1. 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

2. 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.

3. 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
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
Terdiman J P et al. Gastroenterology 2013;145:1459–1463
Dassopoulos T et al. Gastroenterology 2013;145:1464–1478.

4. 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, anti-TNF 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

5. 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

6. Sequential Therapies for Crohn’s
Investigational agent/
Surgery
Disease Severity
at Presentation
Anti-TNF +/IS
Anti-Integrin
Anti-TNF/Anti-Integrin
+IS
Severe
Moderate
Mild
Thiopurine/
MTX
Systemic
Corticosteroid
Budesonide
Budesonide
Induction
Maintenance
Therapy is stepped up according to severity at presentation or failure at prior step

7. Cumulative Probability (%)
We are currently positioning biologics late in game, when they will have the least potential to impact on Structural Damage
High Potential
Low Potential
100 90 80 70
Penetrating 60 50
Cumulative Probability (%) 40
Inflammatory 30
Stricturing 20 10 12 24 36 48 60 72 84 96
108
120
132
144
156
168
180
192
204
216
228
240
Months
Patients at risk:
N =
2002
552
229 95 37
Cosnes J et al. Inflamm Bowel Dis. 2002;8: 7

8. The Problems with Current Positioning
Limited efficacy
Toxicity in the presence of concomitant meds
Loss of Response

9. Anti-TNF Agents Evaluated for Crohn’s Disease
Certolizumab pegol
PEG
PEGylated humanized Fab′ fragment
2 × 20 kDa PEG
Etanercept
IgG1 Fc
Receptor
Infliximab
Adalimumab
IgG1Fc
Fab
Fab′
Chimeric
Human
Human recombinant receptor/Fc fusion protein
Monoclonal antibody 9 9

10. Late Populations

11. Curatio PowerPoint Template
4/15/2017 2:15 PM
Remission at 6 Months with TNF Antagonists in Crohn’s Disease (Patients Failing Aminosaliyclates, Steroids, Immunesuppressants)
Certolizumab pegol – PRECISE 21
Infliximab – ACCENT I2
100
Pbo
CzP
100
Pbo
IFX 80 80
64.1
58.5 60
47.9 60
Patients (%)
Patients (%)
39.0 40
28.6
30.7 40
21.0
22.8
18.3 20 20
12.3
Open-Label Induction
Week 6
Week 26 Remission
Net Remission
Week 26
Open-Label Induction
Week 2
Week 30 Remission
Net Remission
Week 30
Approximately 30%
Certolizumab pegol – PRECISE 14
Adalimumab – CHARM3
Pbo
CzP
100
Pbo
ADA
100 80 80
58.0 60 60
40.0
Patients (%)
Patients (%)
29.5 40 40
23.2
18.3
17.0 20 20
9.9
Net Remission
Week 26
Open-Label Induction
Week 4
Week 26 Remission
Net Remission
Week 26
ADA=adalimumab; CZP=certolizumab pegol; IFX=infliximab 1. Schreiber S et al. N Engl J Med. 2007;357: ; 2. Hanauer SB et al. Lancet. 2002;359: ; 3. Colombel JF et al. Gastroenterology. 2007;132:52-62; 4. Sandborn WJ et al. N Engl J Med. 2007;357:

12. Not much impact with/without Immunomodulators in Pivotal Trials
NO IMM
All p-values = NS
% patients
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.

13. Earlier Populations

14. Top-Down Therapy in Crohn’s Steroid & IS naïve, Episodic Biologics
1-year remission rates ~ 60%
D’Haens G et al. Lancet. 2008;371:

15. Proportion of patients (%)
Evidence for combination therapy in Crohn’s Disease in immunosuppressive-naive patients: SONIC
Corticosteroid-free clinical remission at Week 26
Proportion of patients (%)
p<0.001
p=0.006
p=0.022
51/170
75/169
96/169
30.0
44.4
56.8 20 40 60 80
100
AZA+ placebo
IFX + placebo
IFX + AZA
Colombel JF, et al. NEJM 2010; 362: 15
#### PLEASE DO NOT DELETE CONTENT BELOW THIS LINE ! ####
########### Presentation 'REM_SK025_SONIC Trial_R03_10JUN09.ppt' created on Wednesday, 10 June, 2009 ###########
Author: WEBO QC&C: 10-Jun Review By: 10-Dec-09
Medical Review: Yes Slide: 15/23 15

16. Comparison of Infliximab Trials: Immunosuppressive Experienced vs Naïve Patients (ACCENT I vs SONIC)
1-Year Remission Rates
p=0.035
p=ns

17. Clinical Remission at Weeks 26 by Disease Duration in adalimumab CHARM study
Placebo
All Adalimumab
N=23 N= N=36 N= N=111 N=233
<2 years to <5 years 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. 17

18. 4-week Response According to Prior Therapy with Anti-TNF from adalimumab CLASSIC vs GAIN studies
Placebo
%Remission
Adalimumab
160/80mg
CLASSIC GAIN
(TNF Naïve) (Prior TNF Rx)
Hanauer, S. et al. Gastroenterol. 2006;130:323–33
Sandborn WJ, et al. Ann Intern Med 2007;146:829-38

