The mesalazine chamaeleon Ailsa Hart Lead IBD Unit, St Marks - - PowerPoint PPT Presentation

Oxford Inflammatory Bowel Disease MasterClass

The mesalazine chamaeleon

Ailsa Hart Lead IBD Unit, St Mark’s Hospital Senior Clinical lecturer Imperial College, London

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

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

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Do we know exactly what we are giving our patients?

Liquid enemas foam enemas

Drug Dose/ tablet mg Formulation Delivery site

Sulphasalazine/ salazopyrin 500 5ASA ↔ sulfapyridine azo bond colon Balsalazide/colazal 750 5ASA ↔ 4ABA azo bond 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

Dose & delivery systems of 5ASA formulations

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5ASA in ulcerative colitis

5ASA for induction and maintenance of remission in UC

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

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

Mucosal healing in UC

How to optimise 5-ASA

Optimise 5-ASA Extended duration

• f treatment3

Maximise dose1 Combine oral and rectal 5-ASA2

• 1. Hanauer SB et al. Am J Gastroenterol 2005;100:2478–85; 2. Marteau P et al. Gut 2005;54:960; 3. Kamm MA et al. Inflamm Bowel Dis 2009;15:1-8.

5-ASA 4.8 g/d is better than 2.4 g/d at inducing clinical response or complete remission 5-ASA combined oral and rectal therapy is better than oral therapy alone 60% of patients achieved remission after a further 8 weeks of 5-ASA therapy

Extended duration

• f treatment3

Maximise dose1 Combine oral and rectal 5-ASA2

How to optimise 5-ASA

Adherence

• 1. Hanauer SB et al. Am J Gastroenterol 2005;100:2478–85; 2. Marteau P et al. Gut 2005;54:960; 3. Kamm MA et al. Inflamm Bowel Dis 2009;15:1-8.

Adherence to 5-ASA therapy in UC

Kane SV. Aliment Pharmacol Ther 2006;23:577–585.

Clinical trials

20 40 60 80 100

Average adherence rate (%) Community based trials Rate particularly low (40%) in patients in symptomatic remission

80% 40–60%

Study not designed to measure efficacy

*p<0.05 BD/TDS vs QD

Kane S et al. Clin Gastro Hepatol 2003;1:170–3

Once a day vs conventional dosing UC maintenance

Asacol 2.4 g/day

n=12 n=10 n=10 n=12

100 75 78* 70

10 20 30 40 50 60 70 80 90 100 3 months 6 months

Compliance (% patients)

Once a day BD or TDS

Weak evidence Strong evidence2  Gender  Beliefs about illness (cause, timeline)  Income  Necessity (perceived need) for treatment  Age  Perceived effect of drug  Race  Concerns about treatment (fear of side effects)  Personality

70% of non-compliance is intentional1

• 1. Harris Interactive and the Boston Consulting Group (BCG) survey on reasons for patient non-adherence 2002. 2.McHorney CA, Spain CV. Health Expert. 2011;14:307-20

Predictors of non-adherence in chronic diseases

Optimising adherence

Optimising adherence

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5ASA in Crohn’s disease

Δ CDAI Δ CDAI Ileal disease Remisssion (%) 310 patients. CDAI = 151-400 Randomised to Pentasa 1g, 2g, 4g /day or placebo

Oral 5ASA for induction of remission in CD

1Singleton Gastroenterology 1993;104:1293–1301.

 Pentasa 4g/day – meta-analysis of 3 studies2 :pentasa superior to placebo ? How relevant reduction in CDAI (63)

2Hanauer Clin Gastroenterol Hepatol 2004: 379–388

 6 trials

 ASA 362/663  Placebo 370/676

 1 trial

 ASA 54/80  Placebo 55/81

12/12 24/12

Akobeng Cochrane Database Syst Rev. 2005 (1):CD003715

Oral 5ASA for maintenance of remission in CD

Sulfasalazine Mesalazine Combined

Ford Am J Gastroenterol 2010 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=0.72 – 1.31) 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=0.70–0.92) NNT to prevent relapse in one patient was 10 (95%CI=6–25). RR=0.86 (95%CI=0.74–0.99) NNT=13 (95%CI=7–50)

Oral 5ASA in prevention in post-operative 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

Summary – 5ASA in CD

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5ASA in chemoprevention of IBD

Jess et al. Gastroenterology 2012;143:375–381

IBD as risk for colorectal cancer

Eaden et al. Gut 2001 Apr; 48 (4): 526-35

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; 0.37-0.69)

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) 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 Siwan Thomas- Gibson (Consultant Endoscopist,St. Mark’s) Mr J Warusavitarne (Consultant IBD Surgeon, St. Mark’s) Dr Ryan Choi (IBD Research Fellow,

• St. Mark’s)

 Update St Mark’s IBD surveillance database  Biology of inflammation → cancer pathway

St Mark’s IBD-Cancer Surveillance Group

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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

5-ASA induced nephrotoxicity

 Incidence:  Clinical trials: mean annual risk 0.26%1  BSG/RA 2002 study: 1/4000 patient yrs2  Immune-mediated interstitial nephritis  Clinical recommendations:  Blood monitoring recommended  Failure to detect 5-aminosalicylate nephrotoxicity is a cause of medical litigation

• 1. Gisbert IBD 2007
• 2. Muller APT 2005

GWAS & serious drug reactions

Nat Genet. 2009

SAE Consortium

Prof Graham Radford-Smith Prof Ian Lawrance Prof Mark Silverberg Joanne Stempak Dr Jonas Halfvarsson Dr Annese Vito Dr D'Incà Renata Professor Epameinondas Tsianos Dr Rinse Weersma

So et al. DDW 2013

5ASA 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 - 914 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

So et al. DDW 2013

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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)

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, 2001

 15 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

New PPAR-γ agonist in treatment of IBD

 5-ASA analogues with stronger affinity for PPAR-γ  Synthetic modulator, GED (or GED-0507-34) has 100–150 fold higher PPAR activation than 5-ASA in vitro  In experimental models of colitis, GED demonstrated similar anti- inflammatory 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. 2013 May

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