Emerging g therapies for IBD: A practical approach to positioning Stephen B. Hanauer, MD Sequential Therapies for IBD Disease Severity at Presentation Severe Anti-TNF +/IS Cyclosporine (UC) Colectomy (UC) Natalizumab (CD) Anti-TNF/ Moderate Corticosteroid Aminosalicylate/ Mild Aminosalicylate Oral/Topical/Combo Aminosalicylate ate Oral/Topical/Combo Maintenance Therapy is stepped up according to severity at presentation or failure at prior step 1
New and Near Future Therapies for Ulcerative Colitis Budesonide MMX Golimumab Vedolizumab Tofacitanib ib (phase II) Disease Severity at Presentation and Maintenance for Mild- Moderate UC: Where are the gaps? Severe Moderate Mild Aminosalicylate Oral/Topical/Combo Aminosalicylate ate Oral/Topical/Combo Maintenance 2
Budesonide Metabolism and Characteristics 1,2 Oral budesonide ph release: ileum/right colon MMX: pan-colonic ~1% Budesonide ~9% metabolism in the liver o Budesonide characteristics 2 Rectal budesonide Enema/Foam 1 Brattsand R. Can J Gastroenterol.199;4:7-414 2 Gross V. Expert Opin Pharmacother 8;9:1257-1265 o o Non-halogenated corticosteroid, highly lipophilic o Good tissue penetration o 9x greater receptor binding than dexamethasone o Rapidly absorbed in GI tract o Metabolites are almost inactive o Terminal half-life 2.7 +/-.6 hours Needs specifically designed release system CORE I and II: Budesonide MMX Primary Endpoint Combined Clinical and Endoscopic Remission * ** *** N=121 N=89 N=21 N=123 N=19 N=232 N=121 N=19 N=23 N=124 N=13 *P=.143 **P=.47 ***P=.2 ASA=Asacol; Ent=Entocort; B-MMX=budesonide MMX Sandborn WJ et al. Gastroenterology 11;1 (Suppl): S124; Sandborn WJ et al. Gastroenterology 11;1 (Suppl): S65; Sandborn WJ et al. Am J Gastroenterol 11;16 (Suppl): S485 3
Moderate-Severe UC: Where are the gaps? Disease Severity at Presentation Colectomy Severe Anti-TNF +/IS Cyclosporine Anti-TNF/ Moderate Corticosteroid Aminosalicylate/ Mild Maintenance Therapy is stepped up according to severity at presentation or failure at prior step What is the Optimal Positioning of MMX- Budesonide in Mild-Moderate UC? Disease Severity at Presentation Severe Moderate Mild MMX-Budesonide Before 5-ASA? Tested Aminosalicylate Oral/Topical/Combo With 5-ASA? Before prednisone? Maintenance? Maintenance? Aminosalicylate/ Corticosteroid Aminosalicylate ate Oral/Topical/Combo Maintenance Therapy is stepped up according to severity at presentation or failure at prior step 4
Three classes of anti-tnf: Fusion protein, antibodies and PEGylated Fab' fragment Etanercept Receptor Infliximab Fab Adalimumab Golimumab Fab Certolizumab pegol IgG1 Fc IgG1 Fc PEG Human recombinant receptor/fc fusion protein Chimeric Monoclonal antibody Human PEGylated humanized Fab fragment 2 kda PEG 5 3 1 UC: Comparing ACT (Infliximab), Pursuit (Adalimumab) and Ultra (Golimumab) Clinical Remission 6-8 weeks Patients failing 5-ASA/Steroids/IS Infliximab Adalimumab Golimumab 52-54 weeks 5
PURSUIT-Maintenance: Clinical Response* Through Week 54 Among Subjects in Clinical Response to Golimumab 1 Subjects (%) 8 6 31.4 P=.1 47.1 P<.1 5.6 Placebo 5 mg 1 mg (n=156) (n=153) (n=154) Golimumab *Defined as a decrease from Week of an induction study in the Mayo score by 3% and 3 points, with either a decrease from baseline in the rectal bleeding subscore of 1 or a rectal bleeding subscore of or 1 Sandborn WJ et al. Gastroenterology. 13;1.153/j.gastro.13.6.1. Infliximab + Azathioprine vs Infliximab vs Azathioprine: The SUCCESS Study 1 8 6 *P<.5 compared to IFX; #P<.5 compared to AZA 77 # 69 5 * # 22 24 # IFX+AZA (n=78) IFX (n=77) AZA (n=66) 63 55 37 Steroid-free remission Response Mucosal Healing AZA=azathioprine; IFX=infliximab Panccione R et al. DDW 11; Abstract 835 6
