Positioning Our Recent & Future Therapy in Crohn’s disease Ahmad Alfadhli MD, FRCPC Gastroenterology Unite Haya Al-Habeeb Center Mubarak Al-Kabeer Hospital

Positioning Our Recent & Future Therapy in Crohn’s disease

Ahmad Alfadhli MD, FRCPCGastroenterology UniteHaya Al-Habeeb Center

Mubarak Al-Kabeer HospitalKUWAIT

New Therapeutic Goals in CD

• Modification of long-term course of CD• Complete and persistent healing of bowel

mucosa• Avoidance of complications, including stenoses,

abscesses, and fistulae• Avoidance of hospitalization, surgeries,

and ICU stay• Improved cost-to-efficacy ratio of treatment• Normal bowel function and improved QOL

Corticosteroid

16

38

26

58

32

28

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

1 month 1 year

Pro

po

rtio

n o

f p

ati

en

tsSteroids for the treatment of Crohn’s Disease

– benefit for the patient

remission

partialremission

no response

prolongedresponse

steroiddependent

surgery

N = 74 N = 73

“positive”outcome

“negative”outcome

Faubion WA et al. Gastroenterology 2001;121:255

Benefit risk profile of major CD therapies: infections and mortality

TREAT

0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

HA

ZA

RD

RA

TIO

*p=0.002; †p<0.001

IFX AZA6-MPMTX

Steroids

IFXAZA6-MPMTX

Steroids

*

Serious infectionsMortality

Multivariate analysis

†

Data on file (Lichtenstein et al. DDW 2007 poster with abstract S1124)

Complication of long term corticosteroid use

• Hyperglycemia• Infection• Myopathy• Psychological- dementia• Hypertension• Osteoporosis• Adrenal insufficiency• Hepatic steatosis• Glaucoma• Growth suppression

Azathioprine

Maintenance of clinical remission with Azathioprine in CD patients

80

60

40

20

0

Placebo (n=30)

AZA 2.5 mg/kg per d (n=33)80

60

40

20

0

Placebo (n=30)

AZA 2.5 mg/kg per d (n=33)80

60

40

20

0

Placebo (n=30)

AZA 2.5 mg/kg per d (n=33)

% p

atie

nts

not

faili

ng t

rial

Duration of trial (months)

Candy et al. Gut 1995;37:674

0 15

Remission induced by prednisolone; tapered over 12 weeks

100

ster +AZA AZA

Continuous Immunotherapy is Required to Treat a Chronic Disease

Lemann et al. Gastroenterol. 2005 Jun;128(7):1812-8.

Months after randomisation

Patients in clinical remission with AZA for at least 3.5 years before randomisation

0.0

0.2

0.4

0.6

0.8

1.0

0 6 12 18

Per

cen

tag

e o

f P

atie

nts

in R

emis

sio

n

Azathioprine

Placebo

Remission (months)mean ± SE17.3 ± 0.515.9 ± 0.7

% relapse

7.9

21.3

Analysis of 2573 patients (retrospective, 25 years)

0

10

20

30

40

50

60

70

80

90

100

1978-1982 1983-1987 1988-1992 1993-1997 1998-2002

Cum

ulat

ive

perc

enta

ge

Immunosuppressive Use (P<0.001)

Resection (P=0.5)

Adapted from Cosnes et al. Gut 2005;54:237

More frequent use of immunosuppressives did not decrease the need for surgery in CD

Complications from 6-MP/Azathioprine

• N = 806 • Pancreatitis – 1.0%• Abn liver tests – 2.4%• Leucopenia – 10.0%• Significant infection – 5.2%• Lymphoma – 0.005%• Malignancy - unclear

O’Brien Wt al, gastroenterology 101:39-46, 1991Khan et al, digestion 62:249-54. 2000

Methotrexate

Methotrexate: Induction & Maintenance of Remission

in CD

Feagan BG, et al. N Engl J Med. 2000;342:1627-1632.

0 4 8 12 16 20 24 28 32 36 40

0

30

40

50

60

70

80

90

100

Weeks since randomization

Rem

issi

on

(%

)

P=0.04

Methotrexate

Placebo

Side effects of Methotrexate

Common & mild

Uncommon Rare

NauseaAbdominal painLeukopeniaAbnormal LFT

FatigueHeadacheVomitingThrompcytopeniaHair loss

StomatitisFeverDizzinessAnorexiapneumonitis

InfliximabInflammatory CD

Pre-treatment 4 weeks post-treatment

van Dullemen HM et al. Gastroenterology. 1995;109:129-135

Healing of Colonic UlcerationWith Infliximab

Mucosal Healing With Infliximab

Pre-treatment

4 Weeks post-treatment

Courtesy of K. Geboes, MD.

