MICI : nouvelles idées nouvelles thérapeutiques

Guillaume Savoye

Les MICI sont des maladies progressives…

2

CDAI, Crohn's disease activity index; CDEIS, Crohn’s disease endoscopic index of severity; CRP, C-reactive protein

Inflam

mato

ryactivity

(CD

AI, C

DEIS, C

RP

)

Diseaseonset

Diagnosis Earlydisease

Surgery

Stricture

Stricture

Fistula/abscess

Dig

est

ive

dam

age

(Le

man

nin

dex

)D

isab

ility

(Dis

abili

tyin

dex

)

Pariente B, … Lemann M. Inflamm Bowel Dis 2011; Colombel JF et al. Gastroenterology 2017

Qu’il faut traiter précocément…

3

CDAI, Crohn's disease activity index; CDEIS, Crohn’s disease endoscopic index of severity; CRP, C-reactive protein

Inflam

mato

ryactivity

(CD

AI, C

DEIS, C

RP

)

Diseaseonset

Diagnosis Earlydisease

Surgery

Stricture

Stricture

Fistula/abscess

Window of opportunity?

Dig

est

ive

dam

age

(Le

man

nin

dex

)D

isab

ility

(Dis

abili

tyin

dex

)

Pariente B, … Lemann M. Inflamm Bowel Dis 2011; Colombel JF et al. Gastroenterology 2017

Pour éviter la destruction intestinale et l’invalidité associée

4

Pariente B, et al. Inflamm Bowel Dis 2011;17:1415–22

CDAI, Crohn's disease activity index; CDEIS, Crohn’s disease endoscopic index of severity; CRP, C-reactive protein

Inflam

mato

ryactivity

(CD

AI, C

DEIS, C

RP

)

Diseaseonset

Diagnosis Earlydisease

Dig

est

ive

dam

age

Dis

abili

ty

Pariente B, et al. Inflamm Bowel Dis 2011; Colombel JF et al. Gastroenterology 2017

les anti-TNF rapidement diminuent la destruction intestinale

5

• 130 Crohn

– Score de destruction intestinale

Farre C, et al. Presented at UEG Week 2017

Lém

ann

Ind

ex

140

60

40

20

0

<2 years 2–10 years >10 years Early anti-TNF<2 years

Late anti-TNF>2 years

3.7(IQR: 0.6–13.1)

12.3(IQR: 2.9–22.3)

p=0.015 Lém

ann

Ind

ex

Disease durationCD, Crohn’s disease; IQR, interquartile range

80

140

60

40

20

80

0

La cible dans les MICI

van Dullemen HM et al. Gastroenterology 1995

Rémission clinique+

Mary Jy, Modigliani R. Gut 1989

“le contrôle serré”

7

Pariente B, et al. Inflamm Bowel Dis 2011;17:1415–22

CDAI, Crohn's disease activity index; CDEIS, Crohn’s disease endoscopic index of severity; CRP, C-reactive protein

Inflam

mato

ryactivity

(CD

AI, C

DEIS, C

RP

)

Diseaseonset

Diagnosis Earlydisease

Dig

est

ive

dam

age

Dis

abili

ty

Pariente B, et al. Inflamm Bowel Dis 2011; Colombel JF et al. Gastroenterology 2017

Biomarqueurs (CRP, calprotectine…)

Etude CALM ou décider sur des biomarqueurs…

8Colombel JF, et al. Lancet 2018

-9 -4 -1 0 12 24 36 48Final visit

Weeks:

Ran

do

mis

atio

n1

:1

Prednisone burst & taper

T2T (n=122): escalation driven by CDAI, FC, CRP, prednisone use

De-escalation

ADA 40 mg EOW+AZA

ADA 40 mg EOW

Clinical management (n=122): escalation driven by CDAI, prednisone use

Treatment escalation:

ADA 40 mg EW + AZA 2.5 mg/kg/day

ADA 40 mg EWADA 160/80 mg,

40 mg EOWNo

treatment

Rescue** (escalation needed before next visit)

Earlyrandomisation*

30,3

45,9

0

20

40

60

80

100

Pat

ien

ts (

%)

