Convegno "X Hot Topics in Gastroenterologia 2015" - 07/11/2015 - Sala Rita Levi Montalcini - Ospedale S. Eugenio - Roma

1. Le Malattie Infiammatorie Croniche
Intestinale: la sfida terapeutica
Sandro Ardizzone
Gastroenterologia e Endoscopia Digestiva
Azienda Ospedaliera Fatebenefratelli e Oftalmico
Ospedale di Rilievo Nazionale
Milano

2. General consideration
1. IBD (CD and UC) are a progressive disease
affecting patients at a crucial time of their life
1. The aim of treatment is to:
– control symptoms, induce durable CS-free remission
and avoid complications
2. The aim of any therapeutic strategy for IBD is to:
– induce long-term control of the disease, allowing the
patient to lead a normal life

3. Crohn’s disease
(n=197)
Ulcerative colitis
(n=423)
43% 55%
32% 37%
19% 6%
3% 1%
IBD disease course over first 10 years
1. Solberg IC et al. Gastroenterol Hepatol. 2007;5:1430–8. 2. Solberg IC et al. Scan J Gastroenterol. 2009;44:431–440.
Norwegian IBSEN cohort study (1990-1994)
CD: 54% UC: 44%
CD: 3% missing data;
UC: 1% missing data

4. 37.9%
(95%CI 31.4%–44.4%)
9.8%
(95%CI 7.4-12.4%)
Crohn’s disease (n = 237)
Ulcerative colitis (n = 519)
Probability of surgery in IBD over first 10 years
Norwegian IBSEN cohort study (1990-1994)
1. Solberg IC et al. Gastroenterol Hepatol. 2007;5:1430–1438. 2. Solberg IC et al. Scan J Gastroenterol. 2009;44:431–440.
Independent risk factors at CD diagnosis:
- Terminal ileal location
- Stricturing behavior
- Penetrating behavior
- Age younger than 40 years
Independent risk factors at UC diagnosis:
- Extensive colitis
- ESR > 30

5. Cosnes et al IBD 2002
24022821620419218016815614413212010896847260483624120
0
10
20
30
40
50
60
70
80
90
100
CumulativeProbability(%)
Patients at risk:
Months
2002 552 229 95 37N =
Penetrating
Stricturing
Inflammatory
Long-term evolution of disease behaviour in
Crohn’s Disease

6. Corticosteroid requirement in
Crohn’s disease and outcomes
(Population based studies)
Crohn’s disease: 43-55%
Immediate outcome 1-year outcome
Complete remission 52% Prolonged remission 39%
Partial remission 30% Steroid dependency 33%
No response 18% Surgery 28%
Pooled data from Munkholm P, et al. Gut 1994; Faubion WA, et al. Gastroenterology 2001
The past: “treat symptoms, induce remission and treat on flare”

7. Corticosteroid requirement in
Ulcerative colitis and outcomes
(Population based studies)
Ulcerative colitis: 34-44%
Immediate outcome 1-year outcome
Complete remission 51-54% Prolonged remission 49-55%
Partial remission 30-31% Steroid dependency 17-22%
No response 16-17% Surgery 21-29%
Pooled data from Faubion WA, et al. Gastroenterology 2001; Henriksen M, et al. IBD 2006; Hoie O, et al. Gastroenterology 2007

8. GETAID – up to 92% of prednisolone-treated patients
achieve clinical remission at week 7, but low MH rate
Mod. from Modigliani R et al. Gastroenterology 1990;98:811-8
Prednisolone 1 mg/kg up to clinical remission
Patientsinremission(%)
weeka 4 week 5 week 6 week 7
0
10
20
30
40
50
60
70
80
90
100
63%
80%
88% 92%
29%
Endoscopic
improvement
13% MH

9. A
B
p = 0.0166
Late outcome: combined endpoint A vs B
Mucosal healing predicts late outcomes
after the first course of corticosteroids
for newly diagnosed ulcerative colitis
Ardizzone et al. CGH 2011

