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Positioning our recent and future advances in therapies for Crohn’s disease

Positioning our recent and future advances in therapies for Crohn’s disease. William J. Sandborn, MD Professor & Chief, Division of Gastroenterology Director, UCSD IBD Center. Recent and future advances. Azathioprine – new data Deep remission and treat to target New agents

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Positioning our recent and future advances in therapies for Crohn’s disease

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  1. Positioning our recent and future advances in therapies for Crohn’s disease William J. Sandborn, MD Professor & Chief, Division of Gastroenterology Director, UCSD IBD Center

  2. Recent and future advances • Azathioprine – new data • Deep remission and treat to target • New agents • Mild to moderate disease • Rifaximin EIR • Moderate to severe disease • Vedolizumab (anti-alpha 4 beta 7) • Ustekinumab (anti-interleukin 12/23 • Tocilizumab (anti-interleukin 6) • Tofacitinib (Janus Kinase [JAK] inhibitor) • Eldelumab(Anti-IP 10)

  3. Top Down Therapy With Azathioprine + Prednisone Versus Step Up Therapy With Prednisone And Then Azathioprine In Adults With Newly Diagnosed Crohn’s Disease Cosnes J. Gastroenterology 2013

  4. Top Down Therapy With Azathioprine + Prednisone Versus Prednisone In Adults With Newly Diagnosed Crohn’s Disease Sustained steroid free remission Survival free of relapse Panes J. Gastroenterology 2013

  5. Bouguen G, et al. Clin Gastroenterol Hepatol. 2013 Sep 10. [Epub Ahead of Print] Treat-to-Target Algorithm ) CRP, C-reactive protein.

  6. Rifaximin Extended Intestinal Release for Crohn’s Disease: Results at Week 12 Prantera C, et al. Gastroenterology 2012

  7. Therapeutic Targets for Lymphocyte Trafficking Leucocyte Adhesion NATALIZUMAB CD 11a/CD18 VEDOLIZUMAB LEUCOCYTE 41 (VLA-4) 47 ISIS-2302 CCX282-B CCR9 ETROLIZUMAB MAdCAM mAb (PF-547659) ICAM-1 MAdCAM-1 VCAM-1 CCL-25 ACTIVATED INTESTINAL MICROVASCULAR ENDOTHELIAL CELLS Adapted from Danese S Gut 2011;60:998-1008

  8. N N N N CDR1 CDR2 VH CDR3 VL CH1 CL C C CH2 CH3 C C Vedolizumab: A Humanized, Monoclonal Antibody (mAb) Against 47 Integrins • Targets only a4b7 integrin • Created by insertion of ACT-1 CDRs into human IgG1 framework • Two amino acid substitutions abrogate Fc-receptor binding and complement fixation (ADCC) • IV infusion over 30 – 60 minutes

  9. Vedolizumab For Active Crohn’s DiseaseResponse and Remission at Week 8 P=NS P=0.04 • 185 patients with active Crohn’s disease receiving a stable dose of 5-ASA or antibiotics or no medical therapy • Randomized to receive IV doses of placebo, 0.5 mg/kg, or 2.0 mg/kg MLN-02 on days 1 and 29 • The primary endpoint was % clinical response (decrease in CDAI of 70 points) at day 57 • Secondary endpoint was % remission (CDAI < 150) at day 57 • Saturation of 47 on peripheral blood lymphocytes was not consistently achieved Response or Remission (%) Feagan Clinical Gastroenterology & Hepatology 2008

  10. Vedolizumab For Active Crohn’s DiseaseRemission at Week 8 * p-value < 0.05 ITT population * * * MLN0002 induced a significantly greater clinical remission rate in patients with Crohn’s disease compared to placebo (2 mg/kg group) at days 15, 29, and 57. Feagan Clinical Gastroenterology & Hepatology 2008

  11. Vedolizumab (Anti-Alpha 4 Beta 7 Integrin) For Moderately-to-Severely Active Crohn’s Disease: Results at Week 6 in 368 Patients Induction ITT Population P=0.23 P=0.02 Patients, % Sandborn W. N Engl J Med 2013 95% CI: Δ 7.8 1.2, 14.3 Δ 5.7 –3.6, 15.0

  12. Vedolizumab (Anti- 47 Integrin) For Maintenance of Response in Moderately-to-Severely Active Crohn’s Disease: Results at Week 52 in 461 Patients Maintenance ITT Population ** * ** ** * * Patients, % *P<0.05 **P<0.01 †CS tapering began in responders at 6 weeks; for others, as soon as a clinical response was achieved. Sandborn W. N Engl J Med 2013 Δ17.4 Δ14.7 Δ13.4 Δ15.3 Δ7.2 Δ2.0 Δ15.9 Δ12.9

  13. Other Drugs in this Class • Anti-MAdCAM1 (PF-00547,659) • Etrolizumab (anti-7, rhumab beta 7) • Anti-7 (AMG181)

  14. Anti- IL-12/23 IL-17 (Th17) IL-23R IL-12Rb1 p19 p40 Anti- IL-12/23 IL-23 Anti-IL-12/23 Biology of Interleukins 12 and 23 IL-12 • Ustekinumab and briakinumab are fully human IgG1 monoclonal antibodies • Bind the p40 subunit of human IL-12/23 • Prevent IL-12 and IL-23 from binding IL-12Rb1 • Normalize IL-12 and IL-23 mediated signaling, cellular activation, and cytokine production • In development in Crohn’s disease and psoriasis Stimulus TLR? p35 p40 IL-12Rb1 X IFNg (Th1) b2 CD4+ Ag Antigen Presenting Cell TCR MHCII

