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UEGW 2020 – Table  of  Contents UEGW 2020 – Table  of  Contents

UEGW 2020 – Table of Contents - PowerPoint Presentation

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Selected Vedolizumab Presentations and Posters Title Presentation Longterm treatment with VDZ SC in ulcerative colitis interim results from VISIBLE OLE OP090 Effects of Subcutaneous Vedolizumab on HealthRelated Quality of Life and Work Productivity in Patients With Crohns Disease ID: 915542

week vdz 2020 patients vdz week patients 2020 disease vedolizumab visible clinical treatment remission exposure analysis ole colitis virtual

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Slide1

UEGW 2020 – Table of Contents

Selected

Vedolizumab Presentations and Posters

TitlePresentation Long-term treatment with VDZ SC in ulcerative colitis: interim results from VISIBLE OLEOP090Effects of Subcutaneous Vedolizumab on Health-Related Quality of Life and Work Productivity in Patients With Crohn’s Disease: Results From the Phase 3 VISIBLE 2 TrialP0511Disease Control and Changes in Individual Treatment Outcomes From Week 14 to Week 52 With Vedolizumab or Adalimumab in Ulcerative Colitis: A VARSITY Trial Post Hoc Analysis P0512ERELATE: real-world exposure-response relationship of vedolizumab in inflammatory bowel disease: a pooled multicenter observational cohort analysis of clinical and modeled pharmacological dataP0503Dose-Dependent Differential Effects of Vedolizumab Therapy on Adhesion of Regulatory and Effector T Cells OP003

1

VV-MEDMAT-29500

Slide2

Long-term treatment with vedolizumab SC in ulcerative colitis: interim results from VISIBLE OLE

Séverine

Vermeire, Silvio Danese, Krisztina Kisfalvi, Wenwen Zhang, Shashi Adsul, Siddharth Bhatia, William J. Sandborn

OLE, open-label extension; SC, subcutaneous; VDZ, vedolizumab.2

Slide3

1. Vermeire S, et al. UEG Week Virtual 2020; October 11-13, 2020; Oral Presentation OP090. 2.

Sandborn WJ, et al.

Gastroenterology. 2020;158(3):562-572.

VDZ is approved for the treatment of moderately to severely active UC or CD1The SC formulation of VDZ was evaluated as maintenance treatment in patients with UC in VISIBLE 1, a randomized, double-blind, placebo-controlled, phase 3 study1,2The VDZ SC maintenance treatment group had higher incidence of injection site reactions (10.4%) compared with the VDZ IV (1.9%) or placebo (0%) maintenance groups; these were not treatment limiting, most reactions were mild, and none resulted in discontinuation2Otherwise, the safety profiles of VDZ SC and IV were similarThis analysis reports the interim results from the UC patient population of VISIBLE OLE1,2 Randomized completers: patients who enrolled in VISIBLE OLE after completing 52 weeks of treatment in VISIBLE 1Nonrandomized Week 14 responders: patients who responded by Week 14 in VISIBLE 1 after an additional third VDZ IV induction doseSafety analysis set: all patients who rolled over from VISIBLE 1 who received at least one dose of VDZ SC during VISIBLE OLE

a

Clinical

Remission was defined as

Mayoscore

≤2 and

no

subscore

>1;

bEndoscopic improvement was defined as Mayo-Endoscopic-Subscore ≤1 cDurable clinical response was defined as clinical response at weeks 6 and 52. CD, Crohn’s disease; CI, confidence interval; IV, intravenous; OLE, open-label extension; SC, subcutaneous; UC, ulcerative colitis; VDZ, vedolizumab.

Week 52 efficacy results from the VISIBLE 1 trial

2

P<0.001

P<0.001

P<0.001

Clinical

remission

a

Endoscopic

improvement

b

Durable clinical

response

c

Background

Long-term treatment with vedolizumab SC in ulcerative colitis: interim results from

VISIBLE OLE (1/7)

1

3

Slide4

Long-term treatment with vedolizumab SC in ulcerative colitis: interim results from

VISIBLE OLE (2/7)

1

1. Vermeire S, et al. United European Gastroenterol J. 2020;8(8_suppl):65. 2.Vermeire S, et al. UEG Week Virtual 2020; October 11-13, 2020; Oral Presentation OP090. aClinical response in UC was defined as reduction in total Mayo score of ≥3 points and ≥30% from baseline with an accompanying decrease in RBS of ≥1 or absolute RBS of ≤1. bDefined as a partial Mayo score ≤2 and no individual subscore >1 point. CS, corticosteroid; IV, intravenous; OLE, open-label extension; Q2W, every 2 weeks; Q8W, every 8 weeks; QW, weekly; RBS, rectal bleeding subscore

; SC, subcutaneous; UC, ulcerative colitis; VDZ, vedolizumab;

Wk

, week.

Primary endpoint:

safety

Clinical efficacy outcomes:

long-term clinical remission

b

and CS-free clinical remission

Study design1,2Endpoints1,2

300 mg VDZ IV

at

Wk 0, 2

Evaluation of clinical response

a

Wk

52

Wk

0

Wk

6

Wk

14

Open-label

induction phase

Randomized

Wk

52 completers

108 mg VDZ SC Q2W

Nonrandomized

Wk

14 responders

108 mg VDZ SC Q2W

Randomized early withdrawals

108 mg VDZ SC QW

n=124

Wk

6 Responder

Nonresponder

Wk

14 responder

n=52

n=90

n=39

n=107

n=57

VISIBLE OLE

108 mg VDZ SC Q2W +

Placebo IV Q8W

300 mg VDZ IV Q8W +

Placebo SC Q2W

Placebo IV Q8W +

Placebo SC Q2W

3rd dose of 300 mg VDZ IV

Open-label maintenance phase

Efficacy analysis set

Safety analysis set

Randomized 1:

2

:1

at

Wk

6

VISIBLE 1

4

Slide5

Long-term treatment with vedolizumab SC in ulcerative colitis: interim results from

VISIBLE OLE (3/7)

1

aInterim analysis results through May 17, 2019.AE, adverse event; IV, intravenous; OLE, open-label extension; Q2W, every 2 weeks; Q8W, every 8 weeks; SAE, serious adverse event; SC, subcutaneous; UC, ulcerative colitis; VDZ, vedolizumab.1. Vermeire S, et al. United European Gastroenterol J. 2020;8(8_suppl):65. 2.Vermeire S, et al. UEG Week Virtual 2020; October 11-13, 2020; Oral Presentation OP090. Overview of AEs during VISIBLE OLE in patients with UC (safety analysis set)Overall AEs, n (%)

Previous VISIBLE 1 treatment group

Total

(N=288)

VDZ SC

108 mg Q2W

(n=90)

VDZ IV

300 mg Q8W

(n=39)

Placebo

(n=52)

Nonrandomized Week 14 responders

(n=107)

AEs

64 (71.1)

22 (56.4)

