The mesalazine chamaeleon · 2014-07-24 · 70% of non-compliance is intentional1 1. Harris...

Oxford Inflammatory Bowel Disease MasterClass

The mesalazine chamaeleon

Ailsa Hart

Lead IBD Unit, St Mark’s Hospital

Senior Clinical lecturer Imperial College, London


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


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


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 of 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 of 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.

0 Clinical trials

20

40

60

80

100

Ave

rage

ad

he

ren

ce r

ate

(%

)

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

0

10

20

30

40

50

60

70

80

90

100

3 months 6 months

Co

mp

lian

ce (

% p

atie

nts

) 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


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


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


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

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

The mesalazine chamaeleon · 2014-07-24 · 70% of non-compliance is intentional1 1. Harris...

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