Oxford Inflammatory Bowel Disease MasterClass The mesalazine chamaeleon

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1 Oxford Inflammatory Bowel Disease MasterClass The mesalazine chamaeleon Ailsa Hart Lead IBD Unit, St Mark s Hospital Senior Clinical lecturer Imperial College, London

2 Oxford Inflammatory Bowel Disease MasterClass Disclosure I have received honoraria for speaking, or acting in an advisory capacity for the following companies MSD, AbbVie, Warner Chilcott, Ferring, Shire, Falk Parma, Atlantic

3 Outline :mesalazine chamaeleon Role in ulcerative colitis Induction of remission Maintenance of remission Mucosal healing Role in Crohn s disease Role in chemoprevention Side effect profile Tomorrow s World what s round the corner

4 Oxford Inflammatory Bowel Disease MasterClass Do we know exactly what we are giving our patients?

5 foam enemas Liquid enemas

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7 Dose & delivery systems of 5ASA formulations Drug Sulphasalazine/ salazopyrin Dose/ tablet mg Formulation 500 5ASA sulfapyridine azo bond Balsalazide/colazal 750 5ASA 4ABA azo bond Delivery site colon colon Olsalazine/ dipentum 250 5ASA dimer colon Mesalazine/ salofalk 250 Eudragit L Mid/distal ileum; colon Mesalazine/ pentasa 500,1000,2000 Ethylcellulose microgranules Duodenum to rectum Mesalamine/ asacol 400, 800 Eudragit S TI, colon Mesalamine/ mezavant 1200 Eudragit S multi-matrx system TI, colon

8 Oxford Inflammatory Bowel Disease MasterClass 5ASA in ulcerative colitis

9 5ASA for induction and maintenance of remission in UC

10 Oral 5ASA for induction of remission in UC Summary of findings 5ASA superior to placebo & no more effective than sulphasalazine 5ASA dosed once daily as effective & safe as conventionally dosed 5ASA do not appear to be any differences in efficacy or safety among the various 5ASA formulations Daily 2.4g appears to be effective and safe induction for mild to moderate UC Patients with moderate disease may benefit from initial dose of 4.8g/day

11 Oral 5ASA for maintenance of remission in UC Summary of findings 5ASA superior to placebo for maintenance therapy 5ASA inferior to sulphasalazine* for maintenance 5ASA dosed once daily as effective and safe as conventionally dosed 5ASA for maintenance do not appear to be any differences in efficacy or safety among the various 5ASA formulations Patients with extensive UC/ frequent relapses may benefit from higher maintenance doses * Role in enteropathic arthropathy, particularly peripheral involvement / early disease; Side effects: allergic reactions and intolerance (up to 20%) sulphapyridine

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13 Mucosal healing in UC

14 How to optimise 5-ASA Maximise dose 1 5-ASA 4.8 g/d is better than 2.4 g/d at inducing clinical response or complete remission Optimise 5-ASA Combine oral and rectal 5-ASA 2 5-ASA combined oral and rectal therapy is better than oral therapy alone Extended duration of treatment 3 60% of patients achieved remission after a further 8 weeks of 5-ASA therapy 1. Hanauer SB et al. Am J Gastroenterol 2005;100: ; 2. Marteau P et al. Gut 2005;54:960; 3. Kamm MA et al. Inflamm Bowel Dis 2009;15:1-8.

15 How to optimise 5-ASA Maximise dose 1 Combine oral and rectal 5-ASA 2 Adherence Extended duration of treatment 3 1. Hanauer SB et al. Am J Gastroenterol 2005;100: ; 2. Marteau P et al. Gut 2005;54:960; 3. Kamm MA et al. Inflamm Bowel Dis 2009;15:1-8.

