Selective leucocyte trafficking inhibitors for treatment of IBD

Transcription

1 Selective leucocyte trafficking inhibitors for treatment of IBD Séverine Vermeire MD, PhD Department of Gastroenterology University Hospitals Leuven Belgium

2 Migration of Leucocytes plays a key role in gut inflammation in IBD Bennink R et al Clin Nucl Med. 2001;26:

3 Mosli M et al, Drugs 2014; 74:

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

5 Progressive Multifocal Leucoencephalopathy (PML) Van Assche G et al. N Engl J Med 2005;353:

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

7 Etrolizumab Mechanism of Action Humanized IgG 1 Monoclonal Antibody to the β7 Integrin Epithelium Epithelium Lamina Propria Leukocytes MAdCAM-1 x a4b7 x aeb7 expressing intraepithelial lymphocyte MAdCAM-1 Peyer s Patches HEV M Cell a4b7 x a4b7 x MAdCAM-1 Mesenteric Lymph Node Blocks trafficking into the GI mucosa Clinically validated target Blocks retention of lymphocytes in the mucosal epithelium Role in human IBD unknown Exploration in Phase II Does not interfere with leukocyte trafficking to the CNS or other nonmucosal tissues No PML expected Adapted from Cheroutre and Madakamutil, 2004, Nature Reviews Immunology 7

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

9 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:

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

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

12 Anti-MadCam in UC: Primary End Point: Clinical Remission at Week 12 Remission Rates 25.0% mitt Population 20.0% 15.0% 16.7% * 15.5% * 11.3% * 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

13 Secondary Efficacy End Points: Clinical Remission in Anti-TNF Naïve vs Experienced Central Read (mitt) Central Read (mitt) Naïve Experienced 30.0% 30.0% 25.8%* 25.0% 25.0% 23.3% 20.0% 20.0% 16.7% 15.0% 15.0% 10.0% 6.5% 10.0% 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

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

15 Proportion of patients (%) Mucosal Healing in All Comers & by Anti-TNF status Secondary endpoint at Week 6 & Week 10 (Mucosal healing: endoscopic score of 0 or 1) 95% CI (-2,56) (0,65) P-value % CI (-7,30) (-13,22) % CI (-23,18) (-29,5) n=15 n=16 n=12 n=15 n=16 n=12 n=25 n=22 n=25 n=25 n=22 n=25 All Comers Vermeire S et al Lancet 2014, 384: anti-tnf Naive anti-tnf Failures

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

17 Anti-MadCam in UC Mucosal Healing at Week 12 Central Read (mitt) Mucosal Healing 60.0% 50.0% 40.0% 30.0% 27.8% * 25.4% * 20.0% 15.5% 14.3% 10.0% 8.2% * p< % 0 mg 7.5 mg 22.5 mg 75 mg 225 mg Dose Vermeire S et al ECCO 2015 and Reinisch W et al DDW 2015

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

19 Percent of Subjects Vedolizumab CD induction (GEMINI 2) Response and remission at 6 Weeks Primary: Clinical Remission CDAI 150 Primary: Enhanced Clinical Response (CDAI-100) p< p= (7.8) 60 (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:

20 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

21 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

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

23 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:

24 Vedolizumab

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

26 Patients, % Vedolizumab CD (GEMINI 2): Primary and Secondary Outcomes Through 52 Weeks Maintenance ITT Population Primary Outcome * ** Secondary Outcomes ** ** * * 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:

27 Safety

28 Cochrane: Serious Adverse events Vedolizumab Etrolizumab Anti-MadCam

29 MAdCAM-1 expression is absent from human brain tissue Immunohistochemistry with PF-00547,659 (anti-madcam) and anti-human VCAM antibody on frozen human brain sections (healthy control samples) Grey matter White matter Meninges MAdCAM: no staining VCAM: positive staining ec ec pv Allavena R et al Am J Pathol 2010;176:556-62

30 Effect of Anti-a 4 b 7 Ab (Vedolizumab) on CSF in Healthy Volunteers A single dose of vedolizumab was given to 13 healthy volunteers LP pre-treatment and at week 5 post treatment Milch et al. J Neuroimmunol 2013

31 Effect of Anti-MadCAM in CSF in CD patients TOSCA study Forest plot shows the fold change between the pre-treatment and post-treatment values, with 90% confidence intervals CSF (measured in Cells/mL) Blood (measured in Cells/μL *Beta 7 central memory: CD45RO+B7+CD27+[CD3+/CD4+] Reinisch W et al DDW 2014

32 Vedolizumab affects antibody responses to immunisation selectively in the GI tract N=127 IM Hep B vaccine Oral cholera vaccine Seroconversion? mean anti-hbs titres similar placebo (114.4 IU/L) and vedolizumab (129.6 IU/L) mean anti-ct IgG levels placebo > vedolizumab ( vs ELISA Units (EU)/mL). Wyant T et al GUT 2014 April

33 Conclusion Selective leucocyte trafficking inhibitors are effective in inducing and maintaining clinical remission in UC and CD In ulcerative colitis, this class of drugs is also associated with significant endoscopic healing rates The safety profile of this new class of biologic agents is reassuring but continued monitoring is mandatory Open questions: Which biologic class to choose as first one? How to induce best in patients with severe symptoms? Long term risk for immunogenicity and loss of response? When and how to switch between classes?