What is the optimal positioning for Golimumab in UC? Disease Severity at Presentation Unlikely in Severe/Fulminant Colectomy Severe Golimumab Anti-TNF +/IS Cyclosporine Anti-TNF/ Moderate Possible Tested Corticosteroid Aminosalicylate/ Mild With/Without IS? Maintenance Therapy is stepped up according to severity at presentation or failure at prior step Moderate-Severe UC: Where are the gaps? Disease Severity at Presentation Colectomy Severe Anti-TNF +/IS Cyclosporine Anti-TNF/ Moderate Corticosteroid Aminosalicylate/ Mild Maintenance Therapy is stepped up according to severity at presentation or failure at prior step 7
Janus Kinase Pathway Janus kinase inhibitor Targets a specific intracellular signaling cascade-jak/stat pathway The JAK family binds multiple cytokine receptors including: IL2/IL4/IL7/IL9/IL12 (JAK3) IFNs Tofacitinib is JAK3 inhibitor used for psoriasis and rheumatoid arthritis. TNF, tumor necrosis factor; RA, rheumatoid arthritis Shuai K et al. Nat Rev Immunol 3;11:9. Phase 2 Study of Tofacitinib (CP-69,55), an Oral Janus Kinase Inhibitor, in Active Ulcerative Colitis Sandborn W et al. N Engl J Med 12 SAFETY? Sandborn W et al. N Engl J Med 12 8
L-selectin Recruitment of Neutrophils Into Inflamed Tissue β 2 -integrin activation E/P-selectin IL-8 PAF ICAM-1 Endothelium Rolling Tight adhesion Transmigration Van Deventer SJ. Gut 2;3:362-363. Endothelial and Leukocyte Adhesion: α4 Integrins α4 β1/β7 Leukocyte membrane glycoproteins β1 and β7 subunits Interact with endothelial ligands VCAM-1, fibronectin, and MAdCAM-1 Mediate leukocyte adhesion and trafficking Springer TA. Cell. 1994;76:31-314; Butcher EC et al. Science 1996;272:6-66. 9
Therapeutic Targets LEUCOCYTE Leukocyte Adhesion CD 11a/CD18 NATALIZUMAB VEDOLIZUMAB CCX282-B ISIS-232 α4β1 (VLA-4) α4β7 CCR9 MAdCAM mab (PF-547659) rhumab Beta 7 CCL-25 ICAM-1 MadCAM-1 VCAM-1 Adapted from Danese S. Gut 11;6:998-18. ACTIVATED INTESTINAL MICROVASCULAR ENDOTHELIAL CELLS Vedolizumab Phase III: Study Design Phase Week Week 6 Maintenance Phase Week 6 Week 52 Cohort 1 Blinded N=374 Placebo N=149 VDZ N=225 No Placebo N=149 VDZ N=373 Screening, Enrollment No Cohort 1 complete? Week 6: Responder? Yes Placebo N=126 VDZ Q8 wks N=122 Week 52 Assessments Yes Cohort 2 Open-Label N=521 VDZ N=521 VDZ Q4 wks N=125 Corticosteroid Tapering* *Responders began tapering regimen at 6 weeks; others, as soon as a clinical response was achieved. Feagan BG et al. New Engl J Med 13;369:699-71. 1
Clinical Response, Clinical Remission, Mucosal Healing at 6 Weeks, ITT Population 5 45 35 3 25 15 1 5 95% CI: P<.1 47.1 Placebo Vedolizumab 25.5 24.8 P=.1 16.9 5.4 P=.1.9 Clinical Response Clinical Remission Mucosal Healing Δ 21.7 11.6, 31.7 Δ 11.5 4.7, 18.3 Δ 16.1 6.4, 25.9 Feagan BG et al. New Engl J Med 13;369:699-71. Clinical Response, Clinical Remission, Mucosal Healing at 6 Weeks, ITT Population 5 45 35 3 25 15 1 5 95% CI: P<.1 47.1 Placebo Vedolizumab 25.5 24.8 P=.1 16.9 5.4 P=.1.9 Clinical Response Clinical Remission Mucosal Healing Δ 21.7 11.6, 31.7 Δ 11.5 4.7, 18.3 Δ 16.1 6.4, 25.9 Feagan BG et al. New Engl J Med 13;369:699-71. 11