  15. Ustekinumab (anti-IL 12/23p40) for Induction of Clinical Response in Moderate to Severe Crohn’s Disease All Patients Previously Treated with Infliximab 100 100 Placebo 80 80 Ustekinumab P=.001 P=.022 P=.004 P=.046 P=.02 60 60 P=.019 P=.337 Infliximab-Experienced Patients (%) P=.335 Patients (%) 40 40 20 20 0 0 2 4 6 8 2 4 6 8 Weeks Weeks CRP in All Patients 1.2 Week 0 1.0 Week 8 0.8 Median CRP (mg/dL) 0.6 0.4 0.2 0 Subcutaneous Intravenous Subcutaneous Intravenous Placebo Ustekinumab Sandborn WJ. Gastroenterology 2008;135:1130-1141.

  16. Ustekinumab (Anti-IL-12/23p40) for Induction of Moderate to Severe Crohn’s Disease Clinical Response Clinical Remission + + + + + + + + + + +p<0.05 vs. PBO by CMH test Sandborn WJ. N Engl J Med 2012; 367:1519-1528

  17. Ustekinumab (Anti-IL-12/23p40) for Maintenance of Moderate to Severe Crohn’s Disease p<0.001 p=0.029 Sandborn WJ. N Engl J Med 2012; 367:1519-1528

  18. STAT STAT STAT STAT JAK JAK mRNA Tofacitinib an Oral Janus Kinase (JK) Inhibitor Cytokine Tofacitinib blocks phosphorylation of STAT and downstream activation γ β α P P P P P • Tofacitinib (CP-690,550) is a novel, small-molecule, oral JAK inhibitor • Tofacitinib inhibits JAK1, JAK2, and JAK3 in vitro with functional cellular specificity for JAK1 and JAK3 over JAK2. Importantly, tofacitinib directly or indirectly modulates signaling for an important subset of pro-inflammatory cytokines including IL-2, -4, -7, -9, -15, and -21 Sandborn W. New England Journal of Medicine 2012

  19. Tofacitinib Tofacitinib Tofacitinib for Induction in Moderate to Severe Crohn’s Disease: Clinical Response and Remission at Week 4 Clinical Response-70 Clinical Response-100 49.9% Estimated clinical responserate (80% CIs) 48.0% 42.9% 44.8% 40.8% 38.8% 33.7% 28.1% N=34 N=36 N=34 N=35 N=34 N=36 N=34 N=35 Sandborn W. Gastroenterology 2011 Abstract

  20. Mean percentage change from baseline in log transformed CRP (mg/L) in those patients with baseline CRP ≥5 mg/L (B) Sandborn W. Gastroenterology 2011 Abstract

  21. Tocilizumab (Humanized Monoclonal Antibody Interleukin-6 Receptor – Previously Atlizumab or MRA) For Active Crohn’s Disease P=0.019 • 36 patients with active Crohn’s disease (CDAI > 150, ↑ CRP) • Randomized to receive IV placebo, tocilizumab (previously atlizumab, MRA) 8 mg/kg every 2 weeks, or atlizumab 8 mg/kg every 4 weeks for 12 weeks • The endpoints were % response (decrease in CDAI  70) and remission (CDAI  150) at week 12 • Frequency of adverse events similar in all groups P=NS Ito Gastroenterology 2004

  22. Other Drugs in this Class • BMS-945429 (fully human antibody to interleukin-6) • PF-04236921 (fully human IgG2 antibody to interleukin-6)

  23. CXCR3 ↑Trafficking T cell Unidentified receptor ↓Proliferation & Migration1,2 Epithelial Heparan sulfate IP-10 ↓ Proliferation3 Endothelial TLR4 (?) ↑Apoptosis4 Islet b cell Interferon Gamma Inducible Protein 10 (IP-10 or CXCL-10) • Belongs to CXC family of chemokine ligands • Induced by IFN- and produced by various cell types including hematopoietic & stromal cells • Mechanism of action • CXCR3-mediated recruitment of T cells to inflamed tissues • CXCR3-independent (or dependent) modulation of functions of other cells including epithelial, endothelial and islet b cells 1 Suzuki et al. Pathology International 2007; 57(7):413-420; 2. Soejima et al, J Immun 2001; 167:6576-6582; 3. Luster et al. J Exp Med 1995; 182:219-231; 4. Schulthess et al. Cell Metabolism 2009;9(2):125-139

  24. Drug in this Class • Eldelumab (fully human antibody to IP-10)

  25. Conclusions • Top down therapy with steroids and azathioprine is not effective in adults with newly diagnosed Crohn’s disease • Treatment goals in Crohn’s disease are evolving towards deep remission achieved via a treat to target strategy • Agents targeted against multiple targets including beta 7 integrin, MAdCAM-1, and the p40 subunit of interleukin 12/23, and possibly JAK, IP-10, and interleukin-6, hold great promise for the future

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