1. Conflicts of Interest Consulting: Falk, Janssen, Merck, Takeda,
Lecture fees: Abbvie, Falk, Takeda, Janssen

2. Solberg et al., Clin Gastroenterol Hepatol 2007
Natural course of Crohn´s disease
43% 6%
19%
32%
Solberg et al., Clin Gastroenterol Hepatol 2007

3. 50%
20%
30%

4. 50%
20%
30%

5. Azathioprine dependent
Steroid dependent
Azathioprine dependent
Infliximab dependent
D‘Haens Lancet 2008

6. Crohn`s disease Infliximab ACCENT 1 (5 mg/kg/8Wo) Adalimumab CHARM%
„Response“ (CDAI -70)
„Remission“
Infliximab
ACCENT 1
(5 mg/kg/8Wo) 59 31 23 23 17
[Week]
„Response“ (CDAI -70)
„Remission“ 66
Adalimumab
CHARM
(40 mg/2Wo) % 36 29 27 24
[Week] %
„Response“ (CDAI -100)
„Remission“ 64
Certolizumab
PRECISE 2
(400 mg/4Wo) 40 43 31
[Week]
„Response“ (CDAI -100)
„Remission“

7. Ulcerative colitis Infliximab ACT1 (5 mg/kg/8Weeks) Adalimumab Ultra-2
„Response“ 69
„Remission“
Infliximab
ACT1
(5 mg/kg/8Weeks) 52 % 46 39 34 35
[Week]
Adalimumab
Ultra-2
(40 mg/2Weeks)
„Response“
„Remission“ % 50 17 30
[Week]
[Week]
Golimumab
PURSUIT
(100 mg/4Weeks)
„Response“
„Remission“ % 51 18 25 14

8. Early combined immunsuppression (ECI) with thiopurin plus adalimumab in CD
ECI CM
12 mo % %
Remission
24 mo % %
Khanna et al.
ECCO 2014

9. Amer J Gastro 2012

10. Immunsuppressives and Infections
The risk of infections increases with the number of immunosuppressants
Toruner Gastroenterology 2008

11. Melanoma under Anti-TNF
50% increase of invasive melanoma
Raaschou et al., BMJ 2013

12. 6 weeks
52 weeks
Sandborn et al., NEJM 2013

13. GEMINI III: Vedolizumab Crohn´s disease Induction – Clinical Remission Anti-TNF-α-Failures vs. TNF-α-Naive
Anti-TNF-α-Failures
(n=315, ITT)
Anti-TNF-α-Naive
(n=101, ITT)
PBO
VDZ
35,3
P=0,0012
31,4
26,6
Patients in clinical
Remission, %
p=NS
16,0
15,2
12,1
12,0
12,1
Week 6
Week 10
Week 6
Week 10
CDAI, Crohn’s Disease Activity Index; ITT, intent-to-treat; PBO, placebo; TNF, tumor necrosis factor; VDZ, vedolizumab.
Adapted from: Entyvio® Fachinformation Stand Mai 2014

14. Feagan et al., NEJM 2013

15. % of Week 6 Nonresponders in Clinical Remission
Proportions of week 6 nonresponders in clinical remission at week 10, 14, or 52 were numerically higher with VDZ than with PBO
% of Week 6 Nonresponders in Clinical Remission
Patients, % (95% CI)
4.9
(1.3, 12.0)
11.8
(8.5, 15.8)
9.8
(3.3, 16.2)
14.6
(10.7, 18.5)
(0.2, 9.5)
16.1
(12.1, 20.2)
PBO (Induction cohort 1) (n=82)
VDZ combined (Induction cohorts 1 and 2) (n=322)
Clinical remission was defined as partial MCS of ≤2 points and no subscore >1 point. At week 52, clinical remission was defined as a complete Mayo Clinic score of ≤2 points and no subscore >1 point.
Feagan BG, et al. Gastroenterology. 2014;146(Suppl 1):S590. Abstract Mo1222.
Feagan BG, et al. J Crohns Colitis. 2014;8(Suppl 1):S276-S277. Abstract P501.
GEMINI 1 (UC)

16. Vedolizumab: Remission rates „Real Life“
D: n=212
F: n=294
14 weeks ⎬
Crohn´s disease
Ulcerative colitis D F
20%
31%
19%
36%
Steroid-free
remission
D: Baumgart et al. 2016
F: Amiot et al. 2016

