

%

D26.1 D29.1 D32.8 D28.5 D32.0 D36.3 D11.8 D15.3 D17.6 D31.4

******

****

****** ***

***

*

***

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

n: 72 70 73

Feagan, B.G. et al New Eng J Med 2013

6.8

25.7

14.5

31.4

0

5

10

15

20

25

30

35

Clinical Remission CDAI-100 Response

Clinical Remission and CDAI-100 Response at Week 6

P=0.02

P=0.23

7.8 (1.2, 14.3) 5.7 (–3.6, 15.0)

Patie

nts,

%

Mean D% vs PBO (95% CI)

PBOVDZ

Sandborn WJ. et al. New Eng J Med 2013.

Colombel JF et al. Gut 2017;66(5):839-851

Vedolizumab: Exposure-Adjusted Incidence Rates of Infections, Serious Infections and LRTIs

Placebo Vedolizumab

Adverse event: Infection

UC and CD (n = 504)a UC and CD (n = 2830)d

No. of patients with event

No. of patients with event/100 PY

(95% Cl)

No. of patients with event

No. of patients with event/100 PY (95% Cl)

Any infectione 139 82.9 (68.3-97.5) 1606 63.5 (59.6-67.3)

Upper respiratory tract infections

67 34.7 (26.0-43.3) 967 28.6 (26.6-30.6)

Lower respiratory tract and lung infections

16 7.7 (3.9-11.5) 270 6.1 (5.3-6.8)

Varsity – Trial Design

Sands BE, et al. N Engl J Med 2019;381:1215-26

• Randomized comparison of vedolizumab (IV) to adalimumab at the labelled doses in active UC

• 20% TNF antagonist exposed

• Treat right through design

• 769 patients (effect size of 10%)

• Primary endpoint – remission at week 52

VARSITY: Vedolizumab vs Adalimumab Clinical Remission and Mucosal Healing at Week 52

Sands BE, et al. N Engl J Med 2019;381:1215-26. DOI: 10.1056/NEJMoa1905725.

31.322.5

0

20

40

60

Patie

nts,

%

383

p=0.006

386

Clinical Remission(Primary endpoint)

N=

Vedolizumab IV 300 mg Q8W Adalimumab SC 40 mg Q2W

∆ = 8.8%(95% CI: 2.5%, 15.0%)

39.727.7

0

20

40

60

Patie

nts,

%

383

p<0.001

386

Mucosal Healing

N=

∆ = 11.9%(95% CI: 5.3%, 18.5%)

VARSITYChange in Response Rates by Week

Sands B. et al. The New Engl J Med. 2019;381:1215-26

Varsity Comparative SafetyAdverse Events in the Safety Population

Event Adalimumab (n=386) Vedolizumab (n=383)

Any Adverse event-(%) 69.2 62.7

Mild 30.6 29.0

Moderate 28.2 24.0

Severe 10.4 9.7

Adverse events that led to discontinuation of a trial drug 6.5 4.4

Adverse Events, excluding ulcerative colitis 64.8 59.8

Serious adverse events 13.7 11.0

Serious adverse events that led to discontinuation of a trial drug 3.4 2.6

Serious adverse events, excluding ulcerative colitis 7.0 7.3

Death 0 1

Exposure-Adjusted Incidence Rates of Adverse Events

Sands B. et al. New Eng J Med. 2019;381(13): 1215-26

Infections and infestations – incidence rate per 100 patient-yr 34.6 23.4

Clostridia 0.6 1.1

Herpesvirus 4.2 0.5

Lower respiratory tract 2.0 1.1

Upper respiratory tract 18.1 12.5

Serious infections and infestations 2.2 1.6

Musculoskeletal and connective-tissue disorders 12.3 11.4

Arthralgia 4.5 4.1

Skin and subcutaneous-tissue disorders 14.5 8.6

Psoriasis 1.7 0.2

Practical Considerations

• Mode of Administration

• Onset of Action

• Extraintestinal disease

• Use in Pregnancy

• Dose intensification, therapeutic drug monitoring and immunogenicity

• Combination Therapy

Subcutaneous vs IV Vedolizumab for UC:Clinical Remission at Week 52

0

10

20

30

40

50

60

70

80%

Pat

ient

s (95

% C

I)

n/N: 8/56Placebo

49/106 SC

23/54 IV

46.242.6

14.3

Clinical Remission (Week 52)p<0.001

Clinical Remission

GEMINI 11

Placebo (N=126)

VDZ Q8W (N=122)

VDZ Q4W (N=125)

15.9

***41.8

***44.8

Sandborn WJ, et. al. United European Gastroenterology Week 2018, LB03. Feagan BC, et al. N Engl J Med. 2013;22;369(8):699-710.

