Transcript Document

Vedolizumab Should Be Used Before
Anti-TNFs For Moderate To Severe IBD
William J. Sandborn, MD
Professor and Chief, Division of Gastroenterology
Director, UCSD IBD Center
How to decide?
CTZ
GOL
ADA
Risks and
Benefits
Vedolizumab
1st line
Bioloigc
Infliximab
Incremental benefit (delta)
Induction therapy in ulcerative colitis
35
30
25
20
15
10
5
0
Response
Remission
VDZ
IFX
ADA
Mucosal Healing
GOL
Feagan BG. NEJM 2013
Rutgeerts P. NEJM 2005
Sandborn WJ Gastro 2012
Sandborn WJ Gastro 2014
Efficacy of induction therapy in biologic naïve
Danese S. Annals 2014
Incremental benefit (delta)
Maintenance therapy in ulcerative colitis
35
30
25
20
15
10
5
0
Durable Response
Durable
Remission
VDZ
IFX
CSFREM
ADA
Mucosal healing
GOL
Feagan BG. NEJM 2013
Rutgeerts P. NEJM 2005
Sandborn WJ Gastro 2012
Sandborn WJ Gastro 2014
Efficacy as first line agent
 Good efficacy for Induction and
Maintanence therapy in UC
Vedolizumab
 Good efficacy for Induction and
Maintanence therapy in UC
Anti-TNF
Incremental benefit (delta)
Induction therapy in Crohn’s disease
35
30
25
20
15
10
5
0
Response
VDZ
Remission
IFX
ADA
CTZ
Sandborn WJ. NEJM 2013
Targan et al. NEJM 1997
Hanauer et al. Gastro 2006
Sandborn WJ. NEJM 2007
Impact of time on incremental benefit (delta)
of Vedolizumab induction therapy
25
20
15
10
5
0
Response
Remission
6 week
10 week
Sands BE. Gastro 2014
Incremental benefit (delta)
Maintenance therapy in Crohn’s disease
50
45
40
35
30
25
20
15
10
5
0
Response
Remission
VDZ
IFX
ADA
CSFREM
CTZ
Sandborn WJ. NEJM 2013
Sandborn WJ. NEJM 2007
Colombel et al. Gastro 2007
Hanauer et al. Lancet 2002
Efficacy as first line agent
 Good efficacy for Induction and
Maintanence therapy in UC and CD
Vedolizumab
 Good efficacy for Induction and
Maintanence therapy in UC and CD
Anti-TNF
Incremental benefit (delta) with prior biologic
exposure: Vedolizumab induction therapy
25
20
15
10
5
0
Response
VDZ UC
Remission
VDZ UC Biologic exposed
VDZ CD
Mucosal Healing
VDZ CD Biologic exposed
Feagan BG. NEJM 2013
Sandborn WJ NEJM 2013
Incremental benefit (delta) with prior biologic
exposure: Vedolizumab maintenance therapy
35
30
25
20
15
10
5
0
Durable Response Durable Remission
VDZ UC
VDZ UC Biologic exposed
CSFREM
VDZ CD
Mucosal healing
VDZ CD Biologic exposed
Feagan BG. NEJM 2013
Sandborn 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
 Good efficacy for Induction and
Maintanence therapy in UC and CD
 Prior biologics WILL impact efficacy
 Prior biologics MAY impact efficacy
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)
Geometric Mean HBsAb Concentration,
IU/L
Hepatitis B Surface Antibody (HbsAb)
Concentration Through Day 74*
140
Placebo
129.6
Vedolizumab
120
114.4
100
80
60
40
20
0
Baseline
* Per Protocol Population
Day 18
Day 32
Nominal Visit Day
Day 60
Day 74
Wyant T A. et al. Gut 2014
Serum IgA Response to Oral
Cholera Vaccine Through Day 74*
Placebo
Vedolizumab
Geometric Mean IgA Titer, IU/L
3500
3000
2500
2000
1500
1000
500
0
Baseline
% responders (95% CI): PBO
VDZ
Day 18
Day 32
50.0 (37.6, 62.4) 83.9 (74.7, 93.0)
30.2 (18.8, 41.5) 63.5 (51.6, 75.4)
Day 60
Day 74
74.2 (63.3, 85.1) 59.7 (47.5, 71.9)
57.1 (44.9, 69.4) 50.8 (38.4, 63.1)
*Dukoral Population
Wyant T A. et al. Gut 2014
Black Box Warnings
Vedolizumab
None
Ant-TNF
Serious Infections
Increased 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.
Malignancy
Lymphoma and other malignancies
Fatal hepatosplenic T-cell lymphoma
Comparison of Lymphoma
Lymphoma
Expected Rate
(General Population)
2/10,000 PYF
Anti-TNF therapy
6/10,000 PYF
Anti-integrins
(Vedolizumab, Natalizumab)
3/10,000 PYF
Dulai PS, Siegel CA. GCNA 2014
Other Risks
Vedolizumab
Anti-TNF therapy
Demyelinating
-
+/+
+
Autoimmune
(SLE, vasculitis)
-
+
Dermatology (psoriasis)
Cardiac (CHF)
-
+
+
Pulmonary
(Sarcoidosis, ILD)
-
+
Serious Infection
Opportunistic
Caveat: most new drugs have additional toxicities
identified during post-marketing surveillance
Kopylov U. GCNA 2014
Feuerstein JD. GCNA 2014
Risks of Therapy
 Good efficacy for Induction and
Maintanence therapy in UC and CD
 Good efficacy for Induction and
Maintanence therapy in UC and CD
 Prior biologics WILL impact efficacy
 Prior biologics MAY impact efficacy
 Low risk of malignancy, driven by IMM
 Low risk of malignancy, driven by IMM
 No signal for systemtic risks
 Systemtic risks well established
Which one would you choose?
Drug A
• Efficacy similar
Lower if used second
• Gut selective with no
signal of other risks
Drug B
• Efficacy similar
Unclear if lower as 2nd line
• Clear association to
other systemic risks