33 (63.5)

80 (74.8)

199 (69.1)

Related

to study drug

14 (15.6)

4 (10.3)

10 (19.2)

26 (24.3)

54 (18.8)

Leading to study drug discontinuation

4 (4.4)

1 (2.6)

2 (3.8)

6 (5.6)

13 (4.5)

Severity

Mild

34 (37.8)

12 (30.8)

14 (26.9)

33 (30.8)

93

(32.3)

Moderate

26 (28.9)

8 (20.5)

16 (30.8)

37 (34.6)

87

(30.2)

Severe

4 (4.4)

2 (5.1)

3 (5.8)

10 (9.3)

19 (6.6)

SAEs

12 (13.3)

5 (12.8)

6 (11.5)

16 (15.0)

39 (13.5)

Related to study drug

3 (3.3)

0

0

1 (0.9)

4 (1.4)

Leading to study drug discontinuation

3 (3.3)

0

2 (3.8)

5 (4.7)

10 (3.5)

Enrolled 288 patients from VISIBLE 1 at the time of this interim

analysis

a

The UC safety analysis set included all patients who rolled over from VISIBLE 1 who received at least 1 dose of VDZ SC during VISIBLE OLE

Primary endpoint: safety

During VISIBLE OLE, AEs occurred in 69.1% of patients with UC; serious AEs in 13.5%

There were no cases of progressive multifocal leukoencephalopathy and no deaths

Results

1,2

5

Slide6

Long-term treatment with vedolizumab SC in ulcerative colitis: interim results from

VISIBLE OLE (4/7)

1

Most frequent AEs (≥5%), n (%)Previous VISIBLE 1 treatment group

Total

(N=288)

VDZ SC

108 mg Q2W

(n=90)

VDZ IV

300 mg Q8W

(n=39)

Placebo

(n=52)

Nonrandomized Week 14 responders

(n=107)

UC

15 (16.7)

5 (12.8)

7 (13.5)

24 (22.4)

51 (17.7)­

Nasopharyngitis

7 (7.8)

5 (12.8)

7 (13.5)

14 (13.1)

33 (11.5)

URTI

16 (17.8)

1 (2.6)

3 (5.8)

7 (6.5)

27 (9.4)

Anemia

7 (7.8)

3 (7.7)

4 (7.7)

7 (6.5)

21 (7.3)

Diarrhea

4 (4.4)

0

2 (3.8)

9 (8.4)

15 (5.2)

Cough

2 (2.2)

1 (2.6)

2 (3.8)

7 (6.5)

12 (4.2)

Arthralgia

4 (4.4)

0

1 (1.9)

6 (5.6)

11 (3.8)

Bronchitis

3 (3.3)

3 (7.7)

1 (1.9)

4 (3.7)

11 (3.8)

Headache

1 (1.1)

0

3 (5.8)

7 (6.5)

11 (3.8)

Influenza

2 (2.2)

1 (2.6)

3 (5.8)

4 (3.7)

10 (3.5)

Sinusitis

2 (2.2)

0

3 (5.8)

5 (4.7)

10 (3.5)

Gastroenteritis

3 (3.3)

2 (5.1)

1 (1.9)

2 (1.9)

8 (2.8)

Injection site erythema

1 (1.1)

2 (5.1)

2 (3.8)

2 (1.9)

7 (2.4)

Injection site reaction

1 (1.1)

0

4 (7.7)

1 (0.9)

6 (2.1)

AEs, adverse events; cont’d, continued; IV, intravenous; OLE, open-label extension; Q2W, every 2 weeks; Q8W, every 8 weeks; SC, subcutaneous; UC, ulcerative colitis; URTI, upper respiratory tract infection; VDZ, vedolizumab.

1. Vermeire S, et al.

United European Gastroenterol J

. 2020;8(8_suppl):

65. 2.

Vermeire S, et al. UEG Week Virtual 2020; October 11-13, 2020; Oral Presentation OP090.

Results, cont’d

1,2

There were no deaths or cases of progressive multifocal leukoencephalopathy.

a

The UC safety analysis set included all patients who rolled over from VISIBLE 1 who received at least 1 dose of VDZ SC during VISIBLE OLE.

Most frequent AEs during VISIBLE OLE in patients with UC (safety analysis set)a

6

Slide7

Long-term treatment with vedolizumab SC in ulcerative colitis: interim results from

VISIBLE OLE (5/7)

1

Clinical efficacy outcomes With VDZ SC treatment, clinical remission rates were maintained from Weeks 6 to 108 in VISIBLE 1 randomized completers and from Weeks 14 to 110 in the nonrandomized Week 14 responders1

The UC efficacy population was defined as the full analysis set, which included all patients who rolled over from VISIBLE 1 to VISIBLE OLE. Evaluable patients are shown for each visit, with missing data for evaluable patients categorized as nonresponders.

a

Clinical

remission: partial Mayo score of ≤2 and no individual subscore >1 point.

b

Week 52 of this analysis combined Week 52 of VISIBLE 1 and Week 0 of VISIBLE OLE.

c

Week 54 for patients with Q2W dose in

VISIBLE OLE

. dEvaluable patients at Week 108: placebo, n=17; VDZ SC 108 mg, n=61; VDZ IV 300 mg, n=28. eAnalysis limited to VISIBLE 1 patients who rolled into VISIBLE OLE. fWeek 14 of this analysis combined Week 14 of VISIBLE 1 and Week 0 of VISIBLE OLE. gEvaluable patients at Week 110: n=93.CI, confidence interval; IV, intravenous; OLE, open-label extension; Q2W, every 2 weeks; SC, subcutaneous; UC, ulcerative colitis; VDZ, vedolizumab.Clinical remissiona over time in patients with UC

2,3

Nonrandomized Week 14 responders

Results

Randomized completers

Weeks on Treatment From VISIBLE 1 Baseline

Patients, % (95% CI)

VISIBLE 1

VISIBLE OLE

108 mg VDZ SC Q2W

VISIBLE 1

VISIBLE OLE

Weeks on Treatment From VISIBLE 1 Baseline

Patients, % (95% CI)

108 mg VDZ SC Q2W (n=107)

VDZ IV

e,f

b

c

d

g

1.

Vermeire

S, et al. UEG Week Virtual 2020; October 11-13, 2020; Abstract OP090. 2.

Vermeire

S, et al. UEG Week Virtual 2020; October 11-13, 2020; Oral Presentation OP090. 3.

Vermeire

S, et al. ACG 2020 Virtual Annual Scientific Meeting; October 23-28, 2020; Oral Presentation OP50.