Histologic H&E staining

Study design• N = 108• Randomized, double-blind, placebo-controlled,

multicenter trial• CD > 6 months duration• CDAI score between 220 and 400, inclusive• Stable concomitant medications allowed

by protocol: aminosalicylates, prednisone (< 40 mg/d), 6-MP/AZA

Inflammatory CD

Targan SR et al. N Engl J Med. 1997;337:1029-1035

Clinical Remission With Infliximab at 4 Weeks

Targan SR et al. N Engl J Med. 1997;337:1029-1035

Clinical remission defined as a CDAI score < 150.

Infliximab Fistulizing CD

Infliximab Treatment of Fistulae in CD

Study Design• N = 94• Single or multiple draining enterocutaneous

fistulae• Stable concomitant medications permitted

(aminosalicylates, corticosteroids, 6-MP/AZA, antibiotics)

• Treatment (infusion at Weeks 0, 2, and 6)– Infliximab 5 mg/kg– Infliximab 10 mg/kg– Placebo

Present DH et al. Am J Gastroenterol. 1997;92(suppl):A1746. Abstract

Perianal Fistula: Case StudyPatient was a 42-year-old man with a draining fistula of 3 to 6 months duration who received infliximab 5 mg/kg.

Baseline 2 Weeks

Perianal Fistula: Case Study (cont)

10 Weeks 18 Weeks

Infliximab Treatment of Fistulae in CD: Conclusions

• Primary endpoint: 2/3 demonstrated > 50% reduction in draining fistulae

• Secondary endpoint: 1/2 demonstrated closure of all fistulae

From Trial to ClinicHow Has Practice Changed?

IS

CS

5-ASA

1 2 43 765 8 129 1110

Targan5ACCENT I4GETAID3

SONIC2

SUTD1

Disease Duration (Years)

Pre

vio

us

Dru

g E

xpo

sure

1D’Haens G, et al. Lancet. 2008;371:660-667; 2Colombel J-F, et al. Presented at UEGW 2008. OP001; 3Lemann M, et al. Gastroenterology 2006;130(4):1054-1061; 4Rutgeerts P, et al. Gastroenterology. 2004;126:402-413; 5Targan SR, et al. N Engl J Med. 1997;337(15):1029-1035.

AZA-failure

AZA/6-MP naïve

Remicade® Trials Have Demonstrated Key Learnings in the Management of CD


SONIC2

SUTD1

AZA-failure

AZA/6-MP naïve

Scheduled therapy is better than episodic


IS

CS

5-ASA

Pre

vio

us

Dru

g E

xpo

sure

1 2 43 765 8 129 1110

Disease Duration (Years)1D’Haens G, et al. Lancet. 2008;371:660-667; 2Colombel J-F, et al. Presented at UEGW 2008. OP001; 3Lemann M, et al. Gastroenterology 2006;130(4):1054-1061; 4Rutgeerts P, et al. Gastroenterology. 2004;126:402-413; 5Targan SR, et al. N Engl J Med. 1997;337(15):1029-1035.


SONIC2

SUTD1

AZA-failure

AZA/6-MP naïve

Better results in AZA naïve, ‘bridging’ does not work


IS

CS

5-ASA

Pre

vio

us

Dru

g E

xpo

sure

1 2 43 765 8 129 1110



SONIC2

SUTD1

AZA-failure

AZA/6-MP naïve

Top-down therapy works


IS

CS

5-ASA

Pre

vio

us

Dru

g E

xpo

sure

1 2 43 765 8 129 1110



SONIC2

SUTD1

AZA-failure

AZA/6-MP naïve

Remicade®-based treatment strategy is superior for AZA-naïve patients


IS

CS

5-ASA

Pre

vio

us

Dru

g E

xpo

sure

1 2 43 765 8 129 1110


Adalimumab

HUMIRA Crohn’s Development Program

Induction Maintenance

CHARM Maintenanceof clinical remission/response

GAIN Infliximab Failures Induction trial

M04-690Long-term follow-up

CLASSIC I Inductionof clinical remission/response

CLASSIC IILong-term maintenance

Long term F/U

Greatest and Most Rapid Remission with 160/80 mg Induction Dose

of HUMIRA (Week 4)

Clinical Remission

Clinical Response 100

Clinical Response 70

*p<0.05 vs. placebo (ITT population).