On fait mieux en prenant en compte les biomarqueurs enplus de la clinique…

CDEIS <4and no

deep ulcerations

23,0

15,6

30,3

23,8

16,4

40,236,9

29,5

45,9

29,5

18,0

50,8

0

20

40

60

80

100

Pat

ien

ts (

%)

p=0.014 p=0.006 p=0.010 p=0.229 p=0.728 p=0.067

CDAI <150,no pred ≥8 wks

CDEIS <4no deep ulceration

Clinical management Treat to target

CRP <5 mg/L,FC <250 µg/g,

CDEIS <4

CDEIS <4 CDEIS <4,CDEIS <4 in

all segments

CDEIS=0 CDEISdecrease >5

Clinicalmanagement

Treatto target

37/122 56/122

p=0.010

Deepremission

Biologicremission

Mucosalhealing

Mucosalhealing in

all segments

Completeendoscopicremission

Endoscopicresponse

9

Colombel JF, et al. Lancet 2018

HIGHRISK

Place de l’imagerie “proactive” dans le monitoring

Years: 654321

Diagnosis: Risk stratify

Years: 654321

Diagnosis: Risk stratify

‘Not-High’

RISK

Co

lon

osc

op

y

Imag

ing

Imag

ing

Co

lon

osc

op

y

Imag

ing

Imag

ing

Co

lon

osc

op

y

Co

lon

osc

op

y

Co

lon

osc

op

y

Imag

ing

S1P

Adapted from Danese S, Gut 2012 and Torres J et al. Lancet 2017

Des nouvelles cibles...

IL-23

Th1

Th0

Th17

Th2

Treg

Sagramostim

Basiliximab

Daclizumab

Tenovil

Secukinumab

Vidofiudimus

Fontolizumab

Abatacept Visilizumab

Risankizumab

Ustekinumab

TGFβIL-16

IL-12IFN-γ IL-4

T cell

IL-13

IL-22

IL-17

IL-10

TGFβ

G-CSF

IFN-γ

IL-2GM-CSF

CD3

T cellCD28

Dendriticcell

IL-12

B7

Epithelial cell

Etanercept

Golimumab

InfliximabAdalimumab

Certolizumab pegol

Activatedmacrophage

TNF-αIL-10

IL-6

Effector Th cell

NatalizumabVedolizumabEtrolizumab

PF547659

Endothelial cell

CCR9

VCAM-1MAdCAM-1

α4β1 α4β7

Leukocyte ICAM-1

Tocilizumab

RituximabOcrelizumab

Tofacitinib

Jak3p38

JNK

11

Filgotinib

Upadacitinib

B

IL, interleukin.

TES1P1

Ozanimod

Lymph node

Anti-TNF uniquement

IL-12 and IL-23 et Crohn

p35

IL12-Rβ2 IL12-Rβ1 IL-23R

IL-17IFN-ɣ

IL-12 IL-23

IL12-Rβ1

p19p40p40

Ustekinumab

Ustekinumab et CrohnRéponse à 6 semaines

Feagn B et al. NEJM 2016

28,7

51,755,5 53,6

0

10

20

30

40

50

60

Placebo(N=209)

130 mg(N=209)

~6 mg/kg(N=209)

Combined(N=418)

UNITI-2

Pro

po

rtio

n o

f su

bje

cts

(%)

Ustekinumab

p<0.001p<0.001 p<0.001

21,5

34,3 33,7 34,0

0

10

20

30

40

50

60

Placebo(N=247)

130 mg(N=245)

~6 mg/kg(N=249)

Combined(N=494)

UNITI-1

Pro

po

rtio

n o

f su

bje

cts

(%)

Ustekinumab

p=0.002 p=0.003 p<0.001

AMM: Bolus iv

Ustekinumab et Crohn: rémission à la 44ieme

semaine

35,9

48,853,1

0

20

40

60

80

100

Placebo SC*(N=131)

90 mg SC q12w(N=129)

90 mg SC q8w(N=128)

Pro

po

rtio

n o

f su

bje

cts

(%)

p=0.040p=0.005

14

Δ 12.9%Δ 17.2%

Ustekinumab

Feagn B et al. NEJM 2016 AMM: entretien sc toutes les 8 ou 12 semaines

Vascular permeability

Blood

vessel

Gut submucosa

Vedolizumab

Ly

α4β7

Soler D, Chapman T, Yang L-L, et al. J Pharmacol Exp Ther 2009;330(3):864–875.