16 Average adherence rate (%) Adherence to 5-ASA therapy in UC % 40 60% Rate particularly low (40%) in patients in symptomatic remission 0 Clinical trials Community based trials Kane SV. Aliment Pharmacol Ther 2006;23:

17 Compliance (% patients) Once a day vs conventional dosing UC maintenance Study not designed to measure efficacy * Asacol 2.4 g/day Once a day BD or TDS n=12 n=10 n=12 n=10 3 months 6 months *p<0.05 BD/TDS vs QD Kane S et al. Clin Gastro Hepatol 2003;1:170 3

18 Predictors of non-adherence in chronic diseases 70% of non-compliance is intentional 1 Weak evidence Strong evidence 2 Gender Income Age Race Personality Beliefs about illness (cause, timeline) Necessity (perceived need) for treatment Perceived effect of drug Concerns about treatment (fear of side effects) 1. Harris Interactive and the Boston Consulting Group (BCG) survey on reasons for patient non-adherence McHorney CA, Spain CV. Health Expert. 2011;14:307-20

19 Optimising adherence

20 Optimising adherence

21 Oxford Inflammatory Bowel Disease MasterClass 5ASA in Crohn s disease

22 Oral 5ASA for induction of remission in CD 310 patients. CDAI = Randomised to Pentasa 1g, 2g, 4g /day or placebo Δ CDAI Δ CDAI Ileal disease Remisssion (%) Pentasa 4g/day meta-analysis of 3 studies 2 :pentasa superior to placebo? How relevant reduction in CDAI (63) 1 Singleton Gastroenterology 1993;104: Hanauer Clin Gastroenterol Hepatol 2004:

23 Oral 5ASA for maintenance of remission in CD 12/12 6 trials ASA 362/663 Placebo 370/676 24/12 1 trial ASA 54/80 Placebo 55/81 Akobeng Cochrane Database Syst Rev (1):CD003715

24 Oral 5ASA in prevention in post-operative CD Sulfasalazine Mesalazine Relapse rates were reported after 1 to 3 years. All trials used 3 g sulfasalazine per day. Relapse occurred in 125/225 (55.6%) receiving sulfasalazine 133/223 (59.6%) on placebo / no therapy. RR of relapse with sulfasalazine: 0.97 (95%CI= ) Relapse rates were reported after 48 weeks to 3 years. One trial used 2.4g of mesalamine, 5 trials used 3g/day or more. Relapse occurred in 152/415 (36.6%) receiving mesalamine 191/419 (45.6%) on placebo or no therapy. RR of relapse with mesalazine: 0.80 (95%CI= ) NNT to prevent relapse in one patient was 10 (95%CI=6 25). Combined RR=0.86 (95%CI= ) NNT=13 (95%CI=7 50) Ford Am J Gastroenterol 2010

25 Summary 5ASA in CD Induction While sulphasalazine may be (slightly) effective at inducing remission in (colonic) CD, less evidence for 5ASA and different disease locations Maintenance Little evidence to support 5ASA in maintenance of (medically induced) remission Post-operative prevention 5ASA is mildly effective at preventing post-operative recurrence - NNT > 10

26 Oxford Inflammatory Bowel Disease MasterClass 5ASA in chemoprevention of IBD

27 IBD as risk for colorectal cancer Eaden et al. Gut 2001 Apr; 48 (4): Jess et al. Gastroenterology 2012;143:

28 5-ASA as chemoprevention for CRC Velayos et al, Gastroenterology, 2005 Meta-analysis 9 studies containing 334 cases of CRC/140 dysplasia within total population of 1,932 Significant reduction in CRC risk (OR = 0.51; 95% CI; )

29 St Mark s IBD-Cancer Surveillance Group Dr Ailsa Hart (Inflammatory Bowel Disease Lead, St. Mark s) Prof Brian Saunders (Chief of Wolfson Unit of Endoscopy, St. Mark s) Dr Siwan Thomas- Gibson (Consultant Endoscopist,St. Mark s) Mr J Warusavitarne (Consultant IBD Surgeon, St. Mark s) Prof Sir Nick Wright (Histopathologist, Lead Centre for Tumour Biology, QMUL) Dr Trevor Graham (Lab lead, Cancer evolution laboratory, QMUL) Dr Matt Rutter (Director of BCSP, University hospital of North Tees) Dr Ryan Choi (IBD Research Fellow, St. Mark s)