10. Treatment standards have been raised:
evolution of therapeutic goals
Before anti-TNFs
•Symptomatic remission
•Improve quality of life
•Induction use, then treat
on flare
•Reduce steroid use
What has changed today?
•Timely drug intervention
•Long-term sustainability
(scheduled maintenance)
•Maintain steroid-free (deep)
remission
•Complete mucosal healing
•Reduction in long-term
complications
•Decreased hospitalisations
and surgeries

11. Biologics
• Infliximab
• Adalimumab
• Golimumab
• Vedolizumab
• Etrolizumab
• Ustekinumab
• Morgensen
• ………….mab

12. Anti-TNF in Crohn’s disease
Induction of Remission
Peyrin-Biroulet L et al Clin Ge and Hep 2008:6:644

13. Anti-TNF in Crohn’s disease
Maintenance of Remission
Peyrin-Biroulet L et al Clin Ge and Hep 2008:6:644

14. Clinical Response at Weeks
8, 30 and 54
Rutgeerts P et al, N Engl J Med. 2005;353:2462-76
At week 54: Sustained response was attained in 36.9% of the infliximab-
treated subjects compared with 14.0% of placebo-treated (P < 0.001)

15. Clinical Remission at Weeks
8, 30 and 54
Rutgeerts P et al, N Engl J Med. 2005;353:2462-76

16. Infliximab as rescue therapy in hospitalized patients with
severe steroid-refractory UC
Sjöberg et al. APT 2013;38:377–387
Clinical outcome at 3 (n=211) and 12 months (n=209) after rescue therapy
with IFX for steroid-refractory, moderate to severe ulcerative colitis

17. Adalimumab in Moderately to Severely Active Ulcerative Colitis
Who failed to cortcoisteroids and/or immunosuppressants
Reinisch W et al Gut 2011;60:780

18. Sandborn WJ et al Gastroenterology 2012;142:257
Adalimumab in moderate-to osevere ulcerative colitis
160/80/40 or Placebo

19. GOLIMUMAB Induction in moderate severe
UC: Clinical response and clinical remission
at Week 61,2
1. SIMPONI® (golimumab). Summary of Product Characteristics. September 2013. 2. Data on file. Janssen Research & Development.
GLM=golimumab; PURSUIT=Program of Ulcerative Colitis Research Studies Utilizing an
Investigational Treatment.
aP≤0.001.
Primary end point Major secondary end point
Patients,%

20. GOLIMUMAB mantainance in moderate severe UC
Clinical responsea through Week 54: Randomized
subjects1
1. SIMPONI® (golimumab). Summary of Product Characteristics. September 2013.
aDefined as a decrease of ≥30% and ≥3 points from Week 0 of an induction study in the Mayo score
with either a decrease from baseline in the rectal bleeding subscore of ≥1 or a rectal bleeding subscore
of 0 or 1.
Patients,%
Golimumab
P≤0.01 P≤0.001
PURSUIT-SC Maintenance: Primary End Point

21. Indications
• Refractory luminal CD
• Steroid-dependent CD
• Refractory fistulizing (perianal) CD
• Chronic refractiory UC
• steroid-dependent UC
• Acute severe UC
• Extraintestinal manifestations

22. •Early treatment
•Mucosal healing

24. Adapted from Schreiber S, et al. Gastroenterol 2007;132(4 Suppl 2):A-147
Patients in remission, week 56: <2 years placebo n=4/23, adalimumab n=20/39; 2 to <5 years placebo n=4/36, adalimumab
n=25/57; 5 years placebo n=12/111, adalimumab n=82/233. Data are from randomised responders
Patients received induction therapy of adalimumab 80 mg (week 0) followed by 40 mg (week 2) and were randomised at week 4
Week 56
0
20
40
60
80
100
Patientswithremission(%)
23n= 39
<2 years
17%
51%
36 57
2 to <5 years
11%
44%
111 233
≥5 years
11%
35%
p=0.014 p=0.001 p<0.001
Placebo
All adalimumab
Time from diagnosis to anti-TNF
CHARM: Early Adalimumab Use is
Associated with Higher Rate of Remission
than Later Use

