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 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)

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

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

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

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

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 CCL-25 MAdCAM-1 VCAM-1 ACTIVATED INTESTINAL MICROVASCULAR ENDOTHELIAL CELLS Adapted from Danese S Gut 2011;60:998-1008

Vedolizumab: A Humanized, Monoclonal Antibody (mAb) Against 47 Integrins CH3 CH2 CH1 VH VL CL CDR3 CDR2 CDR1 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

Vedolizumab For Active Crohn’s Disease Response and Remission at Week 8 P=NS 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 P=0.04 Remission (%) Response or Feagan Clinical Gastroenterology & Hepatology 2008

Vedolizumab For Active Crohn’s Disease Remission 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

Induction ITT Population 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

Maintenance ITT Population 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, % Δ17.4 Δ14.7 Δ13.4 Δ15.3 Δ7.2 Δ2.0 Δ15.9 Δ12.9 *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

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

Biology of Interleukins 12 and 23 Anti-IL-12/23 IL-12 Anti- IL-12/23 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 Ag CD4+ Antigen Presenting Cell MHCII IL-23 p40 p19 IL-17 (Th17) IL-23R IL-12Rb1 TCR

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=.004 P=.022 P=.02 P=.046 60 P=.019 60 P=.337 Infliximab-Experienced Patients (%) Patients (%) P=.335 40 40 20 20 2 4 6 8 2 4 6 8 Weeks Weeks CRP in All Patients 1.2 1.0 Week 0 0.8 Week 8 Median CRP (mg/dL) 0.6 0.4 0.2 Subcutaneous Intravenous Subcutaneous Intravenous Placebo Ustekinumab Sandborn WJ. Gastroenterology 2008;135:1130-1141.

+p<0.05 vs. PBO by CMH test 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

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

Tofacitinib an Oral Janus Kinase (JK) Inhibitor Cytokine Effects on the immune system IL-2 Stimulate the proliferation and differentiation of Th, Tc, B, and natural killer (NK) cells IL-4 Induce the differentiation of Th0 to Th2 Induce immunoglobulin switching IL-7 Promote the development, proliferation and survival of T, B, and NK cells IL-9 Stimulate intrathymic T cell development IL-15 Promote the proliferation, cytotoxicity and cytokine production of NK cells IL-21 Enhance T and B cell function Cytokine Tofacitinib blocks phosphorylation of STAT and downstream activation α β γ JAK JAK P STAT P P STAT mRNA 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

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 response rate (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 Tofacitinib Tofacitinib Sandborn W. Gastroenterology 2011 Abstract

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

P=0.019 P=NS Ito Gastroenterology 2004 Tocilizumab (Humanized Monoclonal Antibody Interleukin-6 Receptor – Previously Atlizumab or MRA) For Active Crohn’s Disease 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=0.019 P=NS Ito Gastroenterology 2004

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

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 IP-10 CXCR3 Unidentified receptor Heparan sulfate TLR4 (?) T cell Epithelial Islet b cell Endothelial ↑ Trafficking ↓ Proliferation & Migration1,2 ↓ Proliferation3 ↑ Apoptosis4 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

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

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