Who should receive early anti-TNF therapy: With what benefits and risks?

1. Who should receive early anti-TNF therapy: With what benefits and risks? Ted Denson, MD Cincinnati Children’s 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-TNFαmonotherapy • 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 Crohn’s disease (CD) who have had an inadequate response to conventional therapy.

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

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

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

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

11. Additional Treatment Characteristics of Study Triads Hyams et al. Gastroenterology 2013

12. 12 Month Outcomes For The Three Early Therapy Approaches: PCDAI≤10Without Resection (n=204 for 68 propensity score matched triads) CS-free, Surgery free (p=0.0003) No difference between early IM and no early IM Hyams et al. Gastroenterology 2013

13. Growth Parameters of Study Triads at Diagnosis/One Year *p=0.002, anti-TNFα group only

14. What Does That Mean? • In clinically similar populations of children with Crohn’s 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 doesn’t 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. PooledAdverseEventsfor 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 Crohn’s 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 Bodgeret al Alimen Pharm Ther 2009

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

21. Is the Reward Worth the Risk? RISK REWARD REWARD RISK DON’T DO IT DO IT

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

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

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