vedolizumabshould not be used as a first line biologic in ibd...– a faster biologic agent? •...
TRANSCRIPT
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