New and Future Adhesion Molecule Based Therapies in IBD

New and Future Adhesion Molecule Based Therapies in IBD Brian G. Feagan Professor of Medicine, Epidemiology and Biostatistics University of Western Ontario Robarts Clinical Trials London, Ontario, Canada

Mosli M et al, Drugs 2014; 74: 297-311

Consequences of Leukocyte Entry Cellular immunity Humoral immunity Cytokine/chemokine expression Phagocytic activity Antigen presentation Frohman EM, et al. J Clin Immunol. 1989;9:1-9.

Natalizumab: A Humanized Monoclonal Antibody Against α 4 -Integrins CDRs α 4 -Integrin antagonist CDR grafted from murine antibody Human IgG4 subclass framework Non-complement fixing Human IgG4 framework CDRs, complementarity-determining regions. Sheremata WA, et al. Neurology. 1999;52:1072-1074.

Cumulative Number of New Gd+ Lesions Miller et al., 2003 (1 Year) Mean no. of new Gd+ lesions 12 10 Infusion given 8 6 4 2 0 Placebo (n=71) 3 mg/kg (n=68) 6 mg/kg (n=74) 0 1 2 3 4 5 6 Months 9.6 *P<0.001 vs placebo 1.1* 0.7* Miller DH, et al. N Engl J Med. 2003;348:15-23.

ENACT-2: Patients Removed from Concurrent Steroids 80 Patients not receiving steroids (%) 60 40 20 36% 64% 61% 54% 54% 34% Natalizumab 300 mg (n = 67) 64% 50% 58% * 34% 57% * 30% 55% * 25% 0 Placebo (n = 76) * P < 0.05 3 4 5 6 7 8 9 Time (months) Start ENACT-2 Sandborn WJ. et al. (ENACT-2) N Engl J Med. 2005;353(18):1912-25.

PML JCV- human papova virus Latent in renal tubuloepithelium; 60% of individuals Severe CNS disease in highly immunosuppressed patients (HIV/combination chemotherapy) Very high risk with natalizumab therapy (1:160 to 1:10,000 dependent on risk factors) chilling effect on anti-adhesion molecule Rx

Therapeutic Targets Leucocyte Adhesion CD 11a/CD18 NATALIZUMAB VEDOLIZUMAB LEUCOCYTE CCX282-B ISIS-2302 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 2011;60:998-1008 ACTIVATED INTESTINAL MICROVASCULAR ENDOTHELIAL CELLS

Lobaton T et al AP&T 2014; 39: 579-594

Lobaton T et al AP&T 2014; 39: 579-594

Vedolizumab UC induction (GEMINI 1) Response, Remission, Mucosal Healing at 6 Weeks P<0.0001 Induction ITT Population P=0.0012 % P=0.0009 95% CI: Δ 21.7 11.6, 31.7 Δ 11.5 4.7, 18.3 Δ 16.1 6.4, 25.9 Feagan B et al NEJM 2013; 369: 699-710

Clinical Response and Remission at 6 Weeks: Prior Anti-TNFα Failure vs No Anti-TNFα Exposure ITT Population % 60 50 40 30 20 10 Patients With Prior Anti-TNF Failure 20.6 39.0 3.2 9.8 Patients Without Anti-TNF Exposure 26.3 53.1 Placebo Vedolizumab 6.6 23.1 0 Clinical Response Clinical Remission Clinical Response Clinical Remission 18.4 6.6 26.8 16.5 95% CI: 3.9, 32.9-9.8, 22.8 13.7, 39.9 2.4, 30.2 Feagan, B.G. et al New Eng J Med 2013

Etrolizumab: Clinical Remission in All Comers & by Anti-TNF status Primary endpoint at Week 10 95% CI (12,75) (-2,50) p-value 0.007 0.076 Proportion of patients (%) Proportion of patients (%) Primary Endpoint 95% CI (12,30) (0.2,20) p-value 0.004 0.048 95% CI (-5.1,16.4) (-5.6,14.7) n=15 n=16 n=12 n=15 n=16 n=12 n=25 n=22 n=25 n=25 n=22 n=25 Vermeire S et al Lancet 2014, 384:309-18

Etrolizumab: Clinical Remission in All Comers & by Anti-TNF status Primary endpoint at Week 10 95% CI (12,75) (-2,50) p-value 0.007 0.076 Proportion of patients (%) Proportion of patients (%) Primary Endpoint 95% CI (12,30) (0.2,20) p-value 0.004 0.048 95% CI (-5.1,16.4) (-5.6,14.7) n=15 n=16 n=12 n=15 n=16 n=12 n=25 n=22 n=25 n=25 n=22 n=25 Vermeire S et al Lancet 2014, 384:309-18

Etrolizumab: alphae as predictive marker for response? Real-Time qpcr Immunohistochemistry Vermeire S et al Lancet 2014, 384:309-18

