New and Future Adhesion Molecule Based Therapies in IBD

Transcription

1 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

2 Mosli M et al, Drugs 2014; 74:

3 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.

4 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:

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

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

7 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

8 Therapeutic Targets Leucocyte Adhesion CD 11a/CD18 NATALIZUMAB VEDOLIZUMAB LEUCOCYTE CCX282-B ISIS-2302 α4β1 (VLA-4) α4β7 CCR9 MAdCAM mab (PF ) rhumab Beta 7 CCL-25 ICAM-1 MadCAM-1 VCAM-1 Adapted from Danese S Gut 2011;60: ACTIVATED INTESTINAL MICROVASCULAR ENDOTHELIAL CELLS

9 Lobaton T et al AP&T 2014; 39:

10 Lobaton T et al AP&T 2014; 39:

11 Vedolizumab UC induction (GEMINI 1) Response, Remission, Mucosal Healing at 6 Weeks P< Induction ITT Population P= % P= % CI: Δ , 31.7 Δ , 18.3 Δ , 25.9 Feagan B et al NEJM 2013; 369:

12 Clinical Response and Remission at 6 Weeks: Prior Anti-TNFα Failure vs No Anti-TNFα Exposure ITT Population % Patients With Prior Anti-TNF Failure Patients Without Anti-TNF Exposure Placebo Vedolizumab Clinical Response Clinical Remission Clinical Response Clinical Remission % CI: 3.9, , , , 30.2 Feagan, B.G. et al New Eng J Med 2013

13 Etrolizumab: Clinical Remission in All Comers & by Anti-TNF status Primary endpoint at Week 10 95% CI (12,75) (-2,50) p-value Proportion of patients (%) Proportion of patients (%) Primary Endpoint 95% CI (12,30) (0.2,20) p-value % 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

14 Etrolizumab: Clinical Remission in All Comers & by Anti-TNF status Primary endpoint at Week 10 95% CI (12,75) (-2,50) p-value Proportion of patients (%) Proportion of patients (%) Primary Endpoint 95% CI (12,30) (0.2,20) p-value % 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

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

16 Anti-MadCam in UC: Primary End Point: Clinical Remission at Week % mitt Population 20.0% Remission Rates 15.0% 11.3% * 16.7% * 15.5% * 10.0% 5.0% 2.7% 5.7% * p< % 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

17 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 * p<0.05 Dose 0.0% 0.0% 0 mg 7.5 mg 22.5 mg 75 mg 225 mg Experienced * p<0.05 Dose Odds of remission in naïve population is significantly higher (p<0.001) than experienced population ECCO 2015 and DDW

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

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

20 Vedolizumab UC (GEMINI 1): Primary and Secondary Outcomes Through 52 Weeks Maintenance ITT Population *** *** *** *** *** *** *** * % ** ** 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< Feagan B et al NEJM 2013; 369:

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

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

23 Vedolizumab Induction GEMINI-III in CD CDAI-100 Response ITT Population Patients, % Anti-TNFα Failure Population Overall Population (n=315) (n=416) PBO VDZ * Week 6 Week 10 Week 6 Week 10 CDAI-100 Response *P= vs placebo; P< vs placebo; P= vs placebo Sands et al,gastroenterology 2015

24 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 *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

25 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 *P=0.053 Placebo D Haens et al ECCO 2015 and Sandborn W et al DDW

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

27 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:

28 Cochrane: Maintenance of Remission Week 52 vedolizumab CD Clinical remission

29 Cochrane: Serious Adverse events Vedolizumab Etrolizumab Anti-MadCam

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

31 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

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

33 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 RPC mg (N=65) Mayo Responders RPC mg (N=67) Disease Relapse Open-Label

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

35 1 Endpoint: Proportion of Patients in Remission at Week 8 (Adjudicated Central Read) Δ = 7.8% p = Δ = 10.8% p = Proportion of Patients in Remission Sandborn et al DDW 2015

36 Sandborn et al ECCO 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 = Δ = 22.6% p =

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

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

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

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

41 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 (2.4)

42 Cardiac Safety Profile of RPC1063 Overall Incidence of Cardiac TEAEs SYSTEM ORGAN CLASS Preferred Term Placebo (N=65) RPC mg (N=65) RPC mg (N=67) CARDIAC DISORDERS 2 (3.1) 1 (1.5) 2 (3.0) Bradycardia* (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) RPC mg (N=132) Subjects with 2 nd Degree AVB 0 0 Subjects with Sinus Pause 0 0 Sandborn et al ECCO 2015

43 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.