Transcript When to Start and Stop Biologic Therapy in IBD

Should we change how we position biologics
for their use in Crohn’s disease?
Stephen B. Hanauer, MD
Professor of Medicine,
Northwestern University
Medical Director, Digestive Health Center
2009 ACG Guidelines for
Moderate to Severe CD
• Infliximab monotherapy and infliximab combined with AZA are more effective
than AZA in patients who have failed 1st-line therapy Grade A
• Infliximab, adalimumab and certolizumab pegol may be used as alternatives to
steroids in selected patients in whom corticosteroids are contraindicated or not
desired
Grade B
• Natalizumab is effective in moderate to severe CD after inadequate response or
intolerance to conventional therapies and anti-TNF mAbs Grade A
Lichtenstein G et al. Am J Gastroenterol. 2009;104:465.
American Gastroenterological Association Institute Guideline on the Use
of Anti–TNF-a Biologic Drugs for the Induction and Maintenance of
Remission in Inflammatory Crohn’s Disease
• Using anti-TNF-α drugs to induce remission in patients with moderately severe Crohn’s disease
 (strong recommendation, moderate-quality evidence).
• Using anti-TNF-α monotherapy over thiopurine monotherapy to induce remission in patients who
have moderately severe Crohn’s disease
 (strong recommendation, moderate-quality evidence).
• Using anti-TNF-α drugs in combination with thiopurines over thiopurine monotherapy to induce
remission in patients who have moderately severe Crohn’s disease
 (strong recommendation, high-quality evidence).
• Using anti-TNF-α drugs over no anti-TNF-α drugs to maintain a steroid or anti-TNF-α drug-induced
remission in patients with Crohn’s disease
 (strong recommendation, high-quality evidence).
Terdiman J P et al. Gastroenterology 2013;145:1459–1463
Dassopoulos T et al. Gastroenterology 2013;145:1464–1478.
2010 ECCO Statements
• ECCO Statement 5B Moderately active, localized ileocaecal Crohn's disease
…Anti-TNF therapy should be considered as an alternative for patients with objective evidence of active
disease, who have previously been steroid-refractory, -dependent, or –intolerant…[EL1b, RG B]
• ECCO Statement 5C Severely active localized ileocaecal Crohn's disease
....should initially be treated with systemic corticosteroids [EL1a, RG A]. For those who have relapsed, antiTNF therapy with or without an immunomodulator is an appropriate option for patients with objective
evidence of active disease [EL1a, RG B for infliximab].
• ECCO Statement 5D Active colonic CD
…may be treated with sulfasalazine if only mildly active [EL1b, RG A], or with systemic corticosteroids
[EL1a, RG A]. For those who have relapsed, anti-TNF therapy with or without an immunomodulator is an
appropriate option for patients with objective evidence of moderate or severely active disease [EL1a, RG B
for infliximab].
Dignass, A. et al Journal of Crohn's and Colitis (2010) 4,28–62
2010 ECCO Statements
ECCO Statement 5E Extensive small bowel Crohn's disease
…For patients who have relapsed, anti-TNF therapy with or without azathioprine is an appropriate option if
there is objective evidence of moderate or severely active disease [EL5, RG D].
• ECCO Statement 5F Patients who have clinical features that suggest a poor prognosis
…. most suitable patients for early introduction of thiopurines, methotrexate and or anti-TNF therapy
[EL5 RG D]
• ECCO Statement 5H Patients with objective evidence of active disease refractory to corticosteroids
…should be treated with anti-TNF therapy, with or without thiopurines or methotrexate
[EL1a, RG B for infliximab]
Dignass, A. et al Journal of Crohn's and Colitis (2010) 4,28–62
Sequential Therapies for Crohn’s
Disease Severity
at Presentation
Investigational agent/
Surgery
Anti-TNF +/IS
Anti-Integrin
Severe
Systemic
Corticosteroid
Moderate
Budesonide
Anti-TNF/Anti-Integrin
+IS
Thiopurine/
MTX
Budesonide
Induction
Maintenance
Mild
Therapy is stepped up according to severity at presentation or failure at prior step
We are currently positioning biologics late in game, when they will have
the least potential to impact on Structural Damage
100
High Potential
Low Potential
Cumulative Probability (%)
90
80
70
Penetrating
60
50
40
30
Inflammatory
Stricturing
20
10
0
0 12 24 36 48 60 72 84 96 108 120 132 144 156 168 180 192 204 216 228 240
Patients at risk:
2002
N=
Months
552
229
95
37
Cosnes J et al. Inflamm Bowel Dis. 2002;8:244-250.
