VedolizumabShould Not Be Used as a First Line Biologic in IBD...– A faster biologic agent? •...

Controversy: Vedolizumab Should Not Be Used as a First Line Biologic 

in IBD James Lord, M.D., Ph.D.

Benaroya Research InstituteVirginia Mason Medical Center

Newer Does Not Mean Better

James Lord, M.D., Ph.D.Benaroya Research Institute

Virginia Mason Medical Center

What makes an agent “first line”?

• Cost• Convenience• Safety• Efficacy

Cost:  Vedolizumab is more expensive than infliximab

$0.00

$5,000.00

$10,000.00

$15,000.00

$20,000.00

$25,000.00

$30,000.00

$35,000.00

Vedolizumab Infliximab Vedolizumab Infliximab

Induction Cost Maintenance Cost/yr

Walmart

Sam's Club

Kroger

Kmart

Target

Safeway

Rite Aid

CVS

Walgreens

Data from GoodRx.com Assuming standard dosing for 70 kg patient

Convenience:  Vedolizumab has an infusion schedule identical to infliximab• Induction:

– Infliximab: 5 mg/kg IV at week 0, 2, 6– Vedolizumab:  300 mg IV at week 0, 2, 6

• Maintenance:– Infliximab:  5 mg/kg every 8 weeks IV– Vedolizumab:  300 mg every 8 weeks IV

• No subcutaneous form of Vedolizumab

Free

 drug presen

t in serum

% of cells with

 unb

ound

(inverse of re

ceptor sa

turatio

n)

150 kg

30 kg

50 kg

2 wks

2 wks 8 weeks 8 weeks 8 weeks

Dose 1

Dose 2

Dose 3

Dose 4

Parikh et. el., IBD, 2011

Safety:  Is Vedolizumab a safer drug than an anti‐TNF agent?

Crohn’s Disease• Vedolizumab:

– GEMINI‐II & III• Anti‐TNF agents:

– Infliximab• Targan et. al. ‘97• ACCENT‐I & II

– Adalimumab• CHARM• CLASSIC‐I & II

– Certolizumab• Schreiber at. al. ‘05• PRECISE‐I & II

Ulcerative Colitis• Vedolizumab:

– Feagan et. al., ‘05– GEMINI‐I

• Anti‐TNF agents:– Infliximab

• ACT‐I & II

– Adalimumab• ULTRA‐I & II

– Golimumab• PURSUIT‐SC & M

Safety:  Vedolizumab seems like it should be safer than anti‐TNF

Anti‐TNF agents:– Block a ubiquitous feature of 

inflammation (TNF)– Act throughout the body– Cause immune cell apoptosis– Associated with anti‐drug 

immune responses

Vedolizumab:– Blocks lymphocyte migration, 

not function– Specific to gut only– Does not cause apoptosis– Associated with minimal anti‐

drug immunogenicity

Vedolizumab is not clearly better tolerated than anti‐TNF agents

0.0%2.0%4.0%6.0%8.0%

10.0%12.0%14.0%16.0%18.0%20.0%

vedolizumab infliximab adalimumab golimumab

Headaches

drug

placebo

0.0%

2.0%

4.0%

6.0%

8.0%

10.0%

12.0%

vedolizumab infliximab adalimumab golimumab

Nausea

drug

placebo

0.0%2.0%4.0%6.0%8.0%

10.0%12.0%14.0%16.0%18.0%20.0%

vedolizumab infliximab adalimumab golimumab

Nasopharyngitis

drug

placebo Data from all GEMINI, ACT, ULTRA, PURSUIT, CHARM, CLASSIC and ACCENT trials

Vedolizumab is not clearly safer than anti‐TNF agents

0.0%

5.0%

10.0%

15.0%

20.0%

25.0%

30.0%

vedolizumab infliximab adalimumab golimumab

Serious Adverse Events

drug

placebo

0.0%

0.5%

1.0%

1.5%

2.0%

2.5%

3.0%

3.5%

4.0%

vedolizumab infliximab adalimumab golimumab

Serious Infections

drug

placebo

Note:  No PML reported with vedolizumab to date

Long‐term safety data on anti‐TNF agents, but not vedolizumab

TREAT Registry: 6,273 Crohn’s patients with an average of 5.2 years follow‐up

0

0.5

1

1.5

2

2.5

anyneoplasia

anymalignancy

lymphoma solid tumor mortality seriousinfection

Una

djusted rate per 100

 patient‐years

Infliximab

Other treatments only

Lichtenstein et. al., Am J Gastroenterol 2012; 107:1409–1422.Lichtenstein et. al., Am J Gastroenterol 2014;109:212‐23.