19. Risks with Current Positioning of Anti-TNFs
Infections/Mortality/Neoplasia
Primarily related to concomitant therapies

20. Infections and Mortality in the TREAT Registry: 15,000 Patient-Years of Experience
Serious infections
Steroids
AZA 6-MP MTX
AZA 6-MP MTX
Steroids
IFX
IFX
P<.001
P=.006
P=.002
AZA = azathioprine; IFX = infliximab; MTX = methotrexate.
Lichtenstein GR et al. Am J Gastroenterol. 2012;107:

21. 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
Crudeb
Adjustedc
Adjustedd
Total
18,440 81
469,874
3,465
1.07 ( )
1.25 ( )
1.07 ( )
Female
10,665 43
258,706
1,803
1.01 ( )
1.12 ( )
0.96 ( )
Male
7,776 38
211,168
1,622
1.12 ( )
1.40 ( )
1.20 ( )
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:

22. Durability of Current Positioning
Short due to inadequate dosing and “reactive” (vs. “proactive”) Therapeutic Drug Monitoring

23. Loss of Response to Infliximab in Crohn’s Disease: Health-Care Claims Data
2 years, 77%
Health-care claims database (1999–2005)
Selected patients with CD receiving infliximab maintenance therapy with an initial response
Loss of response inferred from:
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
1 year, ~50%
– Loss of response
Wu EQ et al. Value Health. 2008;11:

24. 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

25. Vedolizumab blocks the interaction of α4β7 integrin with MAdCAM-1
Vedolizumab Binds to α4β7 Integrin and Blocks Its Interaction With MAdCAM-1
Endothelial cell
vedolizumab
MAdCAM-1
Vedolizumab:
A humanized monoclonal antibody (mAb) that binds to the α4β7 integrin
Vedolizumab blocks the interaction of α4β7 integrin with MAdCAM-1 α4
subunit β7
subunit α4
subunit β7
subunit
Memory T lymphocyte
Artist’s rendition

26. Vedolizumab “Late” vs “Early”
Based on Prior TNF Exposure
(Average Disease Duration ~10 Years

27. Vedolizumab Gemini I 52 Week Clinical Remission & Durable Clinical Response by Prior TNF Antagonist Exposure
Patients Without TNF Antagonist Exposure
(n=224)
Prior Anti-TNF Antagonist Exposure
(n=149)
Rutgeerts P et al. UEGW (oral-maintenance):
Slide 12.
VDZ/PBO
VDZ/VDZ Q8W
VDZ/VDZ Q4W
Patients (%)
Clinical
Remission
Durable Clinical
Response
Clinical
Remission
Durable Clinical
Response
Mean % vs VDZ/PBO (95% CI)
VDZ/VDZ Q8W:
VDZ/VDZ Q4W:
25.4 (5.1, 43.8)
29.7 (10.3, 47.7)
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:

28. The Role of Therapeutic Drug Monitoring
Prospective Studies are Needed

29. Therapeutic Windows with Biologics
µg/mL
Peak
AUC
100 10 1
Trough 2 6 14
22 wks.
Sub-treshold trough levels associated with:
Loss of response
Immunogenicity

30. 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:

31. Trough Levels of Infliximab Are Predictor of Continued Response
CLINICAL REMISSION
C- REACTIVE PROTEIN
ENDOSCOPIC CHANGE * * *
P < 0.001 *
P < 0.001 *
P < 0.001 *
Undetectable
 2.0 ug/ml
Undetectable
 2.0 ug/ml
Undetectable
 2.0 ug/ml
Maser EA et al. Clin Gastroenterol Hepatol. 2006;4:

32. 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
Optimal cutoff
3.5 µg/mL
60%
3.5 µg/mL and 60%
3.5 µg/mL or 60%
Sensitivity
0.64
0.91
0.59
0.95
Specificity
0.78
0.53
0.82
0.49
Positive predictive value
0.56
0.47
0.46
Negative predictive value
0.83
0.93
0.96
Cornillie F, et al., Gut; :1-7, EPub

33. 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

34. When to Introduce Biologics in Crohn’s disease?
The “Tipping Point” may be Corticosteroids?

35. Clinical Predictors of Risk of Progressive/Aggressive Crohn’s Disease at Diagnosis
Young age
Fistulae
Need for steroids
Deep ulcerations
High serologic titers
Smoking

36. Positioning Biologics in Crohn’s Disease
Disease Severity
at Presentation
Natalizumab
Surgery
Clinical trials
Natalizumab
Anti-TNF ± Thiopurine?
Anti-TNF ± Thiopurine?
Severe
Moderate
Mild
Earlier?
Thiopurine/
Methotrexate
Prednisone
5-ASA?
Induction
5-ASA?
Budesonide
Maintenance

37. 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

38. 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

39. Thank you