Clinical Response, Clinical Remission, Mucosal Healing at 6 Weeks, ITT Population 5 45 35 3 25 15 1 5 95% CI: P<.1 47.1 Placebo Vedolizumab 25.5 24.8 P=.1 16.9 5.4 P=.1.9 Clinical Response Clinical Remission Mucosal Healing Δ 21.7 11.6, 31.7 Δ 11.5 4.7, 18.3 Δ 16.1 6.4, 25.9 Feagan BG et al. New Engl J Med 13;369:699-71. Clinical Remission, Durable Clinical Response at 52 Weeks by Prior TNF Antagonist Exposure 7 6 5 3 1 1.6 Prior Anti-TNF Antagonist Exposure (n=149) VDZ/PBO VDZ/VDZ Q8W VDZ/VDZ Q4W 36..4 Clinical Remission 44. 46.2 45.8 47.9 19.1 19.1 Durable Clinical Response Clinical Remission Patients Without TNF Antagonist Exposure (n=224) 65.3 26.6 56.2 Durable Clinical Response Mean Δ% vs VDZ/PBO (95% CI) VDZ/VDZ Q8W: 25.4 (5.1, 43.8) VDZ/VDZ Q4W: 29.7 (1.3, 47.7) 24.9 (7.1, 42.6) 27. (9.4, 44.6) 26.8 (12.4, 41.2) 29. (14.6, 43.3) 38.7 (24., 53.4) 29.6 (14.6, 44.6) PBO=placebo; VDZ=vedolizumab Feagan BG et al. New Engl J Med 13;369:699-71. 12
Clinical Remission, Durable Clinical Response at 52 Weeks by Prior TNF Antagonist Exposure 7 6 5 3 1 1.6 Prior Anti-TNF Antagonist Exposure (n=149) VDZ/PBO VDZ/VDZ Q8W VDZ/VDZ Q4W 36..4 Clinical Remission 44. 46.2 45.8 47.9 19.1 19.1 Durable Clinical Response Clinical Remission Patients Without TNF Antagonist Exposure (n=224) 65.3 26.6 56.2 Durable Clinical Response Mean Δ% vs VDZ/PBO (95% CI) VDZ/VDZ Q8W: 25.4 (5.1, 43.8) VDZ/VDZ Q4W: 29.7 (1.3, 47.7) 24.9 (7.1, 42.6) 27. (9.4, 44.6) 26.8 (12.4, 41.2) 29. (14.6, 43.3) 38.7 (24., 53.4) 29.6 (14.6, 44.6) PBO=placebo; VDZ=vedolizumab Feagan BG et al. New Engl J Med 13;369:699-71. What is the optimal positioning for Vedolizumab in UC? Disease Severity at Presentation Severe Vedolizumab Before Anti-TNFs? Anti-TNF +/IS Cyclosporine Colectomy Anti-TNF/ Moderate Before Steroids? Tested Corticosteroid Aminosalicylate/ Mild Maintenance Therapy is stepped up according to severity at presentation or failure at prior step 13
Vedolizumab Crohn s Disease Ustekinemab (phase II) Where are the Gaps for Crohn s Disease? Disease Severity at Presentation Severe Anti-TNF +/IS Natalizumab (CD) Anti-TNF/ Moderate Corticosteroid Aminosalicylate/ Mild Aminosalicylate (Oral/Topical/Combo) Budesonide Aminosalicylate ate Oral/Topical/Combo Maintenance Therapy is stepped up according to severity at presentation or failure at prior step 14
Vedolizumab for CD and Maintenance Phase Week Week 6 Maintenance Phase Week 6 Week 52 Screening, Enrollment Cohort 1 Placebo Placebo Blinded N=148 N=148 N=368 No Cohort 1 complete? VDZ N=2 Week 6: Responder? No Yes VDZ N=56 Placebo N=153 VDZ Q8 wks N=154 Week 52 Assess -ments Yes Cohort 2 Open-Label N=747 VDZ N=747 VDZ Q4 wks N=154 Corticosteroid Tapering* *Responders began tapering regimen at 6 weeks; others, as soon as a clinical response was achieved. VDZ=vedolizumab Sandborn WJ et al. New Engl J Med 13;369:711-721. 1 Clinical Remission and CDAI-1 Response at Week 6 8 Placebo Vedolizumab 6 P=.2 P=.23 31.4 25.7 68 6.8 14.5 Clinical Remission CDAI-1 Response Mean Δ% vs PBO (95% CI) 7.8 (1.2, 14.3) 5.7 ( 3.6, 15.) PBO=placebo; VDZ=vedolizumab Sandborn WJ et al. New Engl J Med 13;369:711-721. 15