17. Vedolizumab: Remission rates „Real Life“
USA: n=212
(Crohn´s disease)
Dulai et al. 2016

18. PBO-Patienten kombiniert VDZ-Patienten kombiniert
GEMINI II Vedolizumab Morbus Crohn Erhaltungsphase - Sicherheitsergebnisse
Häufigkeit, n (%)
PBO-Patienten kombiniert
(n=301)
VDZ-Patienten kombiniert
(n=814)
Pat. mit UE
246 (82)
706 (87)
Schwerwiegendes UE
46 (15)
199 (24)
Häufige UE bei ≥ 10% der Patienten
Morbus Crohn
65 (22)
164 (20)
Gelenkschmerzen
40 (13)
110 (14)
Fieber
103 (13)
Kopfschmerzen
47 (16)
97 (12)
Übelkeit
30 (10)
90 (11)
Abdominale Schmerzen
39 (13)
79 (10)
Infektionen der oberen Atemwege
56 (19)
184 (23)
Infektionen
121 (40)
359 (44)
Schwerwiegende Infektionen
9 (3)
45 (6)
Infusionsreaktionen
14 (5)
33 (4)
Maligne Neoplasien
1 (<1)
4 (<1)
13007 Gemini II (EXTERNAL SPEAKER SLIDE)
Key point: Vedolizumab maintenance treatment, compared to placebo, was associated with a higher rate of serious adverse events (24.4% vs. 15.3%), infections (44.1% vs. 40.2%), and serious infections (5.5% vs. 3.0%).
Adverse events
Nasopharyngitis occurred more frequently, and headache and abdominal pain less frequently, with vedolizumab treatment than with placebo.
Infections
The incidences of infections and serious infections were higher with vedolizumab treatment than with placebo. One case of latent tuberculosis occurred.
Malignant Neoplasms
One case each of the following occurred:
breast cancer, carcinoid tumor in the appendix, squamous-cell carcinoma, and basal-cell skin carcinoma was diagnosed in the vedolizumab groups
a borderline ovarian tumor developed in one patient in the placebo group.
Serious Adverse events
The incidence of any serious adverse event was higher among patients who received vedolizumab than among those who received placebo (24.4% vs. 15.3%).
Deaths
Five deaths occurred during the study period, four among patients receiving vedolizumab (one death each from Crohn’s disease with sepsis, intentional overdose of prescription medication, myocarditis, and septic shock) and one in the placebo group (from bronchopneumonia).
The sepsis and septic-shock events (both culture-negative) involved, respectively, a patient with extensive pre-existing pulmonary emboli and a thrombus in the inferior vena cava and a patient with medically managed pneumoperitoneum after colonoscopy. Myocarditis and intravenous injection of drugs intended for oral use were diagnosed at autopsy in a patient who had a history of endocarditis and deep-vein thrombosis.
Infusion reactions
Clinically important infusion reactions were infrequent; only one patient discontinued the study treatment because of a serious infusion reaction.
No cases of anaphylaxis were reported.
Maintenance safety population = all patients who received any amount of study drug in weeks 0–66;
Combined PBO = patients randomized to PBO at baseline + those randomized to PBO maintenance after meeting response criteria with VDZ induction;
Combined VDZ = patients responded to VDZ induction and randomized to VDZ maintenance + those who did not meet response criteria with VDZ induction and were assigned to VDZ open-label maintenance (of 506 patients who did not achieve clinical response at week 6 during vedolizumab induction, 94 patients discontinued on or before week 6. The remaining 412 patients continued vedolizumab treatment every 4 weeks.)
In relation to serious infections and malignant neoplasms, the exposure-adjusted relative risk for patients receiving vedolizumab versus placebo was 1.30 (95% CI: 0.88, 1.90) for serious adverse events, 1.48 (95% CI: 0.67, 3.24) for serious infections, and 1.39 (95% CI: 0.16, 12.44) for malignancies;
Values consist of events per person per year of exposure, using patient data from both cohort 1 and cohort 2 of the induction and maintenance trials. Exposure was calculated as days from first dose to last dose inclusive for patients who completed or were rescued to open-label vedolizumab in a separate study; exposure was calculated as first dose to last dose date plus up to 113 days, depending on length of follow-up, to account for pharmacologically relevant exposure for patients who permanently discontinued therapy. Days were converted into years. Exposure-adjusted incidence rates were calculated as total number of events/total patient-years.
A serious infection was defined as a serious adverse event of infection using the standardized Medical Dictionary for Regulatory Activities (version 15) classification for adverse event reporting.
UE, unerwünschtes Ereignis; PBO, Placebo; VDZ, Vedolizumab
adaptiert nach: Sandborn WJ et al. N Engl J Med 2013; 369: Supplementary appendix: Table S6.

19. Side effects of Vedolizumab („real life“)
5.1% therapy stopped
Amiot et al.
Clin Gastro Hepatol 2016

20. Anti-TNF failures
Anti-TNF naive
NEJM 2016

21. Biological use in Germany
Who is responsible for the indication?
unrestricted: every physician treating IBD patients
IBD patients on biologicals, on Vedolizumab
Are there restrictions for treatment with biologicals?
yes, with respect to minimum use of biosimilars
Can gastroenterologists use new drugs first line?
yes, indication is open for anti-TNF naive patients
but every physician has a limited overall budget
and treatment is required to be „economical“
Is quality of biological care monitored? no
Do we have a German registry for biological use?
not in general, only as part of the „competence network“

22. Ulcerative colitis (UC, n = 519)
Variables
Ulcerative colitis (UC, n = 519)
Crohn's disease (CD, n = 511)
Total cohort (N = 1,032)
Statistic*
Signifi- cance (p)
Patients´ characteristics
proportion of males
n (%)
253 (48.7)
191 (37.4)
441 (42.9)
chi²
.001
age (years)
M (SD)
45.0 (14.9)
40.3 (13.1)
42.7 (14.2) t
< .001
Anamnesis (proportion of patients with …)
disease duration (years)
9.0 (8.0)
11.0 (9.0)
10.1 (8.5)
tobacco smoking
64 (12.5)
209 (41.4)
275 (26.9)
at least one bowel resection
19 (3.7)
171 (33.5)
190 (18.4)
< .010
Disease Activity
Activity Scores
CAI > 4
140 (27.1) ─
CDAI ≥ 150
231(45.2)
CDAI ≥ 300
56 (11.0)
Medication
aminosalicylates°
363 (69.9)
238 (46.6)
603 (58.4)
budesonide
17 (3.3)
117 (22.9)
134 (13.0)
corticosteroids
84 (16.2)
201 (19.5)
.008
topical medication˜
153 (29.5)
21 (4.1)
174 (16.9)
immunosuppressants
133 (25.6)
241 (47.2)
375 (36.3)
TNF-alpha
13 (2.5)
42 (8.2)
55 (5.3)
Psychosocial impairments (proportions of patients with … )
“fair” or “poor” subjective general health
73 (14.3)
114 (22.8)
187 (18.1)
Period of observation 2006/2007
Bokemeyer, JCC 2013