7

Slide8

Long-term treatment with vedolizumab SC in ulcerative colitis: interim results from

VISIBLE OLE (6/7)

1

Clinical efficacy outcomes (cont’d)CS-free clinical remission rates were maintained in VISIBLE 1 randomized completers from Weeks 52 to 108 and in nonrandomized Week 14 responders from Weeks 54 to 1101CS-free clinical remissiona over time in patients with UC2,3Results

Weeks on Treatment From VISIBLE 1 Baseline

VISIBLE 1

VISIBLE OLE

Patients, % (95% CI)

108 mg VDZ SC Q2W

d

c

b

VISIBLE 1

VISIBLE OLE

Weeks on Treatment From VISIBLE 1 Baseline

e,f

g

Patients, % (95% CI)

VDZ IV

108 mg VDZ SC Q2W (n=107)

Nonrandomized Week 14 responders

Randomized completers

The UC efficacy population was defined as the full analysis set, which included all patients who rolled over from VISIBLE 1 to VISIBLE OLE. Evaluable patients are shown for each visit, with missing data for evaluable patients categorized as nonresponders.

a

Corticosteroid

-free clinical remission is defined as patients on a baseline oral CS wo discontinued oral CS use and were in clinical remission.

b

Week

52 of this analysis combined Week 52 of VISIBLE 1 and Week 0 of VISIBLE OLE.

c

Week 54 for patients with Q2W dose in

VISIBLE OLE

.

d

Evaluable patients at Week 108: placebo, n=7; VDZ SC 108 mg, n=20; VDZ IV 300 mg, n=12.

e

Analysis limited to VISIBLE 1 patients who rolled into VISIBLE OLE.

f

Week 14 of this analysis combined Week 14 of VISIBLE 1 and Week 0 of VISIBLE OLE.

g

Evaluable patients at Week 110: n=44.

cont’d, continued; CI, confidence interval; CS, corticosteroid; IV, intravenous; OLE, open-label extension; Q2W, every 2 weeks; SC, subcutaneous; UC, ulcerative colitis; VDZ, vedolizumab.

1.

Vermeire

S, et al. UEG Week Virtual 2020; October 11-13, 2020; Abstract OP090. 2.

Vermeire

S, et al. UEG Week Virtual 2020; October 11-13, 2020; Oral Presentation OP090. 3.

Vermeire

S, et al. ACG 2020 Virtual Annual Scientific Meeting; October 23-28, 2020; Oral Presentation OP50.

8

Slide9

Long-term treatment with vedolizumab SC in ulcerative colitis: interim results from

VISIBLE OLE (7/7)

1

Long-term safety findings for VDZ SC were consistent with the known safety profile of VDZRates of clinical remission and CS-free clinical remission were maintained for up to 2 years with VDZ SC treatmentCS, corticosteroid; IV, intravenous; OLE, open-label extension; SC, subcutaneous; UC, ulcerative colitis; VDZ, vedolizumab.Conclusions1. Vermeire S, et al. United European Gastroenterol J. 2020;8(8_suppl):65. 2.Vermeire S, et al. UEG Week Virtual 2020; October 11-13, 2020; Oral Presentation OP090. 9

Slide10

Effects of subcutaneous vedolizumab on

health-related quality of life and work productivity in patients with Crohn’s disease: results from the phase 3 VISIBLE 2 trial

Geert D’Haens, William J. Sandborn, Wenwen Zhang, Krisztina Kisfalvi, Song Wang, Séverine Vermeire10

Slide11

Effects of subcutaneous vedolizumab on health-related quality of life and work productivity

in patients with Crohn’s disease: results from the phase 3 VISIBLE 2 trial (1/4)

1

CD, Crohn’s disease; HRQoL, health-related quality of life; SC, subcutaneous; VDZ, vedolizumab. 1. D’Haens G, et al. UEG Week Virtual 2020; October 11-13, 2020; Poster P0511. 2. Vedolizumab [package insert]. Deerfield, IL: Takeda Pharmaceuticals America Inc; 2019. 3. Sandborn WJ, et al. N Engl J Med. 2013;369(8):711-721. 4. Vermeire S, et al. J Crohns Colitis. 2017;11(4):412-424. 5. Sandborn WJ, et al. Gastroenterology. 2020;158(3):562-572. 6. Vermeire S, et al. Gastroenterology. 2020;158(6 suppl 1):S-194. Abstract 950. 7. Vedolizumab [summary of product characteristics]. Taastrup, Denmark: Takeda Pharma A/S; 2020. 8. Vedolizumab [product monograph]. Toronto, Ontario, Canada: Takeda Canada Inc.; 2020. 9. Vedolizumab Australian [product information]. Sidney, Australia: Takeda Pharmaceuticals Australia Pty Ltd.; 2020. Crohn’s disease (CD) is a chronic, progressive, inflammatory disorder that negatively affects patient health-related quality of life (HRQoL

) and work productivity1

Intravenous VDZ (VDZ IV) is approved for the treatment of moderately to severely active ulcerative colitis (UC) and CD.

2,7

In the GEMINI 2 trial, VDZ IV significantly improved patient-reported quality of life and work productivity versus placebo and long-term

HRQoL

benefits in patients with CD

3,4

The VISIBLE 1 and 2 trials demonstrated the efficacy and safety of a subcutaneous (SC) formulation of VDZ in patients with moderately to severely active UC and CD, respectively

5-6VDZ SC is now available in the European Union, Canada, and Australia, and offers patients an alternative route of administration for maintenance treatment of UC (all 3 regions) and CD (European Union and Australia only)7-9 BackgroundEvaluate patient-reported outcomes (PROs), including clinical remission, HRQoL, and work productivity, in patients with moderately to severely active CD who received VDZ IV induction treatment followed by either VDZ SC or placebo maintenance treatmentAim11

Slide12

Effects of subcutaneous vedolizumab on health-related quality of life and work productivity

in patients with Crohn’s disease: results from the phase 3 VISIBLE 2 trial (2/4)

1

Study designVISIBLE 2 (NCT02611817; EudraCT 2015-000481-58) was a pivotal, phase 3, randomized, double-blind, placebo-controlled trialClinical remission at Week 52 was defined using diary items from the Crohn’s Disease Activity Index (CDAI) PRO2 score ≤8 and PRO3 score ≤13 were selected to correspond to CDAI <1502 Daily stool frequency score ≤1.5 and abdominal pain score ≤1 corresponds to 2 of the 3 optimal cut-points for CDAI remission2 HRQoL assessments were collected at baseline, Week 6, Week 30, and Week 52, and included IBDQ3, the EQ-5D instrument4, and the WPAI-CD51. D’Haens G, et al. UEG Week Virtual 2020; October 11-13, 2020; Poster P0511. 2.

Sandborn WJ, et al. N

Engl

J Med. 2013;369(8):711-721. 3. Gregor JC, et al.