Efficacy:  Is Vedolizumab a better drug than an anti‐TNF agent?

Crohn’s Disease• Vedolizumab:

– GEMINI‐II & III• Anti‐TNF agents:

– Infliximab• Targan et. al. ‘97• ACCENT‐I & II

– Adalimumab• CHARM• CLASSIC‐I & II

– Certolizumab• Schreiber at. al. ‘05• PRECISE‐I & II

Ulcerative Colitis• Vedolizumab:

– Feagan et. al., ‘05– GEMINI‐I

• Anti‐TNF agents:– Infliximab

• ACT‐I & II

– Adalimumab• ULTRA‐I & II

– Golimumab• PURSUIT‐SC & M

Vedolizumab is not clearly better than anti‐TNF for UC induction

0.0%

10.0%

20.0%

30.0%

40.0%

50.0%

60.0%

70.0%

80.0%

ACT-12005

ACT-22005

ULTRA-12011

ULTRA-22012

PURSUIT-SC 2014

Feagan et.al. 2005

GEMINI I2013

infliximab adalimimab golimumab vedolizumab

resp

onse

(May

o dr

op o

f >2)

6-8 wk initial response

treatedplacebo

Vedolizumab is not clearly better than anti‐TNF for UC induction

0.0%

5.0%

10.0%

15.0%

20.0%

25.0%

30.0%

35.0%

40.0%

45.0%

ACT-12005

ACT-22005

ULTRA-12011

ULTRA-22012

PURSUIT-SC 2014

Feagan et.al. 2005

GEMINI I2013

infliximab adalimimab golimumab vedolizumab

rem

issi

on (M

ayo

<3)

6-8 wk initial remission

treated

placebo

Vedolizumab is not clearly better than anti‐TNF’s for UC maintenance at 1 year

0%

10%

20%

30%

40%

50%

60%

Infliximab Adalimumab Golimumab Vedolizumab

ACT-1 2005 ULTRA-II 2012 PURSUIT-M2014

GEMINI I 2013

resp

onse

(May

o dr

op o

f >2)

Response at 52-54 wks

treatedplacebo

0%

5%

10%

15%

20%

25%

30%

35%

40%

45%

Infliximab Adalimumab Golimumab Vedolizumab

ACT-1 2005 ULTRA-II 2012 PURSUIT-M2014

GEMINI I 2013

rem

issi

on (M

ayo<

3)

Remission at 52-54 wks

treatedplacebo

Vedolizumabefficacy for UC maintenance is comparable to 

anti‐TNF

GEMINI‐I:   Vedolizumab

PURSUIT‐M:Golimumab

Clinical relapse lags well behind pharmacokinetics

Vedolizumab is less effective than anti‐TNF’s for Crohn’s induction at 4‐6 weeks

0%

10%

20%

30%

40%

50%

60%

70%

Infliximab adalimimab certolizumab vedolizumab vedolizumab

Targan 1997 CLASSIC I2006

PRECISE I2007

GEMINI II2013

GEMINI III2014

resp

onse

(CD

AI d

rop

of >

70-1

00)

4-6 wk initial response

treated

placebo

0%

10%

20%

30%

40%

50%

60%

Infliximab adalimimab certolizumab vedolizumab vedolizumab

Targan 1997 CLASSIC I2006

Schreiber2005

GEMINI II2013

GEMINI III2014

rem

issi

on (C

DA

I <15

0)

4-6 wk initial remission

treated

placebo

NS

Vedolizumab is less effective than anti‐TNF’s for Crohn’s induction at 4‐6 weeks

0%5%

10%15%20%25%30%35%40%45%50%

Infliximab adalimimab certolizumab vedolizumab vedolizumab

Targan 1997 CLASSIC I2006

PRECISE I2007

GEMINI II2013

GEMINI III2014

resp

onse

(CD

AI d

rop

of >

70-1

00)

4-6 wk initial response: absolute benefit (treatment minus placebo)

0%5%

10%15%20%25%30%35%40%45%50%

Infliximab adalimimab certolizumab vedolizumab vedolizumab

Targan 1997 CLASSIC I2006

Schreiber2005

GEMINI II2013

GEMINI III2014

rem

issi

on (C

DA

I <15

0)

