Monotherapy using 6-MP or azathioprine for IBD is not dead yet:

long live the tried and true

Jean-Frederic ColombelIcahn School of Medicine at Mount Sinai

New York, NY

Conflicts of interest

J-F Colombel has served as consultant, advisory board member or speaker for

Abbvie, ABScience, Amgen, Bristol Meyers Squibb, Celltrion, Danone, Ferring, Genentech, Giuliani SPA, Given Imaging, Janssen, Immune Pharmaceuticals, Medimmune, Merck & Co., Millenium Pharmaceuticals Inc., Neovacs, Nutrition Science Partners Ltd., Pfizer Inc. Prometheus Laboratories, Protagonist, Receptos, Sanofi, Schering Plough Corporation, Second Genome, Shire, Takeda, Teva Pharmaceuticals, Tigenix, UCB Pharma, Vertex, Dr. August Wolff GmbH & Co.

0%

20%

40%

60%

80%

100%

no IS

AZA

a-TNF

Maximal prescription during the 4-yr calendar period

Crohn’s disease (n=3852) Ulcerative Colitis (n=1880)

Are we still using azathioprine monotherapy ?Evolution of prescription of drugs in IBD during the last 20 years

Hôpital St-Antoine, Paris Courtesy J.Cosnes

What should we consider ?

• Efficacy

• Safety

• Practicality and cost

For the sake of time let’s concentrate on Crohn’s disease

Efficacy of AZA/6MP vs placebo at inducing remission in Crohn’s disease

NNT = 5

Prefontaine E et al. Cochrane database of systematic reviews 2010

Efficacy of AZA/6MP vs placebo for steroid sparing effect

Prefontaine E et al. Cochrane database of systematic reviews 2010

Efficacy of AZA/6MP vs placebo for fistula improvement or healing

Prefontaine E et al. Cochrane database of systematic reviews 2010

Efficacy of AZA/6MP vs placebo at maintaining remission in Crohn’s disease

NNT = 5

Prefontaine E et al. Cochrane database of systematic reviews 2010

NNT = 6

EndpointMean difference (CI 95%)

with control arms (%) p NNT

Clinical recurrence (1 year) 8 (1–15) 0.021 13

Clinical recurrence (2 years) 13 (2–24) 0.018 8

Endoscopic recurrence (1 year) 23 (9–37) 0.0016 4

Severe endoscopic recurrence (i2–i4) 15 (1.8–29) 0.026 7

Peyrin-Biroulet L et al. Am J Gastroenterol 2009NNT = number needed to treat

AZA for the prevention of post-operative recurrence of Crohn’s disease

Why should we abandon a drug that works ?

Gastroenterology 2013

p=0.022p=0.009

31

44

57

p<0.001

52/170 75/169 96/169

AZA + placeboIFX + placeboIFX + AZA100

80

60

40

20

0

Steroid-free remission = CDAI <150 points

Primary endpoint

Prop

ortio

n of

pati

ents

(%)

Colombel JF et al. NEJM 2010

Sonic: steroid-free remission at week 26

p=0.055p=0.023

17

30

44

p<0.001

18/109 28/93 47/107

AZA + placeboIFX + placeboIFX + AZA100

80

60

40

20

0

Colombel JF et al. NEJM 2010

Mucosal healing: complete absence of mucosal ulcerations in the colon and terminal ileum as assessed by video endoscopy

Prop

ortio

n of

pati

ents

(%)

Sonic : complete mucosal healing at week 26

Diagnosis

of CD

• Age <40 years• Perineal disease• Need for steroids • During first 3 months

≤6 monthsRa

ndom

isati

on

AZA early 2.5mg/kg (n=60)

≥2/3 criteria

AZA if needed (n=60)

Primary endpoint:• Number of trimesters without – activity – steroids – IFX – surgery – hospitalisation

36 m

onth

s

The Rapid studyThe RAPID study

Cosnes J et al. Gastroenterology 2013;145: 758-65

RAPIDAZTEC

Cosnes J et al. Gastroenterology 2013;145: 758-65 Panes J et al. Gastroenterology 2013;145: 766-74Cosnes J et al. Gastroenterology 2013;145: 758-65

Early “top-down” therapy with azathioprine is not more effective than placebo or conventional therapy

Jean Dela Fontaine 1625

The tortoise and the hareRien ne sert de courir, il faut partir a point ! 