Inflamm

Bowel Dis. 1997;3(4):265-276. 4. König HH, et al. Eur J Gastroenterol

Hepatol

. 2002;14:12005-12015. 5. Reilly MC, et al. Clin

Ther

. 2008;30(2):393-404.

aWeek 6 clinical response is defined as a ≥70-point decrease in CDAI from baseline. bOne randomized patient did not receive the study drugCD, Crohn’s disease; CDAI, Crohn’s Disease Activity Index; CS, corticosteroid; EQ-5D, EuroQoL-5D; HRQoL, health-related quality of life; IBDQ, inflammatory bowel disease questionnaire; IMM, immunomodulator; IV, intravenous; PRO, patient-reported outcomes; Q2W, every 2 weeks; SC, subcutaneous; TNF, tumor necrosis factor; WPAI-CD, Work Productivity and Activity Impairment Questionnaire in Crohn's Disease.12

Slide13

Effects of subcutaneous vedolizumab on health-related quality of life and work productivity

in patients with Crohn’s disease: results from the phase 3 VISIBLE 2 trial (3/4)

1

Results More patients on VDZ SC than placebo maintenance achieved clinical remission based on PRO2, PRO3, and daily stool frequency and abdominal pain at Week 52Patient-reported HRQoL and work productivity improved from baseline to Week 6 following VDZ IV induction, with Week 6 changes sustained through Week 52 in both maintenance treatment armsIBDQ, EQ-5D, EQ-5D VAS, and WPAI-CD overall work productivity loss from baseline to Week 52 showed clinically meaningful improvements in both treatment arms, with a trend favoring VDZ SC maintenance treatmentIBDQ subscores and overall WPAI-CD work productivity loss showed numerically greater improvements with VDZ SC versus placebo maintenance at Week 52Patients with moderately to severely active CD were more likely to achieve patient-reported clinical remission with VDZ SC versus placebo maintenance therapy and maintained improvements in HRQoL and work productivity with VDZ SC maintenance therapy

aNominal

p values are reported.

b

PRO2 is defined as a combined CDAI AP

subscore

and SF

subscore

8. cPRO3 is defined as a combined CDAI AP subscore, SF subscore, and general well-being subscore ≤13. AP, abdominal pain; CD, Crohn’s disease; CDAI, Crohn’s Disease Activity Index; CI, Confidence Index; EQ-5D, Euro Quality of Life-5 Dimension; HRQoL, health-related quality of life; IBDQ, inflammatory bowel disease questionnaire; IMM, immunomodulator; IV, intravenous PRO, patient-reported outcomes; SC, subcutaneous; SD, standard deviation; SF, stool frequency; TNF, tumor necrosis factor; VAS, visual analog scale; VDZ, vedolizumab; WPAI-CD, Work Productivity and Activity Impairment Questionnaire in Crohn's Disease.1. D’Haens G, et al. UEG Week Virtual 2020; October 11-13, 2020; Poster P0511.Daily stool frequency score ≤1.5

and abdominal pain score ≤1

PRO2 ≤8

b

PRO3 ≤13c

∆=11.3

(95% CI, 1.7 to 20.9)

p

=0.026a

∆=9.8

(95% CI, 0.1 to 19.5)

p

=0.053

a

∆=5.2

(95% CI, -3.8 to 14.3)

p

=0.263a

% Patients (95% CI)

Placebo

Vedolizumab SC

Shaded areas indicate open-label vedolizumab IV induction prior to randomization to maintenance treatment.

13

Slide14

Effects of subcutaneous vedolizumab on health-related quality of life and work productivity

in patients with Crohn’s disease: results from the phase 3 VISIBLE 2 trial (4/4)

1

More patients treated with VDZ SC versus placebo maintenance therapy achieved clinical remission based on patient-reported CDAI items, improved HRQoL, and improved work productivity These results support the clinical benefits of VDZ SC for patients with moderately to severely active CD The HRQoL benefits of VDZ SC parallel VISIBLE 2 trial primary endpoint results for clinical remission based on CDAI score ≤150 (48.0% versus 34.3% of patients receiving VDZ SC versus placebo maintenance therapy, respectively)2The sustained improvements from baseline in IBDQ and EQ-5D scores with VDZ SC maintenance therapy given every 2 weeks in VISIBLE 2 were consistent with improvements observed with VDZ IV maintenance therapy given every 8 weeks in the GEMINI 2 trial3ConclusionsCD, Crohn’s disease; CDAI, Crohn’s Disease Activity Index; EQ-5D, EuroQoL-5D; HRQoL, health-related quality of life; IBDQ, inflammatory bowel disease questionnaire; IV, intravenous; SC, subcutaneous; TNF, tumor necrosis factor; VDZ, vedolizumab.1. D’Haens G, et al. UEG Week Virtual 2020; October 11-13, 2020; Poster P0511. 2.

Vermeire S, et al.

Gastroenterology

. 2020;158(6 suppl 1):S-194. Abstract 950. 3. 3.

Sandborn

WJ, et al.

N

Engl

J Med.

2013;369(8):711-721

14

Slide15

Disease control and changes in individual treatment outcomes from Week 14 to Week 52 with vedolizumab or adalimumab in ulcerative colitis: a VARSITY trial post hoc analysis

Stefan Schreiber, Silvio

Danese

, Laurent Peyrin-Biroulet, Jean-Frédéric Colombel, Bruce E. Sands, Dirk Lindner, Richard A. Lirio, Christian Agboton, Edward V. Loftus, Jr.15

Slide16

Disease control and changes in individual treatment outcomes from Week 14 to Week 52 with vedolizumab or adalimumab in ulcerative colitis: a VARSITY trial post hoc analysis (1/4)

1

UC, ulcerative colitis.

1. Schreiber S, et al. UEG Week Virtual 2020; October 11-13, 2020; Poster P0512. 2. Sands BE, et al. N Engl J Med. 2019;381(13):1215-1226. 3. Danese S, et al. Nat Rev Gastroenterol Hepatol. 2020;17(1):1-2. 4. Ungaro R, et al. Am J Gastroenterol. 2018;114(6):874-883Vedolizumab is a gut-selective humanized anti-α4β7 integrin antibody approved to treat adult patients with moderately to severely active ulcerative colitis (UC) or Crohn’s disease (CD) VARSITY was the first head-to-head comparison of the efficacy and safety of 2 biologic agents in UC at both Week 14 and Week 522The VARSITY trial demonstrated that vedolizumab achieved higher rates of clinical remission and endoscopic improvement than adalimumab, an anti-tumor necrosis factor (TNF) agent, in patients with UC With the introduction of highly effective biologics, UC treatment goals have evolved from symptom relief to true disease control across multiple measures of efficacy3,4In most clinical trials, endpoints (e.g., clinical, endoscopic, histologic remission) are assessed in parallel but independent of individual patient samples. Analysis of disease control, a novel concept of a combined endpoint evaluation of these high value outcomes in the same patients, would be clinically most meaningful

Background

To evaluate the trajectory of changes in UC key efficacy endpoints and disease control with intravenous (IV) vedolizumab versus subcutaneous (SC) adalimumab treatment between early (Week 14) and late (Week 52) time points

Aim

16

Slide17

Disease control and changes in individual treatment outcomes from Week 14 to Week 52 with vedolizumab or adalimumab in ulcerative colitis: a VARSITY trial post hoc analysis (2/4)

1

IV, intravenous; Q2W, every 2 weeks; Q8W, every 8 weeks; SC, subcutaneous; TNF,

tumour necrosis factor; Wk, Week. Randomisation stratification factors were concomitant use of oral corticosteroids and previous exposure/failure of anti-TNF therapy or naïve to anti-TNF therapy. No dose escalation was permitted for either treatment group. aIncludes 2 patients who were randomised but did not receive a dose of vedolizumab1. Schreiber S, et al. UEG Week Virtual 2020; October 11-13, 2020; Poster P0512 and online supplement. 2. Clinicaltrials.gov. https://clinicaltrials.gov/ct2/show/NCT02497469 Accessed November 2020. 3. Sands BE, et al. N Engl J Med 2019;381:1215-1226.

