You Can Never Stop a Biologic Scott D Lee MD Associate Professor of Medicine Director, Clinical Inflammatory Bowel Diseases Program University of Washington Seattle, WA March 23rd, 2013

Diagnosed with moderate to severe disease General Considerations in IBD Patients Started and Maintained on Biologics Diagnosed with moderate to severe disease At risk for complications of IBD Have had significant improvement Discontinued or on significantly less steroids Do not have related limiting side effects Have not develop contraindication Cancer Active infection Demyelinating disease

Proportion of Patients (%) Remission defined as: CDAI <150 points ACCENT I Week 54 Remission after Response to Infliximab Discontinued vs Continued Therapy P<0.001 P=0.021 Proportion of Patients (%) Single Dose (n=102) 5 mg/kg q 8 wks (n=104) 10 mg/kg q 8 wks (n=105) Remission defined as: CDAI <150 points

Proportion of Patients (%) ACCENT I Week 54 Steroid Free Remission After Response to Infliximab Discontinued vs Continued Therapy Single Dose 5 mg/kg q 8 wks 10 mg/kg q 8 wks Proportion of Patients (%) P=0.005 P=0.059 P=NS 6/54 14/56 18/53

Infliximab Antibody Formation Discontinued vs Continued Therapy ACCENT I Proportion of Patients with ATI* Through Week 54 Proportion of Patients (%) Episodic Strategy Maintenance q 8 weeks 10 mg/kg Maintenance q 8 weeks 5 mg/kg P=0.003 P=0.42 This slide highlights the effect of immunosuppression and episodic treatment on ATI development in the ACCENT  trial. In patients receiving REMICADE episodically, the rate of ATI development without immunosuppression was 38% compared with 16% in patients receiving immunomodulators. This difference was statistically significant. With maintenance dosing, the rate of ATI development was lower and the effect of immunomodulators was less pronounced. In the 5 mg/kg every 8 week group, 7% of patients receiving immunomodulators developed ATI compared with 11% of patients not receiving immunosuppressants and in the 10 mg/kg q 8 week group, 4% of patients receiving immunomodulators developed ATI compared with 8% of patients not receiving immunosuppressants. The differences ATI’s in the maintenance groups between patients receiving and not receiving immunomodulators were not statistically significant. Hanauer S, et al., Clin Gastroenterol Hepatol. 2004;2:542–553.

Duration of Response by Antibody Level Antibody Formation and Effect on Response with Episodic Treatment with Infliximab Duration of Response by Antibody Level Days of Response 37% of Patients (n=46) 140 120 100 40 20 80 60 Negative 1.7 - 7.9 g/mL 8.0 - 20.0 >20.0 71 days of clinical response to Infliximab therapy 35 days of clinical response to Infliximab therapy 63% of Patients (n=79) The median duration of response by antibody level is shown here. The box plots represent the 1st and 3rd quartiles in each group, while the T-bars represent the rest of the data with a maximum of 1.5 times the interquartile range. Patients who were negative for antibodies to infliximab or had low titer antibodies (1.7 – 7.9 µg/mL) had a median of 71 days of clinical response to REMICADE therapy. Patients who developed antibodies to infliximab with titers of 8.0 µg/mL or higher had a median of 35 days clinical response to REMICADE therapy. Baert F, et al. N Engl J Med. 2003;348:601-608.

Continued Therapy Is Associated with Fewer Hospitalizations ACCENT I Continued Therapy Is Associated with Fewer Hospitalizations Episodic Strategy 5 mg/kg Scheduled Strategy 10 mg/kg Scheduled Strategy Combined Schedule Strategy Week 54 P=0.047 P=0.023 P=0.014 10 20 30 40 50 Number of Hospitalizations per 100 Patients Rutgeerts P et al. Gastroenterology. 2004;126:402-413. Rutgeerts P et al. Gastroenterology. 2004;126:402-413.

Continued Therapy Is Associated With Fewer Intra-Abdominal Surgeries ACCENT 1 Continued Therapy Is Associated With Fewer Intra-Abdominal Surgeries Episodic Strategy 5 mg/kg Scheduled Strategy 10 mg/kg Scheduled Strategy Combined Schedule Strategy Week 54 P = 0.04 P = 0.07 P = 0.01 10 20 30 40 50 Proportion of Patients With Surgeries Rutgeerts P et al. Gastroenterology. 2004;126:402-413. Rutgeerts P et al. Gastroenterology. 2004;126:402-413.