Progression of digestive damage and inflammatory activity in a theoretical patient with Crohn’s disease

Pariente B, et al. Inflamm Bowel Dis 2011

Inflamm

atory activity (CDAI, CD

EIS, CRP)

Surgery

Stricture

Stricture

Fistula/abscess

Diseaseonset

Diagnosis Earlydisease

Crohn’s disease as a progressive disease

years

Short duration….

12 months

Limitations of current clinical trials in evaluating long-term impact of therapies

Use of azathioprine delays phenotype progression in Crohn’s disease

No treatmentbefore change

N = 344

AZA Before change

N = 349

AntiTNF + AZA before change

N = 100

P<0.

01

P<0.

01

ns

Magro F , et al. Am J Gastroenterol 2014

Thiopurine use is associated with a 40% lowered risk of surgical resection in Crohn’s disease

Chatu S , et al. Am J Gastroenterol 2014

What should we consider ?

• Efficacy

• Safety

• Practicality and cost

TREAT

Lichtenstein G et al. DDW 2010

Infections and azathioprine

Lymphomas and azathioprine

Beaugerie L et al. Gastroenterology 2013

Avoid azathioprine • Young males

– HSTLs (1/5000)• EBV-negative young males

– Fatal Epstein Barr virus-associated hemophagocytic syndrome (1/500)• Patients >65 yrs

– Lymphoma– Infections

Beaugerie L et al. Lancet 2009

How to reduce the risk of lymphomas associated with azathioprine ?

0.66

2.59

4.04

0.38

1.96

5.70

0

0.600.84

Continuing

Discontinued

Never received

<50 years

50-65 years

>65 yearsThiopurine therapy

Cases of NMSC (n) 039 336 233

6

3

4

5

1

2

0

Peyrin-Biroulet L et al. Gastroenterology 2011

Yea

rly

inci

den

ce r

ate

(pe

r 1,

000

pat

ien

t-ye

ars)

Azathioprine and non-melanoma skin cancers

How to reduce the risk of skin cancers associated with azathioprine ?

Low-risk patients• Dark skin

• No pre-malignant lesions • No history of BCC/SCC• No outdoor occupation

• Young age

Moderate-high risk patients• Sunburns/exposure to ionizing radiation

• Light skin, freckling or facial telangiectasia• Outdoor occupations

• Living in high sun exposure countries• High exposure to sun as a child

• Psoriasis treatment with oral psoralen and PUVA

• High cumulative exposure to thiopurines• Combination therapy

• Increasing ageNew medical skin exam in 3-5 years

Surveillance based on risk stratification

Skin examination every other year

Very high-risk patients

History of cutaneous malignancies

Manage on individual

basis

Torres J et al. Inflam Bowel Dis 2013

More about thiopurines safety…

Beaugerie L et al. Gut 2014

• Azathioprine does not increase the risk of new or recurrent cancers in patients with past history of cancer

• Azathioprine is safe during pregnancy Jharap B et al. Gut 2014

Firstexposure

Drug development

Phase I-IIIatrials

healthy volunteers

selectedpatients

Num

ber o

f sid

e-eff

ects

repo

rted

Launch Firstrenewal

rare ADRs (< 1/1.000)

different population, risk groups

long-term use

co-medication & interactions

medication errors, misuse

The learning curve of side-effects

What should we consider ?

• Efficacy

• Safety

• Practicality and cost

Healthcare costs of IBD have shifted from hospitalisation and surgery towards anti-TNFa therapy

Anti-TNF use accounts for 64% and 31% of total costs in CD and UC

Van der Valke ME et al. Gut 2012

We cannot exclude cost considerations…

With the same 1-year budget one cantreat efficiently 1 patient with anti-TNFAnd 100 with AZA !Bourrier A, Seksik P, Cosnes J. Current Drug Targets 2013

When should we use thiopurine monotherapy ?