Anti-MadCam in UC: Primary End Point: Clinical Remission at Week 12 25.0% mitt Population 20.0% Remission Rates 15.0% 11.3% * 16.7% * 15.5% * 10.0% 5.0% 2.7% 5.7% * p<0.05 0.0% 0 mg 7.5 mg 22.5 mg 75 mg 225 mg Central Read Vermeire et al ECCO 2015 and Reinisch et al DDW 2015

Secondary Efficacy End Points: Clinical Remission in Anti-TNF Naïve vs Experienced Naïve Experienced 30.0% 30.0% 25.8%* 25.0% 25.0% 23.3% 20.0% 20.0% Central Read (mitt) 15.0% 10.0% 6.5% 16.7% 10.0% Central Read (mitt) 15.0% 10.0% 7.3% 9.8%* 9.8%* 5.0% 5.0% 2.5% 0.0% 0 mg 7.5 mg 22.5 mg 75 mg 225 mg Naïve 31 30 31 30 30 * p<0.05 Dose 0.0% 0.0% 0 mg 7.5 mg 22.5 mg 75 mg 225 mg Experienced 42 41 41 41 40 * p<0.05 Dose Odds of remission in naïve population is significantly higher (p<0.001) than experienced population ECCO 2015 and DDW 2015 17

Cochrane: clinical remission induction UC Vedolizumab week 6 Etrolizumab week 10 Anti-MadCam week 12

Cochrane: endoscopic remission induction UC Vedo week 6 Etrolizumab week 10 Anti-MadCam week 12

Vedolizumab UC (GEMINI 1): Primary and Secondary Outcomes Through 52 Weeks Maintenance ITT Population *** *** *** *** *** *** *** * % ** ** 72 70 73 Δ26.1 Δ29.1 Δ32.8 Δ28.5 Δ32.0 Δ36.3 Δ11.8 Δ15.3 Δ17.6 Δ31.4 n: *P<0.05 **P<0.01 ***P<0.0001 Feagan B et al NEJM 2013; 369: 699-710

Cochrane: Maintenance of Remission Week 52 Vedolizumab - UC Clinical remission Endoscopic healing

Vedolizumab CD induction (GEMINI 2) Response and remission at 6 Weeks Primary: Clinical Remission CDAI 150 Primary: Enhanced Clinical Response (CDAI-100) 100 100 Percent of Subjects 80 60 40 p<0.0206 (7.8) 80 60 40 25.7 p=0.2322 (5.7) 31.4 20 0 6.8 N=148 Placebo 14.5 N=220 Vedolizumab 20 0 N=148 N=220 Placebo Vedolizumab Sandborn WJ, et al. NEJM 2013;369:711-21.

Vedolizumab Induction GEMINI-III in CD CDAI-100 Response ITT Population Patients, % 60 50 40 30 20 10 0 39.2 Anti-TNFα Failure Population Overall Population (n=315) (n=416) PBO VDZ 46.8 47.8 22.3 39.2* 24.8 22.7 24.2 Week 6 Week 10 Week 6 Week 10 CDAI-100 Response *P=0.0011 vs placebo; P<0.0001 vs placebo; P=0.0002 vs placebo Sands et al,gastroenterology 2015

Anti-MadCam CD: Secondary Efficacy End Point Remission 40% 30% 29% 27% 27% 28% 29% 24% 23% 20% 17% 10% 0% Week 8 Week 12 Placebo 22.5 75 225 *None of the doses were statistically significant compared to placebo at week 8 or week 12 D Haens et al ECCO 2015 and Sandborn W et al DDW 2015 24

Anti-MadCam CD: Remission by Baseline CRP Quartiles Remission, CRP>7.5 (1st quartile) Remission, CRP>18 (median) 50% 50% 40% 40% 37%* 32% 30% 20% 27%* 24%* 24% 20% 28% 30% 20% 28%* 20% 23% 23% 22% 23% 20% 10% 10% 10% 6% 0% Week 8 Week 12 0% Week 8 Week 12 *P<0.05 Placebo 22.5 75 225 *P=0.053 Placebo 22.5 75 225 D Haens et al ECCO 2015 and Sandborn W et al DDW 2015 25

Cochrane: Clinical remission induction CD Vedo week 6 Anti-MadCam week 12

Vedolizumab CD (GEMINI 2): Primary and Secondary Outcomes Through 52 Weeks Maintenance ITT Population Primary Outcome * ** Secondary Outcomes ** ** * * Patients, % Δ17.4 Δ14.7 Δ13.4 Δ15.3 Δ15.9 Δ12.9 Δ7.2 Δ2.0 *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 WJ, et al. NEJM 2013;369:711-21.

Cochrane: Maintenance of Remission Week 52 vedolizumab CD Clinical remission

Cochrane: Serious Adverse events Vedolizumab Etrolizumab Anti-MadCam

Poisson Probability Distribution of the Likelihood of Observing Cases of PML with Vedolizumab Colombel JF et al. Gastroenterology. Submitted.

