1. Journal Club: Biologic Agents in UC, Systematic Review and Network Meta-analysis, by Danese et al., Annals 2014 Barrett G. Levesque, MD Assistant Professor of Clinical Medicine UC San Diego, IBD Center

2. Panel Larry Stitt, Robarts Biostatistician Gopalan Rajamannar, Robarts Statistician Dr. Siddharth Singh, Advanced Fellow in IBD, Mayo Clinic, Rochester Niels Vande Casteele, PharmD, PhD, Post-doc UCSD, and KU Leuven, Moderated by Dr. Barrett Levesque, Robarts Associate Medical Director

3. Which is the best biologic option in UC?

4. Background A “second-look” meta-analysis, Levesque, Olkin Dig Dis Sci 2010

5. Background A “second-look” meta-analysis, Levesque, Olkin Dig Dis Sci 2010

6. Background: Network Meta-analysis

7. Trial Designs in UC R Induction & maintenance (ACT I & II – “ treat right through”): R Maintenance in open label respondes (Golimumab): RR Induction & maintenance – “ re-reandomization” (vedolizumab): Courtesy William Sandborn

8. ACT 1 and ACT 2: Clinical Remission † † † † P .002 vs placebo ‡ P .003 vs placebo † Rutgeerts et al. N Engl J Med. 2005 Dec 8;353(23):2462-76. ‡ ‡ ‡ ‡ ACT 1 ACT 2

9. ULTRA 1: Clinical Remission at Week 8 ITT-A3 analysis set (NRI) Clinical remission: Mayo score ≤2 with no individual subscore >1 0 5 10 15 20 25 30 35 Mayo score remission (%) Placebo N=130 9.2% ADA 80/40 mg N=130 10.0% ADA 160/80 mg N=130 18.5% N=390 *p=0.031, ADA 160/80 vs placebo Reinisch W, et al. Gut, 2011; 60:780-787

10. Reinisch W et al. Gut doi:10.1136/gut.2010.221127

11. Aim: Assess the comparative efficacy of biologic agents in (biologic naïve) adult UC.

12. Methodology*: Inclusion: Moderate to Severe UC**, RCT Network Meta-Analysis (“WinBUGS”) of: – Clinical Response (OR) – Mucosal Healing (OR) – Adverse Events -{{Maintenance of Remission}} *Registered on PROSPERO **Mayo Score 6-12, w/ endo 2-3

13. Measurements: Clinical Response: – Decrease MCS 30% AND decrease rectal bleeding(RB) by 1 or more, or absolute RB (0,1) Clinical Remission: – MCS 2 or lower (subscores 1 or less) Mucosal Healing – Mayo endoscopic Score 0 or 1

14. Measurements: Serious Adverse Events: – death, hospital, persistent disability,life- threatening Any AE Infectious AE Serious Infections TB CHF

18. Results:

21. Clinical Response

22. Clinical Remission

23. Mucosal Healing

24. Comparing ADA vs IFX in induction of UC remission Clinical TrialReinisch et al.ACT 1 Anti-TNFAdalimumab (ADA) 160/80 mg Infliximab (IFX) 5mg/kg Activity indexMayo score Definition of remissionMayo score 1 Participants130/group121 Prior Anti-TNF therapyNo Mean Mayo Score at trial entry ADA 8.8 ± 1.6IFX 8.5 ± 1.7 Placebo 8.7 ± 1.6Placebo 8.4 ± 1.8 Age (yrs)median 36.5 (range 18-75)42.4 ± 14.3 Disease duration (yrs)6.15.9

27. Placebo arm is not just placebo “a larger portion of the IFX patients (40- 60%) were on concomitant immunomodulator therapy at baseline compared to the ADA (30%), golimumab (20-30%) and vedolizumab (20%)” Dulai P, Personal Communication

28. The ACT Studies: Proportions of Patients with Clinical Remission by Serum IFX Concentration Quartiles Q1 Q2Q3Q4 Q1 Q2Q3Q4 % 26.3 37.0 43.9 43.1 P=0.0504 P<0.0001 Reinisch W. et al DDW 2012

31. Conclusion Biologics superior to “placebo” for induction, maintenance No direct Comparisons Indirect Comparisons of approved dosing favors infliximab for inducing clinical response Limitations of endpoint timing, history of treatments, Biologics were not optimized based on pK/pD Question of best biologic, optimized or not, for moderate to severe UC remains unanswered. What is the best? Consider strategy w/ best Value