Study design

VARSITY (NCT02497469; EudraCT 2015-000939-33) was a phase 3b, randomized, double-blind, double-dummy, multicenter, active controlled study

2,3

Post hoc analyses of changes in disease control (a composite of clinical remission plus endoscopic and histologic improvement) over time with vedolizumab or adalimumab treatment were performed based on the proportion of patients who maintained, improved, or lost treatment benefit from Week 14 to Week 52

3

Endpoints included clinical remission, endoscopic improvement, histologic improvement, and a composite of these 3 endpoints (disease control), with subgroup analyses performed for anti-TNF-naïve or anti-TNF-experienced patients

Primary endpoint of the study:

clinical remission at week 52

2,317

Slide18

Disease control and changes in individual treatment outcomes from Week 14 to Week 52 with vedolizumab or adalimumab in ulcerative colitis: a VARSITY trial post hoc analysis (3/4)

1

Results

1. Schreiber S, et al. UEG Week Virtual 2020; October 11-13, 2020; Poster P0512.VDZ achieves higher rates of clinical efficacy outcomes at Weeks 14 and 52 and maintains greater disease control from Week 14 to Week 52 than adalimumab in patients with moderately to severely active UC, especially in the anti-TNF-naïve populationMore patients with UC maintained or gained clinical efficacy outcomes and the composite disease control outcome from Week 14 to Week 52 with VDZ than with adalimumab, with more pronounced benefits in the anti-TNF-naïve subgroupsDisease control at Week 52 was associated with lower baseline endoscopic subscore, fecal calprotectin and C-reactive protein values, and no prior use of anti-TNFClinical efficacy outcomes and disease control were achieved more frequently in patients with UC treated with VDZ than with adalimumab at Week 14 and Week 52, with more pronounced benefits in the anti-TNF-naïve subgroups aClinical remission: partial Mayo score of ≤2 and no individual subscore >1 point. bEndoscopic improvement: Mayo endoscopic subscore

of ≤1. c

Histologic

improvement: Robarts Histological Index score of <5.

d

Disease control: composite of clinical remission plus endoscopic and histologic improvement.

IV, intravenous; SC, subcutaneous; TNF, tumor necrosis factor; UC, ulcerative colitis; VDZ, vedolizumab.

Week 14

Week 52

Patients (%)

N=201 I N=244N=168 I N=203N=33 I N=41

Patients (%)

N=221 I N=265

N=184 I N=216

N=37 I N=49

Patients (%)

N=232 I N=271

N=190 I N=223

N=42 I N=48

Patients (%)

N=223 I N=271

N=184 I N=225

N=39 I N=46

Patients (%)

N=309 I N=327

N=241 I N=262

N=68 I N=65

Patients (%)

N=342 I N=344

N=270 I N=277

N=72 I N=67

Patients (%)

N=337 I N=345

N=265 I N=278

N=72 I N=67

Patients (%)

N=332 I N=343

N=261 I N=274

N=71 I N=69

Disease

Control,

d

%

Clinical

Remission,

a

%

Endoscopic

Improvement,

b

%

Histologic

Improvement,

c

%

Adalimumab SC

Vedolizumab IV

18

Slide19

Disease control and changes in individual treatment outcomes from Week 14 to Week 52 with vedolizumab or adalimumab in ulcerative colitis: a VARSITY trial post hoc analysis (4/4)

1

VDZ treatment maintains greater early disease control than adalimumab in patients with moderately to severely active UC from treatment Week 14 to Week 52

This benefit is more pronounced in patients without prior exposure to anti-TNF agents These data suggest that VDZ is superior to adalimumab not only during induction treatment evaluated at Week 14 but also during the maintenance phase at Week 52 Each of the clinical efficacy outcomes evaluated is associated with a more favorable long-term course of disease; therefore, achieving disease control as a composite endpoint of these outcomes is expected to deliver additional benefits to patients Most of the observed treatment differences in anti-TNF-naïve patients at Week 52 were established with early response to treatment that occurred between Week 0 and Week 14ConclusionsTNF, tumor necrosis factor; UC, ulcerative colitis; VDZ, vedolizumab. 1. Schreiber S, et al. UEG Week Virtual 2020; October 11-13, 2020; Poster P0512.19

Slide20

ERELATE: real-world exposure-response relationship of vedolizumab in inflammatory bowel disease: a pooled multicenter observational cohort analysis of clinical and modeled pharmacological data

Niels

Vande

Casteele, William Sandborn, Brian Feagan, Séverine Vermeire, Parambir S. Dulai, Julian Panés, Andres Yarur, Xavier Roblin, Shomron Ben-Horin, Iris Dotan, Mark Osterman, Dirk Lindner, Christian Agboton, Maria Rosario, Teresa Osborn20

Slide21

ERELATE: real-world exposure-response relationship of vedolizumab in inflammatory bowel disease: a pooled multicenter observational cohort analysis of clinical and modeled

pharmacological data (1/7)

1

CD, Crohn’s disease; IBD, inflammatory bowel disease; TDM, therapeutic drug monitoring; UC, ulcerative colitis; VDZ, vedolizumab.1. Casteele NV, et al. UEG Week Virtual 2020; October 11-13, 2020; Poster P0503. 2. Entyvio [package insert]. Deerfield, IL: Takeda Pharmaceuticals America Inc; 2020. 3. Ward MG, et al. Therap Adv Gastroenterol. 2018;11:1756284818772786. 4. Feuerstein JD, et al. Gastroenterology. 2017;153(3):827-834. 5. Vande Casteele N, et al. Gastroenterology. 2017;153(3):835-857.e6. 6. Papamichael K, et al. Clin Gastroenterol Hepatol. 2019;17(9):1655-1668.e3. 7. Rosario M, et al. Aliment Pharmacol Ther. 2015;42(2):188-202. 8. Rosario M, et al. J Crohns Colitis. 2017;11(8):921-929. TDM of VDZ, a humanized monoclonal antibody targeting the α4β7 integrin, is under investigation to optimize treatment outcomes in UC and CD2,3However, the lack of an established therapeutic target and assay variability limit the clinical applications of TDM of VDZ4-6Population pharmacokinetics and the induction treatment exposure-response relationship of intravenous VDZ were previously described based on phase 3 clinical trial data from the GEMINI program7,8