25. When to Intervene early with
anti-TNF Therapy: Poor Prognosis Patients
We must intervene with anti-TNF early in:
• Extensive small bowel disease
• Severe upper GI disease
• Severe rectal disease
• Younger patients
• Patients with perianal lesions
• Patients with early stricturing / penetrating disease
• Patients with deep colonic ulcers

26. Natural course of disease
The evolution of IBD therapy in the era of biologics
Treating Early to Increase the Rate of Primary Response
Time
Disability
Disease onset
2010 – Future
treatment
at diagnosis
1998-2007
Later
treatment
Intervention at diagnosis
Later intervention
S U S T A I N A B L E
2008
Earlier
treatment

27. IS MUCOSAL HEALING DISEASE MODIFYING?
• Prolongs remission duration
• Prevents complications
• Reduces hospitalization
• Reduces surgery
• Prevents CRC
• Improves QoL
• Reduces Mortality
Hypothesis

28. D’Haens G, et al. Lancet 2008
Primary end point:
remission (CDAI<150, no GCS, no surgery) at 6 and 12 months
Endoscopic results at year 2 (no ulcers)
P=0.003
Early Combined Immunosuppression
D’Haens G, et al. Lancet 2008; 371: 660-

29. Baert F, et al. Gastroenterology 2010
49 patients from SUTD trial underwent colonoscopy at year 2
and were followed-up through year 3 and 4
Remission off-GCS
Remission off-GCS & off-
IFX
New or active draining
fistulae
SES-CD = 0 (n=24) 71% 63% 4%
SES-CD 1-9 (n=22) 27% 18% 23%
0%
25%
50%
75%
100%
Patientsinremissionyears3-4
(%)
p=0.036
OR=6.48
(95%CI 1.8-23.4)
p=0.032
OR=7.5
(95%CI 1.9-29.3)
p=0.009
OR=0.148
(95%CI 0.016-1.38)
Mucosal Healing in CD at Year 2
Predicts Sustained Clinical Remission

30. MH and Long Term Outcome of
IFX Maintenance (Leuven)
Schnitzler F, et al. IBD 2009

31. Kaplan-Meier Estimates of Time to Colectomy
Week 8 Endoscopy
Score (n=466*)
Number of
Colectomies
Colectomy-free Prob
at Week 54 (%)
P Value**
(log rank)
0 (n=120) 6 95 0.0004
1 (n=175) 8 95
2 (n=114) 14 87
3 (n=57) 10 80
* Patients randomised to infliximab. Patients who had a colectomy or discontinued
before week 8 were not included.
** P value indicates the difference in distributions of time to colectomy among the
4 endoscopy score subgroups.
Patients Achieving Mucosal
Healing With Infliximab Are Less
Likely to Progress to Colectomy
Colombel JF, et al. To be presented at UEGW 2010. P1511.
ACT 1 & ACT 2

32. Evolving goals in IBD: modifying the
disease outcome
REMISSION
PERSPECTIVE GOALS
PATIENT
CLINICIAN
SOCIETY
Complete resolution of
symptoms and normalised
quality of life
Limited side effects
Normal laboratory data
Remission off steroids
Mucosal healing
Avoiding treatment escalation
Preventing non-response
Improved outcomes with
avoidance of complications,
hospitalisations, surgeries
and mortality
Payer costs

