1. Who should receive early anti-TNF therapy: With what benefits and risks? Ted Denson, MD Cincinnati Childrens Hospital Medical Center University of Cincinnati College of Medicine

2. Disclosures Grant support: NIH & CCFA Adapted from NASPGHAN 2013 talk by Jeff Hyams

3. IBD: Treatment Goals Clinical remission: no disease activity Excellent quality of life Intestinal healing Normal growth and development Prevent surgeries and hospitalizations Minimal side effects Acceptable financial cost

4. Therapeutic Options Option 1: Prednisone followed by 5-ASA Option 2:Prednisone followed by 6-MP/Aza Option 3: Prednisone followed by methotrexate Option 4: Exclusive enteral nutrition followed by IM Option 5: Anti-TNFα monotherapy Option 6: Anti-TNFα plus thiopurine Option 7: Anti-TNF α plus methotrexate Option 8: Intensive helminth therapy

5. Label for Infliximab Therapy in Children Approved for pediatric use in 2006 Infliximab is indicated for reducing signs and symptoms and inducing and maintaining clinical remission in pediatric patients with moderately to severely active Crohns disease (CD) who have had an inadequate response to conventional therapy.

6. Accelerated Step-up Therapy for CD Disease Severity Thiopurines Corticosteroids Enteral Nutrition Methotrexate Anti-TNF Surgery

7. Focus Questions How should we position anti-TNFα therapy in 2013? Rescue (i.e., after conventional therapy) vs. primary (at diagnosis) Can we identify patients who will receive the greatest benefit from early anti-TNFα therapy? What are the risks of early anti-TNFα therapy? Should we give monotherapy or combination therapy? Do benefits outweigh risks? Can we stop anti-TNFα therapy?

8. REACH: Response and Remission *Reduction from baseline of 15 points in PCDAI score and a PCDAI score 30. PCDAI score 10. % of Patients n = 99 n = 66 n = 29n = 33 n = 17n = 12 p = 0.002 p < 0.001 * Hyams et al. Gastroenterology 2007;132:863-873

9. Imagine Trial 28%45% P=0.8 P=0.065 Hyams et al. Gastroenterology 2012;143:365 EXP= IFX experienced, N=IFX naïve

10. 2008-2012: 552 children Newly Diagnosed with Crohns Disease Enrolled in CCFA RISK Study Crohns disease: 552 children with complete data and 1 yr f/u Anti-TNFα only n = 68 No early immunotherapy n = 236 Early IM only n=248 Propensity Score Matching Anti-TNFα only n = 68 No early immunotherapy n = 68 IM only n = 68

11. Additional Treatment Characteristics of Study Triads Early Therapy n=204 Agents used in 1 st 3 months Additional agents 3-6 months Additional agents 6- 12 months Total other agents 3-12 months Anti-TNFα only n=68 67 IFX 1 ADA 0 Thio 4 MTX 1 Thio 2 MTX 1Thio 6 MTX IM only N=68 54 Thio 14 MTX 6 IFX 0 ADA 13 IFX 1 ADA 19 IFX 1 ADA No immuno- therapy N=68 48 5-ASA 8 EEN 11 Thio 8 MTX 7 IFX 1 ADA 1 IFX + IM 2 ADA + IM 3 Thio 5 MTX 4 IFX 1 ADA 4 IFX + IM 14 Thio 13 MTX 11 IFX 2 ADA 5 IFX+IM 2 ADA+IM Hyams et al. Gastroenterology 2013

12. TreatmentYes (n=136)No (n=68) Early anti-TNFα only (n=68) 58 (85%)10 (15%) Early IM only (n=68) 41 (60%)27 (40%) No early immunotherapy (n=68) 37 (54%)31 (46%) CS-free, Surgery free (p=0.0003) 12 Month Outcomes For The Three Early Therapy Approaches: PCDAI10 Without Resection (n=204 for 68 propensity score matched triads) No difference between early IM and no early IM Hyams et al. Gastroenterology 2013