The Problems with Current Positioning
•Limited efficacy
•Toxicity in the presence of concomitant meds
•Loss of Response
Anti-TNF Agents Evaluated for Crohn’s Disease
Etanercept
Infliximab
PEG
IgG1
Fc
IgG1
Fc
Chimeric
Human
recombinant
receptor/Fc fusion
protein
Fab′
Fab
Receptor
Certolizumab
pegol
Adalimumab
Human
Monoclonal
antibody
PEGylated
humanized
Fab′ fragment
2 × 20 kDa
PEG
Late Populations
Remission at 6 Months with TNF
Antagonists in Crohn’s Disease
(Patients Failing Aminosaliyclates, Steroids, Immunesuppressants)
Certolizumab pegol – PRECISE 21
Patients (%)
80
64.1
60
40
47.9
30.7
28.6
18.3
20
0
100
CzP
Patients (%)
Pbo
100
Infliximab – ACCENT I2
Pbo
80
58.5
60
39.0
40
Net
Remission
Week 26
Open-Label
Induction
Week 2
100
CzP
60
29.5
40
18.3
Net
Remission
Week 26
Week 30
Remission
Net
Remission
Week 30
Adalimumab – CHARM3
Patients (%)
Patients (%)
Pbo
80
0
12.3
0
Open-Label Week 26
Induction
Remission
Week 6
Certolizumab pegol – PRECISE 14
20
22.8
21.0
20
Approximately 30%
100
IFX
Pbo
ADA
80
60
58.0
40.0
40
20
0
17.0
Open-Label Week 26
Induction Remission
Week 4
23.2
9.9
Net
Remission
Week 26
ADA=adalimumab; CZP=certolizumab pegol; IFX=infliximab
1. Schreiber S et al. N Engl J Med. 2007;357:239-255; 2. Hanauer SB et al. Lancet. 2002;359:1541-1550;
3. Colombel JF et al. Gastroenterology. 2007;132:52-62; 4. Sandborn WJ et al. N Engl J Med. 2007;357:228-237.
Not much impact with/without
Immunomodulators in Pivotal Trials
NO IMM
IMM +
% patients
All p-values = NS
60
50
41
40
37
43
48
32
20
1.9
5.3
3.3
4.6
0
ACCENT I
54 wk
Response
ACCENT I
54 wk
Remission
ACCENT I
54 wk Hosp
ACCENT II
54 wk
Response
ACCENT II
54 wk
Hosp
Remission rates 32-37% at one year
Lichtenstein GR, et al. Aliment Pharmacol Ther. 2009:30;210.
Earlier Populations
Top-Down Therapy in Crohn’s
Steroid & IS naïve, Episodic Biologics
Proportion of Patients
in Remission (%)
100
80
Early combined immunosuppression group
P=.0001
Conventional management group
P=.006
P=.028
60
40
20
0
14
26
52
Weeks
1-year remission rates ~ 60%
D’Haens G et al. Lancet. 2008;371:660-667.
14
Evidence for combination therapy in Crohn’s
Disease in immunosuppressive-naive patients:
SONIC
Corticosteroid-free clinical remission at Week 26
Proportion of patients (%)
100
p<0.001
80
p=0.006
p=0.022
56.8
60
44.4
40
30.0
20
51/170
75/169
96/169
0
AZA+ placebo
IFX + placebo
IFX + AZA
Colombel JF, et al. NEJM 2010; 362:1383-95
Comparison of Infliximab Trials:
Immunosuppressive Experienced vs Naïve Patients
(ACCENT I vs SONIC)
50
45
40
35
30
25
20
15
10
5
0
1-Year Remission Rates
p=0.035
p=ns
+IM
-IM
ACCENT I
SONIC
Clinical Remission at Weeks 26 by Disease Duration in
adalimumab CHARM study
Placebo
All Adalimumab
70
59*
% of patients
60
50
30
20
41**
40
40
25
17
14
10
0
N=23 N=39
<2 years
N=36 N=57
2 to <5 years
N=111 N=233
5 years
*p=0.002, **p<0.001, †p=0.014, ‡p=0.001 all vs placebo
Schreiber S, et al. Gastroenterology 2007;132(4 Suppl 2):A-147.