33. Unmet needs

34. Goal Benefit
Response 
Remission 
Steroid-free remission 
Mucosal healing 
Reduction in hospitalisation 
Reduction in surgeries  / ?
Improved QoL 
Sustained efficacy 
1. D’Haens G, et al. Lancet 2008;371:660–7;
2. Colombel JF, et al. N Engl J Med 2010;362:1383–95;
3. Rutgeerts P, et al. Gastroenterol 2004;126:402–13;
4. Colombel J-F, et al. Gastroenterol 2007;132:52–65;
5. Kamm M, et al. APT 2011;34:306–17;
6. Feagan B, et al. Gastroenterology 2008;135:1493–9;
7. Loftus E, Am J Gastroenterology 2008;103:3132–41;
8. Lichtenstein G, et al. Gastroenterology 2005;128(4):862–9;
9. Rutgeerts P, et al. . Gastroenterol 2012;142:1102–11;
10. Rutgeerts P, et al. Gastrointestinal Endoscopy 2006;63:433–42;
11. Sandborn WJ, et al. Ann Intern Med 2007;146:829–38;
12. Targan SR, et al. N Engl J Med 1997;337:1029–35;
13. Hanauer S, et al. Gastroenterology 2006;130:323–33;
14. Hanauer S, et al. Lancet 2002; 1541–9;
15. Sandborn W, et al. N Engl J Med 2007;357:228–38;
16. Schreiber S, et al. N Engl J Med 2007;357:239–50.
Benefits of anti-TNF therapy in IBD:
Evidence from clinical trials
1. Rutgeerts P, et al. N Engl J Med 2005;353:2462–76
2. Reinisch W, et al. Gut 2011;60:780–7;
3. Sandborn W, et al. Gastroenterology 2012;142:257–65;
4. Sandborn W, et al. Gastroenterology 2014;146:85-95 and 96-109;
5. Sandborn WJ, et al. Aliment Pharmacol Ther 2013;37:204–13;
6. Sandborn WJ, et al. Gastroenterology 2009;137:1250–60;
7. Feagan BG, et al. Gastroenterology 2014;146-110-8;
8. Feagan BG, et al. Am J Gastroenterol 2007;102:794–802;
9. Reinisch W, et al. Am J Gastroenterol 2010;105(Suppl. 1):S441;
10. Feagan B, et al, J Crohns Colitis 2013;7(suppl 1):S99–100;
≈/<1/3 at 1 year

35. • Primary non-response
• Secondary loss of response
• Adverse events
– Infusion / injection reactions
– Delayed hypersensitivity
– Paradoxical inflammation
– Infections
– Pregnancy
– Long-term safety
– Etc.
Clinical scenarios of
anti-TNFα failure

36. • Primary: 20-40% in clinical trials
(10-20% in 'real life' series), no reliable predictors
• Secondary: annual risk 13-20% per patient-year of follow up, no
reliable predictors
• ‘Empirical’ dose-escalation: 60% of response
• TDM: useful in some situations, not routinely used
• Shift ‘in-class’: possible, reduced rates of response
• Shift ‘out-of-class’: possible, reduced rates response (Vedo, Uste,..)
• Colectomy: benefit / risk balance
Non-response to anti-TNF alpha
and management
Hanauer SB, et al. Lancet 2002; Rutgeerts P, et al.NEJM 2005; Hanauer SB, et al. Gastroenterology 2006; Colombel
JF, et al. Gastroenterology 2007; Rudolph SJ, Dig Dis Sci 2008; Afif W, et al. IBD 2009; Schnitzler F, et al. Gut 2009;
Oussalah A, et al. AJG 2010; Kiss LS, et al.APT 2011; Reinisch W, et al.Gut 2011 ; Ben Horin S, et al. Autoimm Rev
2013; Gisbert JP, et al. AJG 2009; Billioud V, et al. AJG 2011

37.  Swap strategies
Is it today possible another way or strategy of treatment ?...
Unmet needs…

38. GEMINI I: Vedolizumab in ulcerative colitis:
Clinical Response, Remission, Mucosal Healing
at 6 Weeks
P<0.0001
P=0.0009
P=0.0012
Δ 21.7
11.6, 31.7
Δ 11.5
4.7, 18.3
Δ 16.1
6.4, 25.995% CI:
%
Induction ITT Population

