Positioning New Therapies Stephen Hanauer, MD Professor of Medicine Medical Director, Digestive Disease Center Northwestern Medicine Chicago, Illinois
Speaker Disclosure Stephen Hanauer, MD has disclosed that he received research support from AbbVie, Janssen Biotech, Inc. and Takeda Pharmaceuticals International, Inc., U.S. Dr. Hanauer has also served as a consultant for AbbVie, Janssen Biotech, Inc., Salix Pharmaceuticals, Inc. and Takeda Pharmaceuticals International, Inc., U.S.
Educational Objectives Describe the current overall approach to managing ulcerative colitis, including current data on the relationship between mucosal healing and longer-term outcomes Identify recent advances in the management of ulcerative colitis
Budesonide Metabolism and Characteristics Oral budesonide 1 ph release: ileum/right colon MMX: pan-colonic ~ Budesonide ~9 metabolism in the liver Rectal budesonide 1 Enema/Foam Budesonide characteristics 2 Non-halogenated corticosteroid, highly lipophilic Good tissue penetration 9x greater receptor binding than dexamethasone Rapidly absorbed in GI tract Metabolites are almost inactive Terminal half-life 2.7 +/- 0.6 hours Needs specifically designed release system Adapted from 1 Brattsand R. Can J Gastroenterol. 1990;4(7):407-414; 2 Gross V. Expert Opin Pharmacother. 2008;9(7):1257-1265.
Patients (%) Therapeutic Opportunity vs Budesonide MMX or Aminosalicylate in Mild-Moderate UC 25 Combined Clinical and Endoscopic Remission 20 * ** *** 17.9 17.4 17.7 *P=.0143, **P=.0047,***P=.0002 15 10 5 7.4 4.5 6.2 13.2 8.3 10.9 12.1 12.6 0 N=121 N=89 N=210 N=123 N=109 N=232 N=121 N=109 N=230 N=124 N=103 Placebo B-MMX 9 mg B-MMX 6 mg Asa. / Ent. ASA=Asacol; Ent=Entocort; B-MMX=budesonide MMX Sandborn WJ et al. Gastroenterology. 2011;140 (Suppl): S124; Sandborn WJ et al. Gastroenterology. 2011;140 (Suppl): S65; Sandborn WJ et al. Am J Gastroenterol. 2011;106 (Suppl): S485
What Is the Optimal Positioning of MMX- Budesonide in Mild-Moderate UC? MMX-Budesonide Severe With 5-ASA? Before prednisone? Maintenance? Maintenance? Moderate Before 5-ASA? Tested Corticosteroid Aminosalicylate/ Thiopurine Mild Aminosalicylate Oral/Topical/Combo Aminosalicylate Oral/Topical/Combo Induction Maintenance
Anti-TNF Biologics: Fusion Protein, Antibodies and PEGylated Fab Fragment Etanercept Receptor Infliximab Fab Adalimumab Golimumab Fab Certolizumab pegol IgG1 Fc IgG1F c PEG Human recombinant receptor/fc fusion protein Chimeric Monoclonal antibody Human PEGylated humanized Fab fragment 2 20 kda PEG
4 2 4 2 Clinical Remission in UC: ACT (Infliximab), ULTRA-2 (Adalimumab) and PURSUIT (Golimumab) Infliximab 8 Weeks ** ** Infliximab 10 mg/kg Infliximab 5 mg/kg Placebo Infliximab 54 Weeks ** ** Infliximab 10 mg/kg Infliximab 5 mg/kg Placebo Patients failing 5-ASA/Steroids/IS 4 2 4 2 Adalimumab 8 Weeks Adalimumab Adalimumab 52 Weeks ** Adalimumab Placebo Placebo 4 2 4 35% 25% 2 15% 5% Golimumab 6 Weeks ** ** Golimumab 400/200 mg Golimumab 100 mg *P<0.05 versus placebo; **P<0.01 versus placebo Sandborn WJ, et al. Gastroenterology. 2014;146(1):96-109; Sandborn WJ, et al. Gastroenterology. 2014;146(1):85-95; Sandborn WJ, et al. Gastroenterology. 2012;142(2):257-265; Rutgeerts P, et al. N Engl J Med. 2005;353(23):2462-2476; Panaccione R, et al. Can J Gastroenterol. 2008;22(3):261-272. * Golimumab 200/100 mg Golimumab 50 mg Placebo Golimumab 54 Weeks ** Placebo
What Is the Optimal Positioning for Golimumab in UC? Unlikely in Severe/Fulminant Anti-Integrin Severe Golimumab Anti-TNF +/IS Cyclosporine (UC) Anti-TNF/ Thiopurine Tested Moderate Corticosteroid Aminosalicylate/ Thiopurine Possible Mild With/Without IS? Induction Maintenance Therapy is stepped up according to severity at presentation or failure at prior step
α4β7 Integrin MAdCAM-1 Is One of the Interactions that Contributes to Chronic Inflammation in UC and CD MAdCAM-1 MAdCAM-1 Memory T lymphocyte α4β7 integrin α4 subunit β7 subunit α4β7 MAdCAM-1 interaction has been implicated as an important contributor to the chronic inflammation that is a hallmark of UC and CD Artist s rendition MAdCAM-1=mucosal addressin cell adhesion molecule-1 Briskin M, et al. Am J Pathol. 1997;151:97-110.
