Positioning New Therapies

Transcription

1 Positioning New Therapies Stephen Hanauer, MD Professor of Medicine Medical Director, Digestive Disease Center Northwestern Medicine Chicago, Illinois

2 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.

3 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

4 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): ; 2 Gross V. Expert Opin Pharmacother. 2008;9(7):

5 Patients (%) Therapeutic Opportunity vs Budesonide MMX or Aminosalicylate in Mild-Moderate UC 25 Combined Clinical and Endoscopic Remission 20 * ** *** *P=.0143, **P=.0047,***P= 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

6 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

7 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

8 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 Adalimumab 8 Weeks Adalimumab Adalimumab 52 Weeks ** Adalimumab Placebo Placebo % 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): ; Rutgeerts P, et al. N Engl J Med. 2005;353(23): ; Panaccione R, et al. Can J Gastroenterol. 2008;22(3): * Golimumab 200/100 mg Golimumab 50 mg Placebo Golimumab 54 Weeks ** Placebo

9 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

10 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:

11 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

12 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 = **P< % CI: Clinical Response Clinical Remission Mucosal Healing , , , 25.9 Feagan BG, et al. New Engl J Med. 2013;369(8):

13 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) 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):

14 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

15 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

16 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