13. Growth Parameters of Study Triads at Diagnosis/One Year Early Therapy Height z- score Weight z- score BMI z-score Anti-TNFα only (n=68) -0.16 (1.1) +0.14 (0.4)* -0.56 (1.4)-0.79 (1.5) IM only (n=68) -0.29 (1.1) -0.02 (0.4) -0.72 (1.3)-0.81 (1.3) No immuno- therapy (n=68) -0.32 (1.1) -0.06 (1.1) -0.67 (1.1)-0.68 (1.1) Difference between groups P=0.6 P=0.039 P=0.8 *p=0.002, anti-TNFα group only

14. What Does That Mean? In clinically similar populations of children with Crohns disease, early (<3 mon) therapy with anti-TNFα was superior to early IM or no early immunotherapy despite later addition of those agents: PCDAI remission, CRP, growth There was no particular clinical or laboratory characteristic that helped predict response or non- response to an initial therapeutic decision It doesnt mean that everyone should get anti-TNFα therapy, rather that we need to better define further characteristics of patients, such as genetics, serology, microbiome. Confirmatory studies will be required.

15. Pooled Adverse Events for Pediatric IFX and ADA Dubinsky et al IBD 2013

16. Infliximab Black Box Warning WARNING: SERIOUS INFECTIONS and MALIGNANCY SERIOUS INFECTIONS Increased risk of serious infections leading to hospitalization or death, including tuberculosis (TB), bacterial sepsis, invasive fungal infections (such as histoplasmosis) and infections due to other opportunistic pathogens. Discontinue infliximab if a patient develops a serious infection. Perform test for latent TB; if positive, start treatment for TB prior to starting infliximab. Monitor all patients for active TB during treatment, even if initial latent TB test is negative. MALIGNANCY Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with tumor necrosis factor (TNF) blockers, including infliximab. Postmarketing cases of fatal hepatosplenic T-cell lymphoma (HSTCL) have been reported in patients treated with TNF blockers including infliximab. All infliximab cases were reported in patients with Crohns disease or ulcerative colitis, the majority of whom were adolescent or young adult males. All had received azathioprine or 6-mercaptopurine concomitantly with infliximab at or prior to diagnosis.

17. T-Cell NHL Reported to FDA AERS with TNF-α Inhibitors: The REFURBISH Study Deepak et al. Am J Gastroenterol 2013:108:99

18. The Option Grid for Shared Decision Making Dubinsky et al IBD 2013

19. UK Markov Model for Cost Effectiveness of Anti-TNF Therapy Bodger et al Alimen Pharm Ther 2009

20. Anti-TNF is Cost Effective for up to 4 Years Bodger et al Alimen Pharm Ther 2009 Surgical care: ~44% of lifetime costs ICER: incremental cost-effectiveness ratio QALY: quality-adjusted life-years

21. Is the Reward Worth the Risk? REWARD RISK REWARD RISK DO IT DONT DO IT

22. Crohns Disease Progresses on Conventional Therapy in Children: 1988-2002 Vernier-Massouille et al. Gastroenterology 2008;135:1106 Inflammatory Stricturing Penetrating 34% at 5 yrs

23. Infliximab Reduces Risk for Surgery Gupta et al Gastroenterology 2006

24. Higher Anti-microbial Serologies (QSS) are Associated with Increased Risk for Complications Dubinsky et al Clin Gastro Hep 2008

25. Systems Dynamics Model for Disease Complications Siegel et al IBD 2011

26. Benefit of Early anti-TNF May Increase as QSS Increases Siegel et al IBD 2011

27. Patient Decision Aid Siegel et al IBD 2011

28. Study: Genetic makeup Bacteria in bowel Immune reactivity Environmental Exposures 1100 children with Crohns at diagnosis 3 years 160 – 200 patients with complication / surgery CCFA Sponsored Clinical Research Network: PRO-KIIDS: Aim to Discover and Validate New Diagnostic & Prognostic Tools

29. Take home messages Anti-TNFα therapy is highly successful in inducing and maintaining remission in most pediatric patients with CD Select the correct patient to treat. Rescue vs. primary Patients with significant growth failure and higher risk of disease complications may derive greater relative benefit Consider anti-TNF withdrawal once treatment goals are met (catch-up growth, mucosal healing) in carefully selected patients: biologic exit strategy