Induction and Maintenance of Remission in IBD: Where Are We Coming - PowerPoint PPT Presentation

Induction and Maintenance of Remission in IBD: Where Are We Coming from; Where Could We Go? Geert D’Haens MD, PhD AMC Amsterdam

CONFLICTS OR INTEREST Abbvie: research support, lecture fee, consultant; Ablynx: consultant; Actogenix: consultant; Amakem: consultant; Amgen: consultant; AM Pharma: consultant; AstraZeneca: consultant; BMS: consultant; Boerhinger Ingelheim: consultant; Cosmo: consultant; Elan: consultant; Ferring: consultant, research support, lecture fee; DrFALK Pharma: research support, lecture fee; Celgene: consultant ; Celltrion: consultant; Centocor/Jansen Biologics: consultant, research support, lectur;e fee; Engene: consultant; Galapagos: consultant; Giuliani: lecture fee; GivenImaging: research support, consultant; GSK: consultant, research support, consultant; Hospira: consultant; Medimetrics: consultant; Millenium/Takeda: consultant, research support, lecture fee; Mitsubishi Pharma: consultant; MSD: consultant, research support, lecture fee; Mundipharma: consultant; Novonordisk: consultant; Norgine: lecture fee; Otsuka: consultant, lecture fee; Pfizer: consultant; Photopill: research support; PDL: consultant; Prometheus laboratories: consultant, research support; Receptos: consultant; Robarts Clinical Trials: Scientific Director, research support; Salix: consultant; Sandoz: consultant; Setpoint: consultant; Shire: consultant, lecture fee; TEVA: consultant; Tigenix: consultant; Tillotts: consultant, lecture fee; Topivert: consultant; UCB: consultant, lecture fee; Versant: consultant; Vifor: consultant, lecture fees.

HISTORY ULCERATIVE COLITIS CROHN’S DISEASE Sulfasalazine • • Sulfasalazine • Aminosalicylates • Aminosalicylates • Corticosteroids (BUD) • Corticosteroids (incl topical) • Thiopurines • Thiopurines • Cyclosporin • Methotrexate • Tacrolimus • Infliximab • Methotrexate • Infliximab • Adalimumab • Adalimumab • Vedolizumab • Golimumab • Vedolizumab 3

ULCERATIVE COLITIS 4

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First Landmark Trial in UC: Steroids 6 Truelove et al., BMJ 1955

7 Truelove et al., BMJ 1955

8 Rachmilewitz et al., BMJ 1989

Rachmilewitz score: CAI RANGE: 0-29; remission ≤ 4 9

Range 0-19; Remission and response criteria not defined in the original study Patient defined remission: < 2.5 points Patient Defined Significant Improvement: Decrease of > 1.5 points from baseline 10

“Mayo score” Coated Oral 5-Aminosalicylic Acid Therapy for Mildly to Moderately Active Ulcerative Colitis Kenneth W. Schroeder, M.D., Ph.D., William J. Tremaine, M.D., and Duane M. Ilstrup, M.S. N ENGL J MED 1987; 317:1625-1629 11

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“Mayo score” • Active disease: 6-12; endoscopy 2-3 • Response: Decrease in Mayo score by ≥ 30% and ≥ 3 points, with decrease in RBS of ≥ 1 or a RBS of 0/1 • Remission : Total Mayo score ≤ 2 points, with no individual subscore >1 13

Vedolizumab in Ulcerative Colitis - Study Design • Induction and maintenance study in patients with moderate to severe Ulcerative Colitis (UC) • Randomized, double-blind, placebo-controlled multicenter phase 3 study (211 centers / 34 countries) Induction Phase Weeks 0–6 (N=895) Maintenance Phase Weeks 6–52 (N=703) Screening and Enrollment Days –21 to –1 PBO PBO/PBO n=149 n=149 Cohort 1 Blinded Induction (n=374) Maintenance (n=373) VDZ/PBO n=126 Randomized VDZ:PBO=3:2 VDZ Yes Randomized 1:1:1 Stratified:+/- GC or +/- IS or n=225 +/- prior anti-TNF α Stratified: by cohort, +/- VDZ Q8W GC, +/- IS, +/- prior anti- n=122 Response at TNF α week 6? VDZ Q4W n=125 No Cohort 2 VDZ Open-label Induction n=521 VDZ Q4W open-label (n=521) n=373 Dosing regimen Induction: 300mg vedolizumab (VDZ) or placebo (PBO) days 1, 15. ITT Population ITT Population Maintenance: 300mg VDZ q8w or Induction Efficacy Maintenance Efficacy q4w or PBO GC, glucocorticoid; IS, immunosuppressant; IT, intent-to-treat; TNF, tumor necrosis factor 14 14 Derived from : Feagan BG et al. N Engl J Med 2013; 369 : 699-710 & supplement

Challenges in UC Trials What should be the population to be included ? 1. Severity of symptoms (Mayo 6-12; other scores ??) 2. Endoscopic severity (Mayo 2-3) 3. Combination of the above ? Aspects or relevance: 1. Recruitability 2. Reduction of placebo response 3. Feasibility of repeated endoscopies 4. Timing of primary endpoint

Challenges in UC Trials Which patients can enter the maintenance phase ? 1. Mayo score response 2. Mayo remission 3. Endoscopic response 4. Endoscopic remission 5. Other biochemical /imaging criteria 6. All patients Aspects or relevance: 1. Attractivity 2. Rerandomization of responders to placebo ?