Prediction: profiling in order to take the best therapeutic decision

Courtesy Tine Jess

Crohn’s disease evaluation and treatment: clinical decision tool

Sandborn WJ . Gastroenterology 2014

Crohn’s disease evaluation and treatment: clinical decision tool

Sandborn WJ . Gastroenterology 2014

Crohn’s disease evaluation and treatment: clinical decision tool

Sandborn WJ . Gastroenterology 2014

Crohn’s disease evaluation and treatment: clinical decision tool

Sandborn WJ . Gastroenterology 2014

Clinical case

Daperno M et al. Gastrointestinal Endosc 2004

1

1

1

1

1

1

3

33 yr old. Non smoker. CD of ileum since 2004. CDAI = 200. No perianal disease. Some bloating and nauseaTPMT : 37; EBV serology +.

Clinical case

Backup slides

Early “top-down” therapy with azathioprine decreases the need for perianal surgery

Cosnes J et al. Gastroenterology 2013;145: 758-65

Algorithm for post-operative CD

Ileocolonic resection

High risk* Low risk***Moderate risk**

Anti-TNF agent Azathioprine No treatment

Endoscopy 6mo-1year

Anti-TNF agent

Anti-TNF agent + IS

Azathioprine

Anti-TNF agent

No treatment

Aza or anti-TNF

•: penetrating disease, prior surgery, smokers, failure to IS; ** : short duration of disease (<10yrs), >10 cm resection; ***: long disease duration (>10 yrs) short fibrostenotic stricture

Swoger JM, Regueiro M. Expert Rev Clin Immunol 2010

Algorithm for the prevention of post-operative recurrence of Crohn’s disease

Azathioprine versus aminosalicylates for steroid-dependent active UC

Series10

20

40

60

80

100

19

53

p=0.006

Patie

nts

trea

ted

succ

essf

ully

at 6

mon

ths

(%)

Patie

nts

trea

ted

succ

essf

ully

at 6

mon

ths

(%)

Treatment success defined as clinical remission (Powell-Tuck Index score of 0) and endoscopic remission (Baron Index score ≤1), plus steroid discontinuation

Ardizzone S, et al. Gut 2006;55:47–53

72 patients treated with concurrent tapering doses of steroids

*0.8g at breakfast and lunch, and 1.6g at dinner

5-ASA 3.2 g/d(in 3 divided doses)*

AZA 2 mg/kg/day

5-ASA, 5-aminosalicylic acid ; AZA, azathioprine

Azathioprine, infliximab and combination in early ulcerative colitis: UC SUCCESS trial

Panaccione R, et al. Gastroenterology 2014

Patients were biologic-naive with moderate-severe UC (Mayo score 6) who were failing corticosteroids and either naive to AZA,or had stopped AZA 3 months before entry.AZA, azathioprine; IFX, infliximab.

Steroid-free remission at Week 16

0AZA (N=76)

20

40

60

80

100

n=18

24%

IFX (N=77)

n=17

22%

IFX + AZA (N=78)

n=31

40%p=0.813

p=0.032

p=0.017

Prop

ortio

n of

pati

ents

(%)

Azathioprine, infliximab and combination in early ulcerative colitis: UC SUCCESS trial

Mucosal healing at Week 16

0AZA (N=76)

20

40

60

80

100

n=28

37%

IFX (N=77)

n=42

55%

IFX + AZA (N=78)

n=78

63%p=0.028

p=0.001

p=0.295

Prop

ortio

n of

pati

ents

(%)

Patients were biologic-naive with moderate-severe UC (Mayo score 6) who were failing corticosteroids and either naive to AZA,or had stopped AZA 3 months before entry.AZA, azathioprine; IFX, infliximab.

Panaccione R, et al. Gastroenterology 2014

Proposed moderate UC algorithm

Respond and taperMaintenance 5-ASA

Fail

Prednisone

10–12 weeks

Steroiddependent

AZA x 10–12weeks

2‒4 weeks

Steroidrefractory

Anti-TNF+/-

Immunomodulators

Adapted from: Panaccione R et al. Aliment Pharmacol Ther 2008;28:674–88.

Moderate