UC Response and Remission IFX Discontinued vs Continued Therapy ACT 1 Remission Response 100 50 †P<0.001 90 † 45 † † ‡P<0.01 39 † 80 † 40 ‡ 37 69 34 70 62 † 35 32 ‡ 60 52 30 51 Percent of Patients 50 Percent of Patients 25 37 40 20 30 16 15 30 15 Clinical response was defined as a decrease in the Mayo score by 30% and 3 points AND a decrease in the rectal bleeding subscore of 1 or a rectal bleeding subscore of 0 or 1. 20 10 10 5 8 Weeks 30 Weeks 8 Weeks 30 Weeks Placebo infusions 5 mg/kg infliximab 10 mg/kg infliximab Rutgeerts P. N Engl J Med. 2005;353:2462-2476. Rutgeerts P. N Engl J Med. 2005;353:2462-2476.

Early Use of AZA After First Steroid Induction EFFICACY OF AZA THERAPY Early Use of AZA After First Steroid Induction 150 125 Mean CDAI 100 75 P= 0.07 50 P< 0.01 25 2 3 4 5 6 7 8 9 10 11 12 13 Visit number Sustained remission up to month 18 NRI p= 0.5 25 50 75 100 % patients LOCF p= 0.2 67,7 57,1 44,1 38,1 AZA Placebo Sans M. Gastroenterology 2011 (Abstract)

Week 50 Steroid Free Remission AZA vs IFX vs Dual Therapy SONIC Week 50 Steroid Free Remission AZA vs IFX vs Dual Therapy All Randomized Patients (N=508)* p<0.001 p=0.028 p=0.035 41/170 59/169 78/169 Colombel JF et al. NEJM 2010.

Mucosal Healing at Week 26 AZA vs IFX vs Dual Therapy SONIC Mucosal Healing at Week 26 AZA vs IFX vs Dual Therapy 100 p<0.001 80 p=0.023 p=0.055 60 Proportion of Patients (%) 44 40 30 16 20 18/109 28/93 47/107 AZA + placebo IFX + placebo IFX+ AZA

Mucosal Healing Predicts Sustained Clinical Remission in Early CD Mucosal Healing is Predictive of Sustained Remission Mucosal Healing Predicts Sustained Clinical Remission in Early CD Simple endoscopic score 0 Simple endoscopic score 1-9 100 80 * ** ** 60 % of patients 40 20 Remission at year 3+4 Remission off steroids at year 3+4 Remission off steroids at year 3+4 and no flare during year 3+4 * P < 0.05; ** P < 0.01 (Fischer’s exact) Baert FJ, et al. Gastroenterology 2010 . 13

Risk of Lymphoma Associated with Immunomodulators RISK OF THERAPY - MALIGNANCY Risk of Lymphoma Associated with Immunomodulators 19,486 IBD patients 30.1% currently receiving thiopurines 14.4% discontinued thiopurines 55.5% never exposed to thiopurines Receiving thiopurines vs. never exposed HR 5.28 (2.01-13.9) Exposure Rate per 10,000 pt-years 95% CI Current use 9 .0 5.0-14.9 Discontinued 2.0 0.2-7.2 Never exposed 2.6 1.0--5.7 Beaugerie et al, Lancet 2009;7:374.

Meta-Analysis Of Lymphoma Rate Associated With Anti-TNF Agents RISK OF THERAPY - MALIGNANCY Meta-Analysis Of Lymphoma Rate Associated With Anti-TNF Agents 8905 patients representing 20,602 pt-years of exposure 13 Non-Hodgkin lymphomas  6.1/10,000 pt years This HR is very similar to SIR with thiopurines Mean age 52, 62% male 10/13 exposed to IM* (This is really a risk of combo Rx) Lymphoma SIR does not appear increase with addition of anti-TNF Lymphoma SIR appears to be dependent on thiopurine use NHL rate per 10,000 SIR 95% CI SEER all ages 1.9 - IM alone 6.1 3.23 Anti-TNF + IM vs SEER 1.5-6.9 Anti-TNF+ IM vs IM alone 1.7 0.5-7.1 *not reported in 2 Siegel et al, CGH 2009;7:874.

Anti-TNF Meta-Analysis And Malignancies RISK OF THERAPY - MALIGNANCY Anti-TNF Meta-Analysis And Malignancies Controls Anti-TNF -0.14% (-0.4-0.2, P=0.39) Risk difference Difference in effect: treatment minus placebo (CI 95%) Peyrin-Biroulet et al CGH 2008;6:664. 16

Discontinued biologic vs continued use leads to: Conclusions Discontinued biologic vs continued use leads to: Higher recurrence rates of disease activity Lower likelihood of steroid free remission Increased risk of antibody formation Antibody formation leads to loss of response Continued biologic therapy vs Thiopurines is: More effective maintenance therapy Thiopurines appear to be the primary risk of lymphoma Results in higher rates of mucosal healing Once biologic therapy it should not be stopped as the risks outweigh the benefits A transition to thiopurines as maintenance is less effective and potentially higher risk