Vedolizumab Should Be Used BeforeAnti-TNFs For Moderate To Severe IBD

William J. Sandborn, MD Professor and Chief, Division of Gastroenterology Director, UCSD IBD Center

How to decide?

1st lineBioloigcVedolizumab Infliximab

ADACTZGOL

Risks andBenefits

Response Remission Mucosal Healing0

5

10

15

20

25

30

35

Incremental benefit (delta)Induction therapy in ulcerative colitis

VDZ IFX ADA GOLFeagan BG. NEJM 2013Rutgeerts P. NEJM 2005

Sandborn WJ Gastro 2012Sandborn WJ Gastro 2014

Efficacy of induction therapy in biologic naïve

Danese S. Annals 2014

Durab

le Res

pons

e

Durab

le Rem

ission

CSFREM

Muc

osal

heali

ng0

5

10

15

20

25

30

35

Incremental benefit (delta)Maintenance therapy in ulcerative colitis

VDZ IFX ADA GOLFeagan BG. NEJM 2013Rutgeerts P. NEJM 2005

Sandborn WJ Gastro 2012Sandborn WJ Gastro 2014

Good efficacy for Induction and Maintanence therapy in UC

Good efficacy for Induction and Maintanence therapy in UC

Efficacy as first line agent

Vedolizumab Anti-TNF

Response Remission0

5

10

15

20

25

30

35

Incremental benefit (delta)Induction therapy in Crohn’s disease

VDZ IFX ADA CTZ

Sandborn WJ. NEJM 2013Targan et al. NEJM 1997

Hanauer et al. Gastro 2006Sandborn WJ. NEJM 2007

Response Remission0

5

10

15

20

25

Impact of time on incremental benefit (delta) of Vedolizumab induction therapy

6 week 10 week

Sands BE. Gastro 2014

Response Remission CSFREM0

5

10

15

20

25

30

35

40

45

50

Incremental benefit (delta)Maintenance therapy in Crohn’s disease

VDZ IFX ADA CTZ

Sandborn WJ. NEJM 2013Sandborn WJ. NEJM 2007

Colombel et al. Gastro 2007Hanauer et al. Lancet 2002

Good efficacy for Induction and Maintanence therapy in UC and CD

Good efficacy for Induction and Maintanence therapy in UC and CD

Efficacy as first line agent

Vedolizumab Anti-TNF

Response Remission Mucosal Healing0

5

10

15

20

25

Incremental benefit (delta) with prior biologic exposure: Vedolizumab induction therapy

VDZ UC VDZ UC Biologic exposed VDZ CD VDZ CD Biologic exposed

Feagan BG. NEJM 2013Sandborn WJ NEJM 2013

Durable Response Durable Remission CSFREM Mucosal healing0

5

10

15

20

25

30

35

Incremental benefit (delta) with prior biologic exposure: Vedolizumab maintenance therapy

VDZ UC VDZ UC Biologic exposed VDZ CD VDZ CD Biologic exposed

Feagan BG. NEJM 2013Sandborn WJ NEJM 2013

Outcomes with anti-TNF in biologic exposed

• Efficacy of subcutaneous biologics impacted by prior biologic exposure

• Impact of prior biologic exposure on efficacy of Infliximab less clear

Chaparro M WJG 2012

Efficacy as first line agent

Good efficacy for Induction and Maintanence therapy in UC and CD

Prior biologics MAY impact efficacy

Good efficacy for Induction and Maintanence therapy in UC and CD

Prior biologics WILL impact efficacy

VedolizumabAnti-TNF

Safety: Is Vedolizumab Gut Selective?

• No peripheral blood lymphocytosis

• No protective effect in primate model of MS (EAE)

• No inversion of CD4\CD8 ratio in CSF of humans

• Clinical data – no cases of PML observed

• Preservation of systemic humoral responses to T cell dependent antigens with modest impairment to oral antigen (vaccine study)

Baseline Day 18 Day 32 Day 60 Day 740

20

40

60

80

100

120

140

0

114.4

0

129.6Placebo Vedolizumab

Nominal Visit Day

Geo

met

ric

Mea

n H

BsA

b Co

ncen

trati

on,

IU/L

* Per Protocol Population

Hepatitis B Surface Antibody (HbsAb) Concentration Through Day 74*

Wyant T A. et al. Gut 2014

Baseline Day 18 Day 32 Day 60 Day 740

500

1000

1500

2000

2500

3000

3500Placebo Vedolizumab

Geo

met

ric

Mea

n Ig

A T

iter,

IU/L

% responders (95% CI): PBO 50.0 (37.6, 62.4) 83.9 (74.7, 93.0) 74.2 (63.3, 85.1) 59.7 (47.5, 71.9) VDZ 30.2 (18.8, 41.5) 63.5 (51.6, 75.4) 57.1 (44.9, 69.4) 50.8 (38.4, 63.1)

*Dukoral Population

Serum IgA Response to Oral Cholera Vaccine Through Day 74*

Wyant T A. et al. Gut 2014

Black Box Warnings

None Serious InfectionsIncreased risk of serious infections leading to hospitalization or death, including tuberculosis (TB), bacterial sepsis, invasive fungal infections (such as histoplasmosis) and infections due to other opportunistic pathogens.

MalignancyLymphoma and other malignanciesFatal hepatosplenic T-cell lymphoma

Vedolizumab Ant-TNF

Comparison of Lymphoma

Dulai PS, Siegel CA. GCNA 2014

  Lymphoma

Expected Rate(General Population) 2/10,000 PYF

Anti-TNF therapy 6/10,000 PYF

Anti-integrins(Vedolizumab, Natalizumab) 3/10,000 PYF

Other RisksVedolizumab Anti-TNF therapy

Serious Infection - +/-

Opportunistic - +

Demyelinating - +Autoimmune

(SLE, vasculitis) - +

Dermatology (psoriasis) - +

Cardiac (CHF) - +Pulmonary

(Sarcoidosis, ILD) - +

Caveat: most new drugs have additional toxicities identified during post-marketing surveillance

Kopylov U. GCNA 2014Feuerstein JD. GCNA 2014

Risks of Therapy

Vedolizumab

Anti-TNF

Good efficacy for Induction and Maintanence therapy in UC and CD

Prior biologics MAY impact efficacy

Low risk of malignancy, driven by IMM

Systemtic risks well established

Good efficacy for Induction and Maintanence therapy in UC and CD

Prior biologics WILL impact efficacy

Low risk of malignancy, driven by IMM

No signal for systemtic risks

Which one would you choose?

Drug A

• Efficacy similarLower if used second

• Gut selective with no signal of other risks

Drug B

• Efficacy similarUnclear if lower as 2nd line

• Clear association to other systemic risks