S1P 1R Modulation Results in Sequestration of Lymphocytes in Lymph Nodes S1P 1R agonism induces receptor internalization on lymphocytes resulting in functional antagonism and loss of ability to respond to S1P gradient Lymphocytes become trapped in lymph nodes, reducing circulating lymphocyte counts Upon drug withdrawal receptor expression is restored and lymphocytes leave nodes reversing peripheral reduction

Fingolomod in MS P<0.001 Adjusted Annualized Relapse Rate 0.33 0.16 0.20 Interferon (N=431) Cohen JA. et al. N Eng J Med 2010;362(5):402-15. Fingolimod 0.5 mg (N=429) Fingolimod 1.25 mg (N=420)

Ozanamod :Study Design Induction Period Maintenance Period 7-Day Dose Titration 8 Weeks Treatment Primary Endpoint: Induction 24 Weeks Treatment Week 32 Maintenance Endpoint Placebo (N=65) Randomization RPC1063 0.5 mg (N=65) Mayo Responders RPC1063 1.0 mg (N=67) Disease Relapse Open-Label

Sandborn et al DDW 2015 Pharmacodynamic Effect: Mean (SE) Percent Change in Absolute Lymphocyte Counts ~32% ~49%

1 Endpoint: Proportion of Patients in Remission at Week 8 (Adjudicated Central Read) Δ = 7.8% p = 0.1422 Δ = 10.8% p = 0.0482 Proportion of Patients in Remission Sandborn et al DDW 2015

Sandborn et al ECCO 2015 2 Endpoint: Proportion of Patients With Mucosal Improvement (Endoscopy score of 0-1 at Week 8, Adjudicated Central Read) Proportion of Patients With Mucosal Improvement Δ = 14.9% p = 0.0348 Δ = 22.6% p = 0.0023

Sandborn et al DDW 2015 2 Endpoint: Proportion of Patients in Clinical Response at Week 8 (Adjudicated Central Read) Proportion of Patients in Clinical Response Δ = 16.1% p = 0.0648 Δ = 21.6% p = 0.0140

Proportion of Patients in Remission Week 8 Week 32 Sandborn et al UEGW 2015

Proportion of Patients in Clinical Response Week 8 Week 32 * central read Sandborn et al UEGW 2015

Proportion of Patients With Mucosal Improvement/Healing (Endoscopy score of 1) Week 8 Week 32 Sandborn et al UEGW 2015

Safety: Treatment Emergent Adverse Events (TEAEs) Maintenance Period Number of Subjects Placebo (N=25) n (%) Ozanimod 0.5 mg (N=36) n (%) Ozanimod 1 mg (N=42) n (%) 1 TEAE 8 (32.0) 4 (11.1) 11 (26.2) Most Common TEAEs Placebo Ozanimod 0.5 mg Ozanimod 1 mg Ulcerative colitis flare 2 (8.0) 0 1 (2.4) Urinary Tract Infection 1 (4.0) 1 (2.8) 0 Serious TEAEs Placebo Ozanimod 0.5 mg Ozanimod 1 mg Number of Subjects with 1 Serious TEAE 2 (8.0) 0 1 (2.4) Anaemia haemolytic autoimmune 1 (4.0) 0 0 Colitis ulcerative 1 (4.0) 0 0 Herpes zoster 1 (4.0) 0 0 Colon adenoma 0 0 1 (2.4)

Cardiac Safety Profile of RPC1063 Overall Incidence of Cardiac TEAEs SYSTEM ORGAN CLASS Preferred Term Placebo (N=65) RPC1063 0.5 mg (N=65) RPC1063 1 mg (N=67) CARDIAC DISORDERS 2 (3.1) 1 (1.5) 2 (3.0) Bradycardia* 0 0 2 (3.0) First Degree AV Block** 0 1 (1.5) 0 Sinus Bradycardia** 0 1 (1.5) 0 Palpitations 2 (3.1) 0 0 * Day 1: Neither subject had HR < 45 bpm (bradycardia cutoff), with screening & pre-dose HR in the 50 s ** Day 8: HR=46, PR interval = 201 ms (ULN=200 ms) occurred in the same subject Day 1: Cardiac Findings on 24-hr Holter Monitoring Placebo (N=65) RPC1063 0.5 mg (N=132) Subjects with 2 nd Degree AVB 0 0 Subjects with Sinus Pause 0 0 Sandborn et al ECCO 2015

Conclusions Monoclonal antibodies to integrins are effective for induction and maintenance of remission in UC and CD The safety profile of these agents is excellent but long term data are needed S1P1 agonists are oral agents that have demonstrated efficacy in both MS and UC Ozanomod is a promising new treatment for UC that is now being evaluated in Phase 3 studies Frohman EM, et al. J Clin Immunol. 1989;9:1-9.