39. 23.8
19.8
8.7
56.6
51.6
20.5
52.0
56.0
24.0
0
10
20
30
40
50
60
Durable Clinical Response Mucosal Healing Durable Clinical Remission
VDZ/PBO (n=126)
VDZ Q8W (n=122)
VDZ Q4W (n=125)
GEMINI I: Vedolizumab in Ulcerative Colitis
Maintenance Phase: Outcomes at Week 52
39
Patients,%
32.8 (20.8, 44.7)
28.5 (16.7, 40.3)
32.0 (20.3, 43.8)
36.3 (24.4, 48.3)
11.8 (3.1, 20.5)
15.3 (6.2, 24.4)
Secondary Outcomes: Maintenance ITT Population
GC, glucocorticoid; PBO, placebo; VDZ, vedolizumab.Derived from: Feagan BG et al. N Engl J Med 2013; 369: 699-710.
Mean % (95% CI)
VDZ Q8W vs PBO
VDZ Q4W vs PBO
p<0.001
p<0.001
p<0.001
p<0.001
p=0.008
p=0.001

40. GEMINI II & III: Vedolizumab in CD
Clinical remission (CDAI <150) in anti-TNF naive
Adapted from: Sands et al, Presentation at: UEGW 20th Annual Meeting 2012
Sands et al, Gastroenterology 2013; 147: 618–27
Adapted from: Colombel et al, Presented at UEGW 20th Annual Meeting 2012
Placebo Vedolizumab Vedolizumab Q8W
Induction
GEMINI II
Patients (%)
Induction
GEMINI III
Maintenance
GEMINI II
p= 0.012 p= 0.025 p= 0.003 / p= 0.015
(n= 76 109) (n= 50 51) (n= 71 66 71)(n= 50 51)
Patients (%)

41. GEMINI II: Vedolizumab in CD
Maintenance phase, primary & secondary outcomes, week 52
Adapted from: Sandborn et al, N Engl J Med 2013; 369: 711-21
Patients (%)
Placebo
(n=153)
Vedolizumab
(n=154)
Vedolizumab Q8W
(n=154)
Primary outcome Secondary outcomes
P<0.001
p=0.004 p=0.01
p=0.005
p=0.02
p=0.04

42. aIFX 5 mg/kg induction treatment (week 0, 2, and 6) followed by q8w as maintenance treatment; bADA 160 mg at week 0, 80 mg at week 2 for
induction treatment followed by 40 mg every other week as maintenance treatment; cGOL 200 mg at week 0, 100 mg at week 2 for induction
treatment followed by 100 mg every 4 weeks maintenance treatment; dVDZ 300 mg induction treatment (week 0,2, and 6) followed by q8w
maintenance treatment.
Cost-efficacy analysis: NNT and cost per clinical outcome in
anti-TNF naïve patients
Jansen et al, Presented at 10th Congress of ECCO; February 18−21, 2015; Barcelona, Spain: P322
Estimate 95% CI Estimate 95% CI Estimate 95% CI Estimate 95% CI
Probability of Induction
Response
Probability of Sustained
Response at 52 Weeks
NNT for Sustained
Response at 52 Weeks
Cost per Sustained Responder
at 52 Weeks, GBP
Placebo 0.34 (0.31; 0.37) 0.12 (0.09; 0.15) Reference Reference
Infliximab 5mg/kga 0.69 (0.62; 0.76) 0.34 (0.23; 0.47) 4.5 (2.9; 8.9) 58,685 (37,664; 116,829)
Adalimumab 160/80/40 mgb 0.49 (0.42; 0.56) 0.22 (0.14; 0.31) 10.2 (5.0; 45.4) 67,529 (32,931; 300,539)
Golimumab 200/100/100
mgc 0.57 (0.49; 0.65) 0.31 (0.22; 0.41) 5.2 (3.4; 9.5) 77,851 (51,421; 142,299)
Vedolizumab 300 mgd 0.63 (0.51; 0.75) 0.40 (0.26; 0.59) 3.6 (2.2; 7.5) 53,130 (33,210; 111,482)
Probability of Induction
Remission
Probability of Sustained
Remission at 52 Weeks
NNT for Sustained
Remission at 52 Weeks
Cost per Sustained Remission
at 52 Weeks, GBP
Placebo 0.09 (0.07; 0.11) 0.04 (0.03; 0.05) Reference Reference
Infliximab 5mg/kga 0.34 (0.27; 0.41) 0.16 (0.09; 0.24) 8.5 (4.8; 18.9) 111,435 (63,789; 249,642)
Adalimumab 160/80/40 mgb 0.17 (0.13; 0.22) 0.08 (0.04; 0.14) 22.4 (9.7; 108.8) 148,087 (63,884; 719,599)
Golimumab 200/100/100
mgc 0.23 (0.17; 0.29) 0.13 (0.08; 0.21) 10.2 (6.0; 20.7) 153,213 (90,593; 309,873)
Vedolizumab 300mgd 0.28 (0.18; 0.40) 0.19 (0.11; 0.32) 6.5 (3.5; 15.4) 95,833 (51,855; 228,719)