30 St Mark s IBD-Cancer Surveillance Group Update St Mark s IBD surveillance database Biology of inflammation cancer pathway

31 Oxford Inflammatory Bowel Disease MasterClass Side effect profile of 5ASA in IBD Generally well tolerated nephrotoxicity blood disorders (aplastic anaemia, leucopaenia, neutropaenia, thrombocytopaenia) skin reactions (lupus erythematous-like syndrome, Stevens-Johnson) pancreatitis, hepatitis worsening of IBD symptoms

32 5-ASA induced nephrotoxicity 1. Gisbert IBD Muller APT 2005 Incidence: Clinical trials: mean annual risk 0.26% 1 BSG/RA 2002 study: 1/4000 patient yrs 2 Immune-mediated interstitial nephritis Clinical recommendations: Blood monitoring recommended Failure to detect 5-aminosalicylate nephrotoxicity is a cause of medical litigation

33 GWAS & serious drug reactions Nat Genet. 2009

34 So et al. DDW 2013 SAE Consortium Dr Rinse Weersma Dr Jonas Halfvarsson Professor Epameinondas Tsianos Prof Mark Silverberg Joanne Stempak Dr Annese Vito Dr D'Incà Renata Prof Graham Radford-Smith Prof Ian Lawrance

35 So et al. DDW ASA nephrotoxicity - Results 151 patients with 5ASA nephrotoxicity (M>F) 118 (78.7%) presented due to routine monitoring Median time from starting 5ASA to first abnormal creatinine days (range 5 12,924 days) Median oral dose 5ASA 2.25g daily (range 400mg 8g), 1 patient received only rectal 5-ASA 42 patients (28%) demonstrated full recovery of renal function 14 (9.3%) patients had renal replacement therapy

36 Oxford Inflammatory Bowel Disease MasterClass

37 PPAR-γ 5-ASA = ligand for PPARγ partially explains efficacy in UC PPAR-γ nuclear receptor controls expression of regulatory genes in lipid metabolism/ insulin sensitisation AND it directly interfere with activities of transcriptional factors such as NF-kB Negatively regulates gene expression of pro-inflammatory genes (e.g. TNF)

38 PPAR-γ: a target for IBD therapy? TZDs (thia-zolidine-diones) e.g. rosiglitazone = PPAR-gamma agonist used in Type II DM marketing authorisation suspended by EMA cardiovascular risks Lewis JD et al, AJG, patients with mild-moderate refractory UC were given rosiglitazone Clinical remission achieved in 4/15 (27%), endoscopic remission in 3/15 (20%). Liang et al, WJG, 2008 Randomized multicentre, double-blind, placebo-controlled clinical trial comparing rosiglitazone versus placebo 12 weeks of therapy in 105 patients with mild-mod UC Clinical remission (Mayo score of 2 or less) in 9 patients (17%) in rosiglitazone group vs 1 (2%) in placebo group

39 New PPAR-γ agonist in treatment of IBD 5-ASA analogues with stronger affinity for PPAR-γ Synthetic modulator, GED (or GED ) has fold higher PPAR activation than 5-ASA in vitro In experimental models of colitis, GED demonstrated similar antiinflammatory effect to 5-ASA used at 30 fold-higher concentration In phase I - non of the study subjects (n=24) experienced adverse effects such as CHF, fractures, weight gain or peripheral oedema Currently under Phase II trial Reviewed in Bertin et al. Curr Drug Targets May

40 Summary :mesalazine chamaeleon Role in ulcerative colitis Induction of remission Maintenance of remission Mucosal healing Role in Crohn s disease Role in chemoprevention Side effect profile Tomorrow s World what s round the corner