Inhibition spécifique interaction

α4β7/MADCAM1

von Andrian UH, N Engl J Med 2000;343(14):1020–1034.

Vedolizumab = Entyvio® – Anti intégrine α4β7

Lymphocyte

Tethering Rolling ArrestActivation Gut submucosa

Blood vessel

6,8

25,7

14,5

31,4

0

5

10

15

20

25

30

35

Clinical remission CDAI-100 response

Pat

ien

ts, %

PBO (n=148)

VDZ (n=220)

p=0.02

p=0.23

CDAI-100 response

• Entyvio® = VedolizumabAMM

et remboursement : RCH et Crohn

AMM et remboursement : RCH et Crohn

Voie intraveineuseInduction puis entretien 300 mg/8S

Feagan BG, N Engl J Med 2013;369(8):699–710Sandborn WJ, N Eng J Med 2013;369:711–721.

23,819,8

8,7

56,651,6

20,5

52.056.0

24.0

0

10

20

30

40

50

60

Durable clinical response Mucosal healing Durable clinical remission

VDZ/PBO (n=126)VDZ Q8W (n=122)VDZ Q4W (n=125)

Pat

ien

ts, %

p<0.001 p<0.001

p=0.008

p=0.001

p<0.001 p<0.001

RCH S52

MC S6MC S52

Spadaccini M, et al. Int. J. Mol. Sci. 2017, 18, 1276

Sandborn WJ, et al. N Engl J Med 2016;374:1754–1762

Peyrin-Biroulet L, et al. Autoimmun Rev 2017;16:495–503.

L’arrivée des petites molécules par voie orale

InternalisedS1P1R

ExternalS1P1

JAK

stat P-stat

PDE4

cAMP AMP

apremilast3

ozanimod4

etrasimod5,6

tofacitinib1

filgotinib1

upadacitinib1,2

Internal S1P1

Cytokines Immune cells

Sandborn W, et al. N Engl J Med 2017;376:1723–1736

Tofacitinib, inhibiteur panJAK: Phase III dans la RCH

P=0.007 P<0.001

8,218,5

3,6

16,6

0

20

40

60

80

100

Placebo (n=122)

tofacitinib10 mg

(n=476)

Placebo (n=112)

tofacitinib10 mg

(n=429)

11,1

34,340,6

0

20

40

60

80

100

Placebo (n=198)

tofacitinib5 mg

(n=198)

tofacitinib10 mg

(n=197)

15,6

31,3

11,6

28,4

0

20

40

60

80

100

Placebo (n=122)

tofacitinib10 mg

(n=476)

Placebo (n=112)

tofacitinib10 mg

(n=429)

13,1

37,445,7

0

20

40

60

80

100

Placebo (n=198)

tofacitinib5 mg

(n=198)

tofacitinib10 mg

(n=197)

Pa

tie

nts

(%

)P

atie

nts

(%

) Week 8

OCTAVE Induction 1 OCTAVE Induction 2 OCTAVE Sustain

Week 52

P<0.001P<0.001

P<0.001 P<0.001P<0.001

P<0.001

Endoscopic remission

Clinical remission

Nom commercial XeljanzAMM et remboursement dans la PR

Nouvelles approches : cellules souches

51,5

35,6

0

20

40

60

80

100

Cx601 Control

Pati

ents

, %

Δ= 15.8 percentage pointsP=0.021

53/103 36/101

56,3

38,6

0

20

40

60

80

100

Cx601 Control

Pati

ents

, %

Δ= 17.7 percentage pointsP=0.010

Des cellules souches d’origine graisseuses

Co

mb

ined

clin

ical

an

d M

RI r

emis

sio

n

Panes J et al. Lancet 2017 and Gastroenterology 2018Panes J et al. Nat Rev Gastroenterol Hepatol 2017

conclusion