Vedolizumab Binds to α4β7 Integrin and Blocks Its Interaction With MAdCAM-1 Endothelial cell MAdCAM-1 Vedolizumab: A humanized monoclonal antibody (mab) that binds to the α4β7 integrin Vedolizumab blocks the interaction of α4β7 integrin with MAdCAM- 1 α4 subunit β7 subunit α4 subunit β7 subunit Memory T lymphocyte Artist s rendition
Vedolizumab Phase III Trial in UC: Clinical Response, Clinical Remission, and Mucosal Healing at 6 weeks 5 45% 4 35% 25% 2 15% 5% ** * * Placebo Vedolizumab ITT population, 6 weeks *P = 0.001 **P<0.0001 95% CI: Clinical Response Clinical Remission Mucosal Healing 21.7 11.6, 31.7 11.5 4.7, 18.3 16.1 6.4, 25.9 Feagan BG, et al. New Engl J Med. 2013;369(8):699-710.
Vedolizumab Phase III Clinical Trial in UC: Clinical Remission and Durable Clinical Response at 52 Weeks Prior Anti-TNF Antagonist Exposure (n=149) Patients Without TNF Antagonist Exposure (n=224) 7 7 6 6 5 5 4 2 Clinical Response Durable Clinical Response 4 2 Clinical Response Durable Clinical Response VDZ/PBO VDZ/VDZ Q8W VDZ/VDZ Q4W Mean % vs VDZ/PBO (95% CI) VDZ/VDZ Q8W: VDZ/VDZ Q4W: 25.4 (5.1, 43.8) 29.7 (10.3, 47.7) 24.9 (7.1, 42.6) 27.0 (9.4, 44.6) 26.8 (12.4, 41.2) 29.0 (14.6, 43.3) 38.7 (24.0, 53.4) 29.6 (14.6, 44.6) PBO = placebo; VDZ = vedolizumab Feagan BG, et al. New Engl J Med. 2013;369(8):699-710.
What Is the Optimal Positioning for Vedolizumab in UC? Vedolizumab Before Anti-TNFs? Anti-Integrin Severe Anti-TNF +/IS Cyclosporine (UC) Anti-TNF/ Thiopurine Moderate Before Steroids? Corticosteroid Aminosalicylate/ Thiopurine Mild Induction Maintenance
Conclusions: Optimization Optimize treatment through 6-TGN and HACA monitoring Combination therapy results in greater level of mucosal healing and greater rate of corticosteroid-free remission Dose escalation or therapeutic switching if anti-tnf agent failure occurs Prospective therapeutic drug monitoring in future
Conclusions: Novel Therapies Budesonide MMX for mild-moderate UC Position before or after (?) 5-ASA Golimumab is sub-q alternative anti-tnf for moderate-severe UC Optimal dosing tbd Not likely for hospitalized severe UC Vedolizumab is novel integrin inhibitor for moderate-severe UC Long-term efficacy and safety for biologic naïve and exposed patients