Efficacy and Safety of 2 or 3 VDZ IV Infusions as Induction Therapy for UC and CD: VISIBLE 1 & 2

106/225 410/644 114/143 122/193 330/383 329/383

56.1

79.786.2

63.7 63.2

82.6

0

10

20

30

40

50

60

70

80

90

100

Responders after 2 VDZ infusions Responders after 3 VDZ infusions Overall

UC (N=383) CD (N=644)

b

Patie

nts

with

clin

ical

resp

onse

, %

106/225 410/644 114/143 122/193 330/383 329/383

Clinical Response

Loftus EV Jr, Sandborn WJ, Wolf D, et al. P499 Efficacy and safety of 2 or 3 vedolizumab intravenous infusions as induction therapy for ulcerative colitis and Crohn’s disease: results from VISIBLE 1 and 2. J Crohns Colitis. 2019;13(suppl 1):S361-S362. doi:https://doi.org/10.1093/ecco-jcc/jjy222.623.

Onset of Action in UC

Rectal bleeding subscore (RBS)2

% C

hang

e fr

om B

asel

ine

-19.8-28.0 -27.1

-29.8

-45.6-59.0

-20.7-29.6 -26.8-28.6

-42.3-49.5

-70

-60

-50

-40

-30

-20

-10

0

10

Baseline Week 2 Week 4 Week 6

Anti-TNF Naïve (n=115 VDZ; 65 PBO)a

Overall ITT (n=196 VDZ; 127 PBO)a

-10.0(-25.6, 5.6)

-17.6*(-33.6, -1.6)

-31.9*(-46.4, -17.4)

-7.9(-19.0, 3.2)

-12.8*(-24.2, -1.4)

-22.6*(-34.8, -10.5)

Anti-TNF Naïve PBOVDZ

Overall ITTPBOVDZ

Sands B. et al. The New Engl J Med. 2019;381:1215-26

Feagan et al. Clinical Gastroenterol and Hepatology. 2019;17:130-138

Vedolizumab: Onset of Action in CDGEMINI 2, CDAI composite score of Stool Frequency and Abdominal Pain

-6.7

-14.0-16.3

-21.3

-29.6-31.1

-7.4

-13.8 -15.6-15.7

-21.6-25.0

-40

-30

-20

-10

0

Baseline Week 2 Week 4 Week 6

% C

hang

e fro

m B

asel

ine

(95%

CI

)Anti-TNF Naïve PBOVDZ

Overall ITTPBOVDZ

Anti-TNF Naïve (n=105 VDZ; 74 PBO)a

Overall ITT (n=215 VDZ; 141 PBO)a

% diff from PBO (95% CI)

-14.6*(-23.1, -6.0)

-15.7*(-25.3, -6.0)

-14.8*(-25.9, -3.7)

-8.2*(-14.1, -2.4)

-7.8*(-14.3, -1.3)

-9.4*(-16.8, -2.0)

Q4W dosing is not an approved dosing regimen in CanadaFeagan et al. Clinical Gastroenterol and Hepatology. 2019;17:130-138

Evidence for Vedolizumab Benefit in EIMs

KM Estimates for Resolution of arthritis/arthralgia in Patients With EIMs at Baseline in GEMINI 2

VDZàPBO

Combined VDZ

PBO

Time to sustained resolution of arthritis/arthralgia

Abbreviations: AIBD, Advances in Inflammatory Bowel Disease; CD, Crohn’s disease; EIMs, extraintestinal manifestations; PBO, placebo; VDZ, vedolizumab.1. Feagan BG, et al. ECCO 2017. 2. Rubin D, et al. Inflamm Bowel Dis. 2016;22(suppl 1):S42-S43. 3. Ungaro R, et al. Inflamm Bowel Dis. 2017;23(suppl 1):S47-S48.

Practical Considerations: Immunogenicity, TDM, Dose Intensification: PK-PD Analysis

Week 6• VDZ CLL estimates by Mayo endoscopic subscore

• CLL 25% higher for patients with endoscopic subscore of 3 vs. 01

• Potentially influenced by protein losing enteropathy2

1 Rosario M., et al. Aliment Pharmacol Ther 2015 [Epub ahead of print]; 2 Beeken WL, et al. Gastroenterology 1972;62(2):207-15

Disease activity

Clearance

SERENE UC Primary Efficacy Endpoint Remission at Week 8

10.9 13.3

0

20

40

60

80

100

37/340

Patie

nts,

%

68/512

p=0.273

Standard induction dosing

Higher induction dosing

∆ = 2.5a

Panés, J., et al. United European Gastroenterology Week 2019. Abstract OP216

43.7 39.343.2 42.5

0

20

40

60

80

100p= 0.509p=1.000

Standard induction dosing

Standard induction dosing

Patie

nts,

%

Higher inductiondosing

Higher induction dosing

Clinical remission at Week 4CDAI < 150

Endoscopic response at Week 12 Decrease > 50% SES-CD from BL

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

∆ = -0.0a ∆ = 2.9a

90/206 133/308 81/206

SERENE CD: Co-Primary Efficacy Endpoint

D'Haens et al. United European Gastroenterology 2019 Abstract LB27

Higher induction dosing (n=512)Standard induction dosing (n=340)