1 8 6 Primary and Secondary Outcomes at 52 Weeks Primary Outcome Secondary Outcomes VDZ/PBO VDZ/VDZ Q8W VDZ/VDZ Q4W 43.5 45.5 39. 36.4 3.1 31.7 28.8 21.6 21.4 15.9 14.4 16.2 Clinical Remission CDAI-1 Response CS-Free Remission Durable Remission Mean Δ% vs VDZ/PBO 17.4 14.7 13.4 15.3 7.2 2. 15.9 12.9 P<.1 vs placebo; P<.5 vs placebo CS=corticosteroid; VDZ=vedolizumab Sandborn WJ et al. New Engl J Med 13;369:711-721. Clinical Remission, CDAI-1 Response at 52 Weeks by Prior TNF Antagonist Exposure Maintenance ITT Population* 1 8 6 Patients With Prior Anti-TNFα Exposure (n=253) VDZ/PBO VDZ/VDZ Q8W VDZ/VDZ Q4W 38.6 29.5 27.7 3.7 23.2 17.1 Patients Without Prior Anti-TNFα Exposure (n=8) 6.6 51.5 53.5 46.5 38. 26.8 Clinical Remission CDAI-1 Response CS-Free Remission Durable Remission Mean Δ% vs VDZ/PBO (95% CI) VDZ/VDZ Q8W: 12.5 (.1, 25.) VDZ/VDZ Q4W: 1.6 ( 2., 23.2) 7.5 ( 5.8,.8) 15.4 (1.5, 29.3) 24.8 (8.9,.6) 19.7 (4.2, 35.2) 22.6 (6.3, 38.9) 15.5 (.7, 31.7) VDZ=vedolizumab Sandborn WJ et al. New Engl J Med 13;369:711-721. 16
Vedolizumab Phase 3 Trial in CD CDAI-1 Response ITT Population 1 Anti-TNFα Failure Population (n=315) Overall Population (n=416) 8 6 Placebo Vedolizumab 39.2* 46.8 39.2 47.8 22.3 24.8 22.7 24.2 Week 6 Week 1 Week 6 Week 1 CDAI-1 Response *P=.11 vs placebo; P<.1 vs placebo; P=.2 vs placebo PBO=placebo; VDZ=vedolizumab Sands B et al. Presented at ECCO 13. IL-12 and IL-23 Cytokines and Receptors Are First Cousins IL-12 Presky DH et al. Proc Natl Acad Sci U S A. 1996;93:12. IL-23 Oppmann B et al. Immunity. ;13:715. p p35 p19 p NK or T cell membrane Chua AO et al. J Immunol. 1995;155:4286. Parham C et al. J Immunol. 2;168:5699. Intracellular Signaling (eg, STAT-P) 17
Anti-p Mechanism of Action IL-12 Presky DH et al. Proc Natl Acad Sci U S A. 1996;93:12. Oppmann B et al. Immunity. ;13:715. IL-23 p p35 Ustekinumab p19 p NK or T cell membrane Chua AO et al. J Immunol 1995;155:4286. No Signal Parham C et al. J Immunol. 2;168:5699. Ustekinumab for Crohn s disease: blocks IL-12/IL-23 Clinical Response and Remission at Weeks 6 and 8 5 3 Placebo UST 1 mg/kg UST 3 mg/kg UST 6 mg/kg UST combined 1 Clinical Response Week 6 (primary end point) Clinical Response Week 8 Clinical Remission Week 6 Clinical Remission Week 8 *P<.5 Sandborn W, et al. N Engl J Med 12 Oct 18;367(16):1519-28. 18
Disease Severity at Presentation Positioning Vedolizumab and Ustekinemab in Crohn s? Vedolizumab? Natalizumab (CD) Severe Ustekinemab? Anti-TNF +/IS Anti-TNF/ Moderate Corticosteroid Aminosalicylate/ Mild Aminosalicylate Oral/Topical/Combo Aminosalicylate ate Oral/Topical/Combo Maintenance Therapy is stepped up according to severity at presentation or failure at prior step Positioning New and Future Therapies for UC MMX Budesonide Clinical Trials Position as First Line Clinical Practice more likely after 5-ASA Potential for maintenance? 19
Positioning New and Future Therapies for UC Golimumab Clinical Trials in Mod-Severe Outpatients Clinical Practice as a sub-q alternative anti- TNF Potential for therapeutic Drug monitoring Positioning New and Future Therapies for UC Vedolizumab Clinical Trials in Mod-Severe Outpatients failing Steroids/IS/Anti-TNF Clinical Practice as & Maintenance as Anti-TNF alternative No PML in clinical trials but likely to have FDA monitoring requisites
Positioning New and Future Therapies for Crohn s Disease Vedolizumab Before (?)/After (?) anti-tnf Maintenance benefits> Earlier disease? Steroid induction? Ustekinemab How to dose? Before (?)/After(?) anti-tnf 21