4-6 wk initial remission: absolute benefit (treatment minus placebo)

NS

0%5%

10%15%20%25%30%35%40%45%50%

Infliximab adalimumab vedolizumab

ACCENT I CHARM GEMINI II

resp

onse

(CD

AI d

rop

of >

70-1

00)

maintenance of response at 52-56 wks

treatedplacebo

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

Infliximab adalimumab adalimumab vedolizumab

ACCENT I CHARM CLASSIC II GEMINI II

rem

issi

on (C

DA

I<15

0)

maintenance of remission at 52-56 wks

treatedplacebo

Vedolizumab is not clearly better than anti‐TNF’s for Crohn’s maintenance at 1 year

Vedolizumab is not clearly better than anti‐TNF’s for Crohn’s maintenance at 1 year

0%

5%

10%

15%

20%

25%

30%

Infliximab adalimumab vedolizumab

ACCENT I CHARM GEMINI II

resp

onse

(CD

AI d

rop

of >

70-1

00)

maintenance of response at 52-56 wks: absolute benefit (treatment minus placebo)

0%

5%

10%

15%

20%

25%

30%

35%

40%

Infliximab adalimumab adalimumab vedolizumab

ACCENT I CHARM CLASSIC II GEMINI II

rem

issi

on (C

DA

I<15

0)

maintenance of remission at 52-56 wks: absolute benefit (treatment minus placebo)

Anti‐TNF agents work better in combination with immunomodulators

Crohn’s:  SONICColombel et. al., N Engl J Med 2010;362:1383‐95

UC:  SUCCESSPanaccione et. al., Gastroenterology 2014;146:392–400

No data on combination therapy with vedolizumab

So, for efficacy:  • if vedolizumab = anti‐TNF alone

And • anti‐TNF + azathioprine > anti‐TNF alone

Then• anti‐TNF + azathioprine > vedolizumab

Vedolizumab is slow to show maintenance efficacy in Crohn’s

Vedolizumab shows more efficacy at week 10 than week 6 for Crohn’s induction of remission (GEMINI‐III)

Week 6 Week 10

Infliximab (cA2) works quickly

Is Vedolizumab a slower biologic?

• Fast drugs—good for induction– Glucocorticoids– Calcineurin inhibitors– Anti‐TNF biologicals

• Slow drugs—good for maintenance– Thiopurines– Methotrexate– Vedolizumab

Mechanism of action may differentiate speed of biopharmaceuticals

• Anti‐TNF agents– Block soluble hormone with a 

short half life– TNF is rapidly synthesized– TNF effects are immediate

• Anti‐integrins (Vedolizumab)– Block circulating cells with a 

long half life– Mucosal lymphocyte 

recirculation is slow

How would one use a slow drug as “first line” therapy?

• Too slow to be practical for inpatient use• Too slow to be induction therapy for urgent patients

• Use alongside a faster induction agent?– Steroids or calcineurin inhibitor?

• Increased toxicity

– A faster biologic agent?• Increased cost, immunogenicity

What if it doesn’t work?:Cannot dose‐optimize vedolizumab

• Only one dosing regimen– Not weight‐based– Fixed schedule

• No assays to monitor levels– Serum levels of free drug– Receptor saturation on circulating lymphocytes

Should Vedolizumab be “first line”?• Cost

– More than infliximab, unless:• Patient >100 kg • Infliximab dose > 5 mg/kg or interval < q8 wks• Vedolizumab dose interval > q8 wks

– Cannot compare to SQ medications due to IV fees• Convenience

– Similar to infliximab (unless able to lengthen dose interval)– Worse than SQ medication

• Safety– Similar to anti‐TNF’s for common or early events– Unknown for rare or late events (minimal post‐marketing data)

• Efficacy– Similar to anti‐TNF for UC induction and maintenance– Worse than anti‐TNF for Crohn’s induction– Possibly comparable to anti‐TNF for Crohn’s maintenance

Conclusion

• First line therapy for UC or Crohn’s should be combination therapy with anti‐TNF + thiopurine, if possible

• If thiopurine‐intolerant or obese, vedolizumaband anti‐TNF  therapy are comparable for UC

• Vedolizumab is inferior to anti‐TNF monotherapy for Crohn’s