4-week Response According to Prior Therapy with AntiTNF from adalimumab CLASSIC vs GAIN studies
%Remission
40
35
30
Placebo
25
Adalimumab
160/80mg
20
15
10
5
0
CLASSIC
(TNF Naïve)
GAIN
(Prior TNF Rx)
Hanauer, S. et al. Gastroenterol. 2006;130:323–33
Sandborn WJ, et al. Ann Intern Med 2007;146:829-38
Risks with Current Positioning of Anti-TNFs
Infections/Mortality/Neoplasia
Primarily related to concomitant therapies
Infections and Mortality in the TREAT Registry: 15,000
Patient-Years of Experience
Multivariate Analysis
4.5
Mortality
Adjusted Odds Ratio
4.0
Serious infections
3.5
Steroids
3.0
2.5
2.0
1.5
IFX
AZA
6-MP
MTX
IFX
AZA
6-MP
MTX
Steroids
1.0
P<.001
0.5
P=.006
P=.002
0.0
AZA = azathioprine; IFX = infliximab; MTX = methotrexate.
Lichtenstein GR et al. Am J Gastroenterol. 2012;107:1409-1422..
20
Overall Risk of Cancer in IBD with Anti-TNF Agents:
Denmark, 1999-2012
Rate Ratios for incident Overall Cancer Among 56,146 Patients With Inflammatory Bowel Disease Exposed and
Unexposed to TNF-a Antagonists*
TNF-a Antagonist Exposure
Exposed
Unexposed
Rate Ratio (95%(1)
Person-years
Cases
Person-years
Cases
Crudeb
Adjustedc
Adjustedd
Total
18,440
81
469,874
3,465
1.07 (0.86-1.33)
1.25 (1.00-1.58)
1.07 (0.85-1.36)
Female
10,665
43
258,706
1,803
1.01 (0.75-1.37)
1.12 (0.82-1.54)
0.96 (0.69-1.33)
Male
7,776
38
211,168
1,622
1.12 (0.82-1.85)
1.40 (1.00-1.96)
1.20 (0.85-1.69)
Adjusted for age, calendar year, disease duration, baseline propensity scores, use of 5-ASAs/sulphasalazine, local/systemic
corticosteroids, methotrexate/cyclosporine/cyclophosphamide, and azathioprine.
After adjusting for azathioprine use, risk disappears
Nyboe Andersen N et al. JAMA. 2014;311:2406-2413.
Durability of Current Positioning
Short due to inadequate dosing and “reactive” (vs.
“proactive”) Therapeutic Drug Monitoring
Loss of Response to Infliximab in Crohn’s Disease:
Health-Care Claims Data
Loss of-Response Rate
100%
2 years, 77%
1 year, ~50%
80%
• Health-care claims database (1999–2005)
• Selected patients with CD receiving infliximab
maintenance therapy with an initial response
• Loss of response inferred from:
60%
40%
– Loss of response
20%
0%
0
50 100 150 200 250 300 350 400 450 500 550 600 650 700 750 800
–
Upward dose adjustment
–
New drug therapy for CD
–
CD-related emergency room or inpatient
visits
• Annual total health-care and CD-related costs
estimated and adjusted for inflation to 2005 US
dollars
Days from Index Date
Wu EQ et al. Value Health. 2008;11:820-829.
Comparative Effectiveness of Infliximab and
Adalimumab for Crohn's Disease
• Retrospective cohort study by using U.S. Medicare data from 2006 through 2010.
• Patients with CD who were new users of infliximab (n = 1459) or adalimumab (n = 871)
after January 31, 2007.
• Primary outcome measures were disease persistence on therapy at week 26
After 26 weeks of treatment,
49% of patients receiving infliximab remained on drug,
compared with 47% of those receiving adalimumab
Osterman, M. CGH 2014;12:811-17
Vedolizumab Binds to α4β7 Integrin and Blocks Its
Interaction With MAdCAM-1
Endothelial cell
MAdCAM-1
Vedolizumab:
A humanized monoclonal
antibody (mAb) that binds
to the α4β7 integrin
α4
subunit
β7
subunit
Vedolizumab blocks the
interaction of α4β7
integrin with MAdCAM1
α4
subunit
Memory T lymphocyte
β7
subunit
Artist’s rendition
Vedolizumab “Late” vs “Early”
Based on Prior TNF Exposure
(Average Disease Duration ~10 Years
Vedolizumab
Gemini I 52 Week Clinical Remission & Durable Clinical
Response by Prior TNF Antagonist Exposure
Prior Anti-TNF Antagonist Exposure
(n=149)
70
VDZ/PBO
VDZ/VDZ Q8W
VDZ/VDZ Q4W
60
Patients (%)
Patients Without TNF
Antagonist Exposure
(n=224)
65.3
50
40
36.0
56.2
44.0
40.4
46.2
45.8
47.9
26.6
30
20
10
0
19.1
19.1
10.6
Clinical
Remission
Mean % vs VDZ/PBO (95% CI)
25.4 (5.1, 43.8)
VDZ/VDZ Q8W:
29.7
(10.3, 47.7)
VDZ/VDZ Q4W:
Durable Clinical
Response
Clinical
Remission
Durable Clinical
Response
24.9 (7.1, 42.6)
27.0 (9.4, 44.6)
26.8 (12.4, 41.2)
29.0 (14.6, 43.3)
38.7 (24.0, 53.4)
29.6 (14.6, 44.6)
Feagan BG et al. New Engl J Med. 2013;369:699-710.