48.7

37.3

32.4

24.3

57.954.7

52.7

33.835.5

24.0

17.6

12.2

Pe

rce

nta

ge

of

Su

bje

cts

*

**

* *n=74 n=74 n=75 n=76

0

10

20

30

40

50

60Placebo/placebo 40/20 mg 80/40 mg 160/80 mg

Hanauer, S. et al. Gastroenterol. 2006, Hanauer, late-breaking abstract, DDW 2004. Panaccione, et al. Oral Presentation UEGW

2005, Data on file.

Rapid and Significant Δ 70 Response Rates With All doses of HUMIRA

As observed; ITT population

*

†‡**

*p=0.025 80/40 vs PBO**p=0.002 80/40 vs PBO; p=0.038 160/80 vs PBO #p=0.02 40/20 vs PBO; p=0.01 80/40 vs PBO; p=0.003 160/80 vs PBO Based on Hanauer, S. et al. Gastroenterol. 2006

#

0

10

20

30

40

50

60

70

80

0 Week 1 Week 2 Week 3 Week 4

Pa

tie

nts

ac

hie

vin

g7

0-p

oin

t re

sp

on

se

(%

)

Placebo

40/20 mg

80/40 mg

160/80 mg

Significant Rates of Remission with adalimumab treatment

*P<0.001 vs. placebo

Full analysis population

Week

% o

f P

atie

nts

6

46 7

*

21 21

*

0

5

10

15

20

25

30

0 1 2 3 4

Placebo 160/80 mg

Sandborn, et al. Presented as oral presentation, ACG 2006, Las Vegas

Disability

What is “Early”?Which “Outcomes”?

DiseasePrevention

Prevention ofSymptomatic Disease

Prevention ofComplications

Prevention ofRelapse

Health SubclinicalInflammation

SymptomaticInflammation

Complications

New Approaches to Therapeutic Intervention in CD?

Steroids

Steroids

+AZA MTX

+IFX

Steroids

+(episodic) IFX

IFX+

AZA

Hommes D, et al. Presented at DDW 2006.

Step-Up Versus Top-Down Trial

0

5

10

15

20

25

30

35

Per

cent

of P

atie

nts

020406080

6 Months 12 Months

% o

f P

atie

nts

010203040

6 Months 12 Months

% o

f Pat

ient

s

*Remission (CDAI < 150), discontinuation of steroids and infliximab, and no resection.

Hommes D, et al. Presented at DDW 2006. [Abstract 749].

CDAI<150 & No Steroids

Steroid Use

Treatment Success* From Week 14 Through 2 Years

P = 0.03 P = 0.19

P < 0.001 P < 0.001

P < 0.001

0 0

Top Down Step Up

60 41 61 50

3117

29

5

Safety Considerations WithTNF Inhibitors

• Infections

• Lymphoma

• Antibodies against the compound– Infusion/injection site reactions

• Other– Autoimmunity and autoantibodies– Demyelination– Congestive heart failure (CHF)– Hematologic disorders– Liver toxicity

Evolving Goals in IBD

Perspective

Society

Clinician

Patient

Improved outcomes

Normal laboratory data

Remission off steroids

Mucosal healing

Improved signs, symptomsand quality of life

Goals

Remission more than symptom control

Accomplishments in IBD

• Shift in the treatment paradigm

• Optimal use of Anti-TNF

• Appropriate patient identification

• Raising the bar for treatment standards– Steroid-free remission– Complete mucosal healing– Improved outcomes– Ultimately strive for changing the natural course of

disease

26 June 2012

GCSO 2013 Business Planning

1999

UCB launch Cimzia for CD (US)

Remicade ulcerative colitis launch

Abbott launch Humira in CD (US and EU)

US Remicade launch in Crohn’s disease (1998 US)

2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010

Remicade paediatric CD launch

Current & Future Landscape : Biologic IBD market map 1998–2018

2011 2012 20142013 2015 201820172016

Stelara launch for CD (2015)

Humira launch for UC

Simponi launch for UC

Remicade approved for paediatric UC

Launch of infliximab biosimilars

Takeda launch vedolizumab IV for UC

Takeda launch vedolizumab IV for CD

Remicade approved for moderate CD

Pfizer launch tofacitinib (JAK-3) for UC

Janssen(JAK-3) for UC

paediatric CD

Looking to The Future

Documents

Positioning Our Recent & Future Therapy in Crohn’s disease Ahmad Alfadhli MD, FRCPC Gastroenterology Unite Haya Al-Habeeb Center Mubarak Al-Kabeer Hospital