0

10

20

30

40

50

60

UC CD

Response Remission

Effects of Increased Dosing Frequency: GEMINI I & II Long-Term Extension

%

n=32 n=57

1. Loftus E. et al. Journal of Crohn’s Colitis. 2017, 400-411.2. Vermeire S. et al. Journal of Crohn’s Colitis. 2017, 412-424.

53%

25%

54%

23%

Safety in Pregnancy

Practical Considerations: Combination Therapy

Efficacy of Combination Therapy: SONIC

Colombel JF, Sandborn WJ, et al. N Engl J Med. 2010;362):1383-1395

SONIC: Immunogenicity Status at Week 30

114

1

1520

68

94

0

20

40

60

80

100

PBO + AZA IFX + PBO IFX + AZA

Frac

tion

of p

ts (%

)

Postive Negative Inconclusive

n=89 n=106 n=120

98

Colombel JF, et al. Infliximab, azathioprine, or combination therapy for Crohn's disease. N Engl J Med 2010;362:1383-95

Bressler B., et al. United European Gastroenterology Week 2019. P1091

* n at riskUnadjusted p-values compare the 2L and 1L cohorts using the log-rank test.

87.4%

38.4%

9.7%

94.3%

44.8%

11.0%

0.010.020.030.040.050.060.070.080.090.0

100.0

Tx Persistence Tx Clinical Response Tx Clinical Remission

Cum

ulat

ive

Rate

(%)

1L 2L

n=195* n=47* n=16*n=109* n=136* n=24*

P=0.18

P=0.54

P=0.92

3 Months 6 Months

76.6%

57.1%

19.6%

79.5%

61.1%

14.7%

0.010.020.030.040.050.060.070.080.090.0

100.0

Tx Persistence Tx Clinical Response Tx Clinical Remission

Cum

ulat

ive

Rate

(%)

1L 2L

P=0.50

P=0.58

P=0.69

n=170* n=26* n=6*n=61* n=104* n=12*

EVOLVE: Second-line TNF Antagonist Effectiveness in UC

Bressler B., et al. United European Gastroenterology Week 2019. P1091

* n at riskUnadjusted p-values compare the 2L and 1L cohorts using the log-rank test.

95.2%

30.1%22.9%

96.4%

41.3%49.2%

0.010.020.030.040.050.060.070.080.090.0

100.0

Tx Persistence Tx Clinical Response Tx Clinical Remission

Cum

ulat

ive

Rate

(%)

1L 2L

n=256* n=17* n=7*n=160* n=174* n=6*

P=0.82

P=0.13P=0.02

3 Months 6 Months

90.0%

43.5%36.2%

92.2%

74.8% 74.6%

0.010.020.030.040.050.060.070.080.090.0

100.0

Tx Persistence Tx Clinical Response Tx Clinical Remission

Cum

ulat

ive

Rate

(%)

1L 2LP=0.82

P=0.13 P˂0.01

n=241* n=10* n=3*n=125* n=136* n=1*

EVOLVE: Second-line TNF Antagonist Effectiveness in CD

Current Guidelines: Crohn’s Disease

Panaccione R. et al. CAG 2019,2(3), e1-e34

Moderate to Severe Active UC

Bressler B, Marshall JK, et al. Gastroenterology 2015

EUCALYPTUS: Etrolizumab in Ulcerative Colitis

Vermeire et al, Lancet 2014; 384:309

Prop

ortio

n of

pat

ient

s (%

)

Clinical Remission in All Comers & by Anti-TNF statusPrimary endpoint at Week 10

Primary Endpoint 95% CI (12,30) (0.2,20)p-value 0.004 0.048

95% CI (12,75) (-2,50)p-value 0.007 0.076

95% CI (-5.1,16.4) (-5.6,14.7)

Prop

ortio

n of

pat

ient

s (%

)

n=15 n=16 n=12 n=15 n=16 n=12 n=25 n=22 n=25 n=25 n=22 n=25

Conclusions: Anti-integrin Therapy

• Vedolizumab has a superior safety profile to TNF antagonists – first line agents in both UC and CD

• Can be administered SC or IV as a first line therapy • Effective treatment for arthralgias as EIMs• Dose intensification to q4 weekly may be necessary and effective in 20 to 40% of

patients • Clinical safety data in pregnancy is evolving – no signals detected • Combination therapy is unproven but recommended in high risk patients • Etrolizumab is on the horizon