The Role of Therapeutic Drug Monitoring
Prospective Studies are Needed
Therapeutic Windows with Biologics
µg/mL
Peak
100
10
AUC
1
Trough
0
2
6
14
Sub-treshold trough levels associated with:
• Loss of response
• Immunogenicity
22 wks.
Factors that Influence the PK of Biologics Antagonists
Impact on TNF antagonist PK
Presence of ADAs
Decreases drug concentration
Increases clearance
Worse clinical outcomes
Concomitant use of immunosuppressives
Reduces ADA formation
Increases drug concentration
Decreases drug clearance
Better clinical outcomes
Low serum albumin concentration
Increases drug clearance
Worse clinical outcome
High baseline CRP concentration
Increase drug clearance
High baseline TNF concentration
May decrease drug concentration by
increasing clearance
High body size
May increase drug clearance
Sex
Males have higher clearance
Ordas I et. al. Clin Gastroenterol Hepatol. 2012; 10:1079-1087.
30
Trough Levels of Infliximab Are Predictor of Continued Response
CLINICAL REMISSION
*
100
ENDOSCOPIC CHANGE
C- REACTIVE PROTEIN
100
30
* P < 0.001
* P < 0.001
80
* P < 0.001
*
80
20
60
60
40
40
10
20
*
0
0
0
Undetectable
 2.0 ug/ml
20
Undetectable
 2.0 ug/ml
Undetectable
 2.0 ug/ml
Maser EA et al. Clin Gastroenterol Hepatol. 2006;4:1248-54
Predictors of Sustained Response in ACCENT 1
• The proportion of patients with sustained response was
significantly lower with IFX trough levels <3.5 at week 14
compared to IFX trough levels ≥3.5, in patients receiving 5
mg/kg maintenance dose (18% vs. 39%, p=0.0042)
Change from baseline
IFX level
CRP
IFX level and
CRP
IFX level or
CRP
3.5
µg/mL
60%
3.5 µg/mL and
60%
3.5 µg/mL or
60%
Sensitivity
Specificity
0.64
0.78
0.91
0.53
0.59
0.82
0.95
0.49
Positive predictive
value
0.56
0.47
0.59
0.46
Negative
predictive value
0.83
0.93
0.82
0.96
Optimal cutoff
Cornillie F, et al., Gut; 2014.0:1-7, EPub
So what are the real issues regarding
introduction of biologic therapies?
• If biologics cost $Dollars vs. $$$$Dollars we would not be having these
discussions
 Cost of therapy is the overriding issue for all parties
• Fear of infections/neoplasia
 Primarily risk of lymphoma in young patients
• Fear of “running out” of options
 Reserving therapy for refractory patients
When to Introduce Biologics in Crohn’s
disease?
The “Tipping Point” may be
Corticosteroids?
Clinical Predictors of Risk of Progressive/Aggressive
Crohn’s Disease at Diagnosis
•Young age
•Fistulae
•Need for steroids
•Deep ulcerations
•High serologic titers
•Smoking
Positioning Biologics in Crohn’s Disease
Disease Severity
at Presentation
Clinical trials
Natalizumab
Surgery
Anti-TNF ±
Thiopurine?
Severe
Earlier?
Prednisone
Natalizumab
Anti-TNF ±
Thiopurine?
Thiopurine/
Methotrexate
Moderate
5-ASA?
Mild
5-ASA?
Budesonide
Induction
Maintenance
Should we change how we position biologics for
their use in Crohn’s disease?
YES
•The earlier the better…
•In the patients that need them…
•With (short-term) combination therapy…
•And therapeutic drug monitoring
What will it take to change positioning?
•Long-term pharmaco-economics
(Beyond hospitalizations & surgeries)
•Trials in early populations (before steroids) assessing
disease modification
•Prospective trials of therapeutic drug monitoring
Thank you