The relationship between VDZ serum concentrations and clinically important outcomes is being studied in the real-world setting

1

Background

To evaluate the VDZ exposure-response relationship in patients with UC or CD in a multicenter real-world setting and delineate VDZ exposure thresholds that are associated with clinically important outcomes

1

Aim

21

Slide22

ERELATE: real-world exposure-response relationship of vedolizumab in inflammatory bowel disease: a pooled multicenter observational cohort analysis of clinical and modeled

pharmacological data (2/7)

1

aThe FAS included all eligible patients enrolled in the study who had at least 1 postbaseline data point for at least 1 treatment outcome. bThe ERR population included all patients with data on baseline body weight, serum albumin concentrations, and VDZ dosing history that were included in the population PK modeling. cAn additional VDZ induction dose at Week 10 was implemented at some European centers. dSerum VDZ exposure thresholds determined using the optimal Youden index point along the ROC curve. eClinical remission: complete resolution of IBD-related symptoms in the PGA. If PGA was not available at a time point, pMCS ≤2 with no individual subscore >1 for patients with UC and CDAI ≤150 or HBI ≤4 for patients with CD. fEndoscopic remission: absence of large ulcers >5 mm for patients with CD and MCES 0/≤1 for patients with UC. If data on ulcers were not available at a time point for patients with CD, CDEIS ≤4 or SES-CD total score <3. gDeep remission: clinical and endoscopic remission (absence of large ulcers >5 mm for patients with CD and MCES ≤1 for patients with UC), or clinical and biologic remission (CRP <5 mg/L) if endoscopic assessment was not available.CD, Crohn’s disease; CDAI, Crohn’s Disease Activity Index; CDEIS, Crohn’s Disease Endoscopic Index Score; CLL, linear clearance; CLNL, nonlinear clearance; CRP, C-reactive protein; ERR, exposure-response relationship; FAS, full analysis set; HBI, Harvey-Bradshaw Index; IBD, inflammatory bowel disease; IV, intravenous; MCES, Mayo Clinic Endoscopic Subscore; NONMEM, nonlinear mixed effects modeling; PGA, physician’s global assessment; PK, pharmacokinetic; pMCS, partial Mayo Clinic subscore; ROC, receiver operating characteristic; SES-CD, Simplified Endoscopic Subscore for Crohn’s Disease; UC, ulcerative colitis; VDZ, vedolizumab.Study design and methodsERELATE was a retrospective, multinational, multicenter cohort study that pooled RWD from patients with UC or CD treated with IV VDZ in clinical practice

2

Using a population PK model

3

, VDZ dosing, baseline body weight, and albumin concentration were used to predict VDZ concentrations

4

A Bayesian approach incorporated observed VDZ concentrations to refine individual predicted concentrations

4

Relationships between predicted concentrations and observed clinically important outcomes were investigated

4

VDZ concentration thresholds were determined using the optimal Youden index point along the ROC curve4Correlation and agreement between observed and predicted concentrations were evaluated using Spearman (ρ) and ICC coefficients, respectively41. Casteele NV, et al. UEG Week Virtual 2020; October 11-13, 2020; Poster P0503. 2. Casteele NV, et al. ACG 2020 Virtual Annual Scientific Meeting; October 23-28, 2020; Oral Presentation OP49. 3. Rosario M, et al. Aliment Pharmacol Ther. 2015;42(2):188-202. 4.

Casteele NV, et al. UEG Week Virtual 2020; October 11-13, 2020; Abstract P0503.

Data Collection

May 2014 – Nov 2019

22

Study Outcomes

Outcomes

Week

Outcomes

0

6

10

14

22

26

46

52

Predicted measures of exposure

VDZ serum concentration

VDZ exposure

thresholds

d

Patient response to VDZ therapy

Clinical

remission

e

Endoscopic

remission

f

Deep

remission

g

Data collection

May 2014–Nov 2019

Population PK Modelling With Bayesian Updating

Population PK modelling

ERR,

b

N=658 (UC=291, CD=367)

Required

Baseline body weight

Baseline serum albumin

Vedolizumab dosing

history

c

Optional

Observed serum VDZ concentrations

Patients ≥17 years with UC or CD from 9 centers in

6 countries treated with VDZ

≥12 months from

data collection

FAS,

a

N=695

(UC=304, CD=391)

Patient’s individually predicted VDZ serum concentration-time curve

Population PK modelling

6

Two-compartment model

Central

compartment

Peripheral

compartment

CL

NL

CL

L

Dose

Intercompartmental

clearance

Maximum

a posterioriestimation usingNONMEM®

Slide23

ERELATE: real-world exposure-response relationship of vedolizumab in inflammatory bowel disease: a pooled multicenter observational cohort analysis of clinical and modeled

pharmacological data (3/7)

1

ResultsCD, Crohn’s disease; ERR, exposure-response relationship; ICC, intraclass coefficient; PK, pharmacokinetic; ρ, Spearman coefficient; TNF, tumor necrosis factor; UC, ulcerative colitis; VDZ, vedolizumab.Study included a total of 695 patients, of whom 304 were patients with UC and 391 were patients with CD2Of the total population, 47.9% were male Median age was 39 yearsMedian disease duration was 9 years Of the total population, 86.3% had prior anti-TNF exposureThere was adequate Bayesian model prediction of individual VDZ concentrations1,3Significant correlation between observed and predicted concentrations ([ρ=0.907; P=0.0001] across all time points)

Significant agreement between observed and predicted concentrations (ICC=0.607; P=0.0017)

a

The

ERR population included all patients with data on baseline body weight, serum albumin concentrations, and VDZ dosing history that were included in the population PK modeling. Only patients with observed VDZ concentrations were included in this analysis, and observations from more than 1 time point were included for some patients. N = total number of patients with observed VDZ concentrations available. Observations = number of plotted observed VDZ concentration values.

Individual predicted serum VDZ concentrations among patients

with UC and CD were significantly correlated with observed concentrations across all time points (ERR

population

a

)

1,31. Casteele NV, et al. UEG Week Virtual 2020; October 11-13, 2020; Poster P0503. 2. Casteele NV, et al. UEG Week Virtual 2020; October 11-13, 2020; Abstract P0503. 3.Casteele NV, et al. ACG 2020 Virtual Annual Scientific Meeting; October 23-28, 2020; Oral Presentation OP49.