OBJECTIVE (INDEPENDENT) ASSESSMENT 17

Clinical Remission with Mesalazine 100 90 Proportion of patients (%) Week 6 Weeks 6 & 10 Week 10 80 70 60 Asacol P = 0.011 50 Placebo 40.7 *P = 0.069 40 P = 0.072 30 30 25 21.3 20.6 20 16.3 10 0 *Primary endpoint Feagan BG, Sandborn WJ, D’Haens G, et al. Gastroenterology 2013

Clinical Remission 100 90 Proportion of patients (%) ITT Central-reader 80 confirmed eligible 70 60 Asacol P = 0.011 P <0.001 50 Placebo 40.7 40.2 40 *P = 0.069 P = 0.011 P = 0.072 P = 0.040 30 29 30 25 24.3 21.3 20.6 20 16.3 16.1 13.8 12.6 10 0 Week 6 Week 10 Weeks 6 & 10 Week 6 Week 10 Weeks 6 & 10 Feagan BG, Sandborn WJ, D’Haens G, et al. Gastroenterology 2013

Proportion of Patients in Clinical Remission at Week 32 (Adjudicated Central Read - ITT) Δ = 15.2% Δ = 20.0% 35% p = 0.0021 p = 0.0108 Proportion of Patients in Clinical Remission 30% 26.2% 25% 20.9% 20% 15% 10% 6.2% 5% 0% n = 65 n = 67 n = 65 Placebo Ozanimod 0.5 mg Ozanimod 1 mg Sandborn, ECCO 2015 RPC01-202 Topline Maintenance Results April 2015 - CONFIDENTIAL 20

Anti-MAdCAM-1 Antibody (PF00547659) for UC: Different Endoscopic Assessment Modalities Mucosal Improvement 40 37 36 32 35 31 28 Patients (%) 30 26 25 25 23 23 25 20 19 17 17 20 16 14 12 15 11 11 8 10 5 0 Local Read Single Central ReadAdjudicated Central Adjudicated Central Read* Read** Placebo 7.5 mg 22.5 mg 75 mg 225 mg *All patients scored with 2 central reads, in the case of discrepancy, then consensus between 2 central reads **For patients with discrepancy between 1 st central read and local read, then 2 nd central read, in case of discrepancy, then consensus between 2 central reads Vermeire ECCO 2015

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ULCERATIVE COLITIS: CONCLUSIONS 23

ULCERATIVE COLITIS: CONCLUSIONS • Independent read of entry endoscopy and end-of-induction endoscopy appears essential • Single reads are usually sufficient • Available disease instruments to measure disease activity all have their flaws. Rectal bleeding and BM frequency alone (both PRO’s) in addition to endoscopy may suffice. Duration of symptom scoring (1-3-7 days) remains matter of debate. 24

CROHN’S DISEASE 25

The National Cooperative Crohn’s Disease Study 26 Summers, Gastroenterology 1979

Activity Indices in Crohn’s disease (adults) Clinical activity • CDAI developed by the NCCDS • HBI Harvey - Bradshaw simple index Endoscopic activity • CDEIS Crohn’s disease endoscopic index of severity • SES-CD Simplified version of CDEIS • Rutgeerts Score: dedicated to postoperative recurrence Histologic activity • D’Haens, Geboes et al. Scoring system for histological abnormalities in CD biopsies

THE CDAI Number of liquid/semisolid BM’s per day (x7) N x 2 Abdominal pain score 0-3 (x7) N x 5 PRO General Well-Being 0-4 (x7) N x 7 EIM’s, fever, fistula N x20 Antidiarrheals + 30 Abdominal mass no-questionable-definite 0-20-50 Weight (compared to ‘normal’) Hematocrit (compared to ‘normal’) Remission:<150 Mild disease: 150-220 Moderate: 220 (250) -450 Severe:>450

Mesalazine in CD: Induction of Remission 80 79% 70 % Patients With Remission 60 60%* 60% 61% (*or Improved ) 50 40 43% 30 5-ASA Micro- Oral 5-ASA 20 5-ASA granul 5-ASA 6-Me- Tab 4 g 4 g 3.2 g 18% 22% Pred 4 g 10 Placebo * Placebo 40 mg 0 Singleton 1993 Tremaine 1994 Prantera 1999 N=310 N=38 N=94 12 wks 17 wks 16 wks

Clinical Response with IFX at 4 W Clinical response defined as a ≥ 70-point decrease in CDAI score from baseline. Targan SR et al. N Engl J Med. 1997

Anti-MAdCAM and Placebo CDAI-70 Response 70% 65% 63% 62% 60% 59% 58% 60% 53% 48% 50% 40% 30% 20% 10% 0% Week 8 Week 12 Placebo 22.5 75 225 RESPONDERS COULD MOVE ON TO THE MAINTENANCE PHASE 32 D’Haens, ECCO 2015

What’s wrong with the CDAI ? 33

High Placebo Response in Some Recent CD Trials 80 Percent of Patients in Clinical P=0.051 P=0.278 P<0.05 P=0.082 Response (CDAI ≥ 70) 60 51.0 48.6 43.0 40 35.0 20 0 ENACT 1 Schreiber Hanauer Korzenik Natalizumab Certolizumab Adalimumab Sargramostim Wk 10 Wk 12 Wk 4 Wk8 N=181 N=73 N=74 N=43

The CDAI- Subjective and Non-Specific • Cohort study – 91 183 consecutive patients (p=0.1) with CD or IBS Mean CDAI Score • CDAI scores and item 157 scores calculated • Higher CDAIs in IBS patients • Pain scores higher Lahiff C. et al. Aliment Pharmacol Ther. 2013