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

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

50% 20% 30%

50% 20% 30%

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

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“

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

Early combined immunsuppression (ECI) with thiopurin plus adalimumab in CD ECI CM 12 mo 66% 62% Remission 24 mo 73% 65% Khanna et al. ECCO 2014

Amer J Gastro 2012

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

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

6 weeks 52 weeks Sandborn et al., NEJM 2013

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

Feagan et al., NEJM 2013

% 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)

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

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

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; 369:711-21. Supplementary appendix: Table S6.

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

Anti-TNF failures Anti-TNF naive NEJM 2016

Biological use in Germany Who is responsible for the indication? unrestricted: every physician treating IBD patients 40.000 IBD patients on biologicals, 6.800 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“

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