0

20

40

60

80

100

120

0

20

40

60

80

100

120

Individual Predicted Vedolizumab Concentration, mg/L

Observed Vedolizumab Concentration, mg/L

N=324, Observations=874

Identity line

CD

UC

ρ

=

0.907; P<0.0001

ICC=0.607; P

=0.0017

23

Slide24

ERELATE: real-world exposure-response relationship of vedolizumab in inflammatory bowel disease: a pooled multicenter observational cohort analysis of clinical and modeled

pharmacological data (4/7)

1

Results, cont’dCD, Crohn’s disease; CDAI, Crohn’s Disease Activity Index; CDEIS, Crohn’s Disease Endoscopic Index Score; cont’d, continued; CRP, C-reactive protein; FAS, full analysis set; HBI, Harvey-Bradshaw Index; IBD, inflammatory bowel disease; MCES, Mayo Clinic Endoscopic Subscore; PGA, physician’s global assessment; pMCS, partial Mayo Clinic subscore; SES-CD, Simplified Endoscopic Subscore for Crohn’s Disease; UC, ulcerative colitis.All proportions are relative to the FAS population with nonmissing information. Patients who discontinued VDZ because of no response to induction or loss of response during maintenance therapy were considered treatment failures for subsequent time points.aClinical remission: complete resolution of IBD-related symptoms in the PGA. If PGA was not available at a time point, pMCS ≤2 with no individual subscore >1 for patients with UC and CDAI ≤150 or HBI ≤4 for patients with CD. bEndoscopic remission: absence of large ulcers >5 mm for patients with CD and MCES 0/≤1 for patients with UC. If data on ulcers were not available at a time point for patients with CD, CDEIS ≤4 or SES-CD total score <3. cDeep remission: clinical and endoscopic remission (absence of large ulcers >5 mm for patients with CD and MCES ≤1 for patients with UC), or clinical and biologic remission (CRP <5 mg/L) if endoscopic assessment was not available.Clinically important outcomes in patients with UC and CD (FAS)1,21. Casteele NV, et al. UEG Week Virtual 2020; October 11-13, 2020; Poster P0503. 2. Casteele NV, et al. ACG 2020 Virtual Annual Scientific Meeting; October 23-28, 2020; Oral Presentation OP49.

Deep

remission

c

Clinical

remission

a

Endoscopic

remission

b

194

280

114

32

163

234

174

235

59

50

147

205

158

206

94

66

137

168

CD:

Week 26

Week 52

Week 14

UC:

Week 26

Week 52

Week 14

Patients, %

24

Slide25

ERELATE: real-world exposure-response relationship of vedolizumab in inflammatory bowel disease: a pooled multicenter observational cohort analysis of clinical and modeled

pharmacological data (5/7)

1

Analyses were conducted in the ERR population using the nonresponder imputation method. Predicted exposure thresholds were delineated for Weeks 6, 10, and 14. *Lower 95% CI >0.5.The ERR population included all patients with data on baseline body weight, serum albumin concentrations, and VDZ dosing history that were included in the population PK modeling.aClinical remission: complete resolution of IBD-related symptoms in the PGA. If PGA was not available at a time point, pMCS ≤2 with no individual subscore >1 for patients with UC and CDAI ≤150 or HBI ≤4 for patients with CD. The AUC of ROC for clinical remission for UC and CD separately ranged between 0.615 and 0.680. Results, cont’dAUC, area under the curve; CD, Crohn’s disease; CDAI, Crohn’s Disease Activity Index; CI, confidence interval; cont’d, continued; CRP, C-reactive protein; ERR, exposure-response relationship; HBI, Harvey-Bradshaw Index; IBD, inflammatory bowel disease; IQR, interquartile range; MCES, Mayo Clinic Endoscopic Subscore; nd, not determinable; ns, nonsignificant; PGA, physician’s global assessment; PK, pharmacokinetic; pMCS, partial Mayo Clinic subscore; ROC, receiver operating characteristic; UC, ulcerative colitis; VDZ, vedolizumab. 1. Casteele NV, et al. UEG Week Virtual 2020; October 11-13, 2020; Poster P0503. 2. Casteele NV, et al. ACG 2020 Virtual Annual Scientific Meeting; October 23-28, 2020; Oral Presentation OP49. Positive ERR between serum VDZ concentrations and clinical outcomes were more pronounced in UC than in CD, and early VDZ exposure thresholds were modestly associated with treatment outcomes at Weeks 14 and 52 (ERR population)1Exposure-response relationships between serum VDZ concentrations and clinical remission1,2,a

UC

CD

Periodic Serum Vedolizumab

Concentration, mg/L, Median (IQR)

Weeks from Dose

Initiation

6

10

14

22

46

Week 14

34.4*

28.9*

10.5*

6

10

14

22

46

Remitters (N=62)

Nonremitters (N=88)

Week 52

31.9*

33.2*

14.8*

6

10

14

22

46

Remitters (N=111)

Nonremitters (N=153)

Week 14

ns

ns

28.2*

0

1

0

2

0

3

0

4

0

5

0

6

10

14

22

46

Remitters (N=69)

Nonremitters (N=125)

Week 52

ns

41.5*

nd

Remitters (N=104)

Nonremitters (N=83)

0

1

0

2

0

3

0

4

0

5

0

0

1

0

2

0

3

0

4

0

5

0

0

1

0

2

0

3

0

4

0

5

0

Predicted

V

edolizumab Exposure

Threshold, mg/L

25

Slide26

ERELATE: real-world exposure-response relationship of vedolizumab in inflammatory bowel disease: a pooled multicenter observational cohort analysis of clinical and modeled

pharmacological data (6/7)

1

Analyses were conducted in the ERR population using the nonresponder imputation method. Predicted exposure thresholds were delineated for Weeks 6, 10, and 14. *Lower 95% CI >0.5.The ERR population included all patients with data on baseline body weight, serum albumin concentrations, and VDZ dosing history that were included in the population PK modeling.aDeep remission: clinical and endoscopic remission (absence of large ulcers >5 mm for patients with CD and MCES ≤1 for patients with UC), or clinical and biologic remission (CRP <5 mg/L) if endoscopic assessment was not available. The AUC of ROC for deep remission for UC and CD separately ranged between 0.630 and 0.724.Results, cont’dAUC, area under the curve; CD, Crohn’s disease; CDAI, Crohn’s Disease Activity Index; CI, confidence interval; cont’d, continued; CRP, C-reactive protein; ERR, exposure-response relationship; HBI, Harvey-Bradshaw Index; IBD, inflammatory bowel disease; IQR, interquartile range; MCES, Mayo Clinic Endoscopic Subscore; nd, not determinable; ns, nonsignificant; PGA, physician’s global assessment; PK, pharmacokinetic; pMCS, partial Mayo Clinic subscore; ROC, receiver operating characteristic; UC, ulcerative colitis; VDZ, vedolizumab. 1. Casteele NV, et al. UEG Week Virtual 2020; October 11-13, 2020; Poster P0503. 2. Casteele NV, et al. ACG 2020 Virtual Annual Scientific Meeting; October 23-28, 2020; Oral Presentation OP49. Positive ERR between serum VDZ concentrations and clinical outcomes were more pronounced in UC than in CD, and early VDZ exposure thresholds were modestly associated with treatment outcomes at Weeks 14 and 52 (ERR population)Exposure-response relationships between serum VDZ concentrations and deep remission1,2,a

