Gazing into the Crystal Ball: How will Evolving Future Therapies Change how we Position Biologics for Use in IBD? William J. Sandborn, MD Professor & Chief, Division of Gastroenterology Director, UCSD IBD Center

Therapies for IBD: the Pipeline Anti-Selective Adhesion Molecule Anti-integrin antibodies Etrolizumab (anti-β7) AMG 181 (anti- β7) Anti-MAdCAM-1 S1P1 Receptor modulator (RPC1063) Antagonist to Janus kinase 3 (JAK3) Tofacitinib Anti-Interleukin 12/23 Ustekinumab (CNTO 1275, Stelara) Anti-Interleukin-23 Anti-interleukin 6 Anti-IP 10 antibody Eldelumab

Clinical trials of JAK STAT inhibitors (jakinibs) in autoimmunity and cancer O’Shea, J. J. et al. (2013) Back to the future: oral targeted therapy for RA and other autoimmune diseases Nat. Rev. Rheumatol. doi:10.1038/nrrheum.2013.7

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 Moderately to Severely Active Ulcerative Colitis: Clinical Response at Week 8 Sandborn W. New Engl J Med 2012.

Tofacitinib for Moderately to Severely Active Ulcerative Colitis: Clinical Remission at Week 8 P<0.001 P<0.001 P=0.76 Sandborn W. New Engl J Med 2012.

Tofacitinib for Moderately to Severely Active Ulcerative Colitis: Endoscopic Response Sandborn W. New Engl J Med 2012.

Tofacitinib for Moderately to Severely Active Crohn’s Disease: Clinical Remission at Week 4 P=.42 P=.54 Sandborn W. Clin Gastroenterol Hepatol 2014

Mean percentage change from baseline in log transformed CRP (mg/L) in those patients with baseline CRP ≥5 mg/L (B) Sandborn W. Clin Gastroenterol Hepatol 2014

Mean percentage change from baseline in log transformed fecal calprotectin (mg/kg) in in those patients with baseline fecal calprotectin ≥250 mg/kg (B) Sandborn W. Clin Gastroenterol Hepatol 2014

Tofacitinib: Adverse Events in Rheumatoid Arthritis Severe, sometimes fatal, infections have occurred. Tuberculosis (TB) and other opportunistic infections have been reported. 11 solid cancers and 1 lymphoma were diagnosed among 3328 patients taking tofacitinib with or without a DMARD for ≤12 months, compared to no solid cancers or lymphoma in 809 patients taking a placebo with or without a DMARD for 3-6 months Gastrointestinal perforation has been reported during clinical trials with tofacitinib; patients with a history of diverticulitis may be at higher risk. LDL and HDL cholesterol have increased in patients taking tofacitinib; cholesterol levels should be checked 4-8 weeks after starting treatment.

Tofacitinib: Adverse Events in Rheumatoid Arthritis (Continued) Elevations in liver aminotransferase levels have occurred; liver enzymes should be monitored regularly. Lymphocytopenia, neutropenia and low hemoglobin levels can develop in patients taking tofacitinib. Lymphocytes should be monitored at baseline and then every 3 months. Neutrophils and hemoglobin levels should be monitored at baseline, after 4-8 weeks of treatment, and then every 3 months. Tofacitinib is classified as category C (risk cannot be ruled out) for use during pregnancy. It is fetocidal and teratogenic in rats and rabbits.

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 (Stelara) Approved for psoriasis and psoriatic arthritis at a dose of 45 mg (90 mg for weight > 100 kg) at weeks 0 and 4 and then every 12 weeks Indication is for the treatment of adults with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy

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

Corticosteroid-free Remission at 22 Weeks Following Treatment with Ustekinumab Sandborn WJ, et al. N Engl J Med 2012;367:1519-28.

Ustekinumab: Adverse Events in Psoriasis and Psoriatic Arthritis Serious infections requiring hospitalization occurred including diverticulitis, cellulitis, pneumonia, appendicitis, cholecystitis, sepsis, osteomyelitis, viral infections, gastroenteritis and urinary tract infections 1.7% of ustekinumab-treated patients reported malignancies excluding non-melanoma skin cancers (0.60 per hundred patient-years of follow-up). Non-melanoma skin cancer was reported in 1.5% of ustekinumab-treated patients (0.52 per hundred patient-years of follow-up). Malignancies other than non-melanoma skin cancer in ustekinumab-treated patients were similar in type and number to what would be expected

Ustekinumab: Adverse Events in Psoriasis and Psoriatic Arthritis (Continued) Reversible Posterior Leukoencephalopathy Syndrome (RPLS). RPLS is a neurological disorder, which is not caused by demyelination or a known infectious agent. RPLS can present with headache, seizures, confusion and visual disturbances. Conditions with which it has been associated include preeclampsia, eclampsia, acute hypertension, cytotoxic agents and immunosuppressive therapy. One case of RPLS was observed in the clinical trial safety databases for psoriasis and psoriatic arthritis.

Sphingosine 1‐Phosphate Receptor 1 Modulation Mechanism of Action S1P1R agonism induces receptor internalization lymphocytes lose response to S1P gradient Become trapped in lymph nodes causing peripheral lymphopenia Upon drug withdrawal receptor expression is restored and lymphocytes leave nodes reversing lymphopenia Courtesy Dr. Alan Olsen

RPC1063 (an S1P receptor modulator) RCT of oral RPC1063 at doses of 0.5 mg and 1 mg versus placebo in 199 patients with moderate to severe UC Remission at week 8 in 16.4% on 1 mg dose (p<0.05), 13.8% on 0.5 mg dose (p=NS), and 6.2% on placebo Clinical response at week 8 in 58.2% on 1 mg dose (p<0.05), and 36.9% on placebo All other secondary endpoints at week 8, including change in the Mayo score and mucosal improvement on endoscopy were also positive and statistically significant for the 1 mg dose, trends were observed for the 0.5 mg dose group that demonstrated dose response Receptos press release October 27, 2014

Conclusions Agents targeted against multiple targets including the p40 subunit of interleukin 12/23, JAK, and S1P receptor hold great promise for the future