43. aADA 160 mg at week 0, 80 mg at week 2 for induction treatment followed by 40 mg every other week as maintenance treatment; bVDZ 300 mg
induction treatment (week 0,2, and 6) followed by q8w maintenance treatment.
Cost-efficacy analysis: NNT and cost per clinical outcome in
anti-TNF experienced patients
Jansen et al, Presented at 10th Congress of ECCO; February 18−21, 2015; Barcelona, Spain: P322
Estimate 95% CI Estimate 95% CI
NNT for Sustained
Response at 52 Weeks
Cost per Sustained
Responder at 52 Weeks, GBP
Placebo Reference Reference
Adalimumab 160/80/40 mga 13.3 (5.0; 82.2) 69,736 (26,176; 431,971)
Vedolizumab 300 mgb 4.0 (2.2; 9.7) 49,912 (27,535; 122,364)
NNT for Sustained
Remission at 52 Weeks
Cost per Sustained
Remission at 52 Weeks, GBP
Placebo Reference Reference
Adalimumab 160/80/40 mga 41.4 (11.7; 303.9) 217,457 (61,237; 1,597,033)
Vedolizumab 300 mgb 9.2 (4.1; 27.8) 116,100 (51,233; 349,433)

44. GED-0301: oral gastro-resistant
delayed release formulation
GED-0301 developed as an
oral gastro-resistant Ph-
dependent-release
formulation to:
• deliver GED-0301 in the
terminal ileum and right colon
• obtain a “topical” effect
• avoid systemic adsorption

45. NEJM 2015;372:1104-13

46. RESULTS

47. SAFETY

48. A “treat to target” approach has been adopted in
the management of these progressive diseases
Condition Treatment target
Diabetes <7% HbA1c
Hypertension
Blood pressure: 140/90 mm Hg
(135/80 mm Hg for diabetes patients)
LDL-cholesterol: 70 mg/dL to decrease
incidence of cardiac events
Rheumatoid arthritis Remission; low disease activity

49. Treat-to-target in IBD
Condition Treatment target
Diabetes <7% HbA1c
Hypertension
Blood pressure: 140/90 mm Hg
(135/80 mm Hg for diabetes patients)
LDL-cholesterol: 70 mg/dL to decrease
incidence of cardiac events
Rheumatoid arthritis Remission; low disease activity
Crohn’s disease
Ulcerative colitis
Deep remission?

50. Challenges to improve IBD
management
CHALLENGES
Early diagnosis
(before complications
occur) and accurate
assessment of the
inflammatory burden
of the disease
Prediction of
disease course
High precision
prediction of the
response to
targeted therapies
before start
Sensitive and non-
invasive biomarkers
to monitor therapy
Induction and
long-term
maintenance of
complete treatment
effect