UC

CD

Weeks from Dose

Initiation

6

10

14

22

46

Week 14

34.1*

31.9*

11.6*

6

10

14

22

46

Remitters (N=31)

Nonremitters (N=99)

Week 52

33.2*

32.5*

10.6*

6

10

14

22

46

Remitters (N=54)

Nonremitters (N=171)

Week 14

30.4*

32.7*

22.8*

0

1

0

2

0

3

0

4

0

5

0

6

10

14

22

46

Remitters (N=36)

Nonremitters (N=125)

Week 52

28.9*

32.2*

ns

Remitters (N=65)

Nonremitters (N=95)

0

1

0

2

0

3

0

4

0

5

0

0

1

0

2

0

3

0

4

0

5

0

0

1

0

2

0

3

0

4

0

5

0

Predicted

V

edolizumab Exposure

Threshold, mg/L

Periodic Serum Vedolizumab

Concentration, mg/L, Median (IQR)

26

Slide27

ERELATE: real-world exposure-response relationship of vedolizumab in inflammatory bowel disease: a pooled multicenter observational cohort analysis of clinical and modeled

pharmacological data (7/7)

1

This is the largest exposure-response analysis of VDZ real-world data to date, and results confirm observations from the GEMINI trials1,2,3The Bayesian updated population PK model showed good correlation between predicted and observed serum VDZ concentrations and allowed for robust exposure-response analysis of pooled multicenter real-world data1Positive exposure-response relationships between VDZ serum concentrations and clinically important disease outcomes were observed overall and were more pronounced in UC than in CD1Positive exposure-response relationships between predicted vedolizumab serum concentrations and clinically important outcomes in real-world data of patients with UC and CD suggest that drug concentrations early in therapy may predict treatment outcomes1In a real-world setting, early serum VDZ concentrations, at weeks 6 and 14, were modestly associated with treatment outcomes at weeks 14 and 52Causality remains to be confirmed in a prospective interventional studyCD, Crohn’s disease; PK, pharmacokinetic; UC, ulcerative colitis; VDZ, vedolizumab.Conclusions

1. Casteele NV, et al. UEG Week Virtual 2020; October 11-13, 2020; Poster P0503. 2. Rosario M, et al. Aliment Pharmacol Ther.

2015;42(2):188-202. 3. Rosario M, et al.

J Crohns Colitis

. 2017;11(8):921-929.

27

Slide28

Dose-dependent differential effects of vedolizumab therapy on adhesion of regulatory and effector T cells

Becker E.,

Wiendl

M., Dedden M., Schulz-Kuhnt A., Atreya I., Atreya R., Neurath M.F., Zundler S.28

Slide29

Dose-dependent differential effects of vedolizumab therapy on adhesion of

regulatory and effector T cells (1/3)

1

RNA, ribonucleic acid; Teff, effector T cell; Treg, regulatory T cell; VDZ, vedolizumab. 1. Becker E, et al. UEG Week Virtual 2020; October 11-13, 2020; Oral Presentation OP003. Differential binding of VDZ to regulatory and effector T cells leads to non-linear exposure-efficacy correlationHYPOTHESISThe α4β7 expression on different human T cell subsets as well as the binding characteristics of VDZ to these cells at different exposure levels were analyzed via flow cytometryFunctional effects of different VDZ concentrations on the adhesion of Treg and Teff to mucosal addressin cell adhesion molecule 1 (MAdCAM-1) were examined using dynamic adhesion and transmigration assays in vitro as well as in vivo 

homing assays in a humanized mouse model

The 

in vivo

 binding of VDZ to

Treg

and

Teff

in patients receiving therapy was quantified and correlated with VDZ

serum levels

To investigate the mechanisms underlying differential VDZ binding to Treg and Teff, single cell RNA sequencing was performedMETHODS29

Slide30

Dose-dependent differential effects of vedolizumab therapy on adhesion of

regulatory and effector T cells (2/3)

1

Results*P<0.05. **P<0.01.IBD, inflammatory bowel disease; MAdCAM-1, mucosal addressin cell adhesion molecule 1; RNA, ribonucleic acid;Teff, effector T cell; Treg, regulatory T cell; VDZ, vedolizumab. Becker E, et al. UEG Week Virtual 2020; October 11-13, 2020; Oral Presentation OP003.With an exposure of 10 µg/mL, VDZ preferentially bound to Teff compared to Treg. At an exposure level of 50 µg/mL equal binding to both cell types was observed. Consistently, at 10 µg/mL, dynamic adhesion of Treg to MAdCAM-1 was increased compared to Teff, but no difference was noted at 50 µg/mL. Additionally, a higher number of Treg compared to Teff

were able to transmigrate in a MAdCAM-1-dependent manner at an exposure of 10 µg/mL VDZ. 

In vivo

 data from homing experiments in a humanized mouse model and IBD patients treated with VDZ support

these observations.

Single cell RNA sequencing of VDZ-binding compared with non-binding α4β7-expressing

Treg

and

Teff

revealed subsets of

Treg with profound differences in integrin and chemokine receptor pathways consistent with “resistance” to medium VDZ concentrations.

Cells with free VDZ

binding sites [%

α

4

+

β

7

+

]

Trough level VDZ [µg/ml]

*

PI16

ITGB1

Differential gene expression

UMAP1

2.00

1.75

1.50

1.00

0.75

0.50

0.25

0.00

1.25

CCR10

UMAP2

3.0

2.5

1.5

0.5

0.0

2.0

1.0

UMAP1

UMAP2

UMAP2

UMAP1

1.4

1.2

1.0

0.6

0.4

0.2

0.0

0.8

150

100

050

β1+ cells [%]Vedo+

Vedo‒

**

50

40

30

10

0

20

PI

16

+ cells [%]Vedo+Vedo‒

*

80

60

20

0

40

CCR9

CCR10

+

cells [%]

Vedo

+

Vedo

*

Week 6

30

Slide31

Dose-dependent differential effects of vedolizumab therapy on adhesion of

regulatory and effector T cells (3/3)

1

Findings support a dose-dependent differential binding of VDZ to different T cell subpopulations and suggest an optimal “therapeutic window” of exposure, in which effects on Teff predominate over TregThis differential binding seems to be due to α4β7-expressing Treg subsets with particular trafficking properties impairing VDZ bindingWhile offering a potential explanation for earlier findings in dose-ranging studies, this data might lay the basis for the establishment of individualized dose optimization in IBD patientsConclusionsIBD, inflammatory bowel disease; Teff, effector T cell; Treg, regulatory T cell; VDZ, vedolizumab. 1. Becker E, et al. UEG Week Virtual 2020; October 11-13, 2020; OP003.31