A personalized approach to choosing therapies in IBD: Can we do this smarter?

Stephen B. Hanauer, MD

Treating IBD beyond symptoms

‘Personalised’ management for IBD will depend on:• Disease severity at presentation• Clinical and biologic prognostic factors• Achievement of clinical and biologic remission• Maintenance of clinical and biologic remission

– Patient adherence– Therapeutic monitoring

• Pharmacoeconomics

Goals of therapy 2013

• Induce (clinical) remission– Mucosal healiing

• Maintain remission• Prevent complications

– Disease– Therapy

• Optimise timing of surgery

0

20

40

60

80

100

Low activity(20%)

Moderate tohigher activity

(71%)

Fulminantdisease (9%)

Pat

ien

ts W

ith

UC

(%

)

Disease Activity

Distribution of UC Disease Severityat Presentation

N=1161

Langholz EP et al. Scand J Gastroenterol. 1991;26:1247-1256. 4

Course of UC

Disease Course One Year After Diagnosis

No symptoms(50%)

Low activity(30%)

Moderate-high activity (20%)

100

80

60

40

20

0Disease activity

Colectomy Rate (%)

Years

40

0

30

20

10

0 5 10 15 20

Pat

ien

ts W

ith

UC

(%

)

Hendriksen C et al, Gut. 1985;26:158-163.5

Predictors of Poor Response or Colectomy1-5

• Serum albumin

• ESR >30 mm/h

• Bandemia

• Prolonged flare

• Active infection

• Hospitalization setting

• Severe endoscopic lesions

• Disease duration

• Stool frequency

• Percentage of bloody stools

• Body temperature >37.5°C

• Heart rate >90 bpm

• Increased CRP

• Toxic megacolon

• Low hemoglobin <10.5 g/dL

6

BPM=beats per minute; CRP=c-reactive protein; ESR=erythrocyte sedimentation rate.1. Lindgren SC et al. Eur J Gastroenterol Hepatol. 1998;10:831-835; 2. Gonzalez-Lama Y et al. Hepatogastroenterology. 2008;55:1609-1614; 3. Suzuki Y et al. Dig Dis Sci. 2006;51:2031-2038; 4. Cacheux W et al. Am J Gastroenterol 2008;103:637-642. 5. Ananthakrishnan AN et al. Am J Gastroenterol. 2008;103:2789–2798.

Inflammatory activity and progression of bowel damage in a theoretical patient with

Crohn’s Disease

Pariente B et al. Inflamm Bowel Dis. 2011;17(6):1415.

Inflamm

atory activity (CDAI, CD

EIS, CRP)

Surgery

Stricture

Stricture

Fistula/abscess

Diseaseonset

Bow

el d

amag

e

Diagnosis Earlydisease

Relationship Between Clinical Symptoms and Endoscopic Indices at Presentation of Acute CD

R=0.13; NS

Cro

hn

’s D

isea

se A

ctiv

ity

Ind

ex(

CD

AI

)

Crohn’s Disease Endoscopic Index of Severity (CDEIS)

00

100

200

300

400

500

600

5 10 15 20 25 30 35

Modigliani R et al. Gastroenterology. 1990;98:811.

ULN

Baseline CDAI

150 200 250 300 350 400 450 500

Log CRP mg/L

0.01

0.1

1

10

100

CDAI vs CRP

Gastroenterology, 1990. 98(4): 811-18

Step-up according to severityat presentation or failure at prior step

Example of sequential therapies for IBD

Aminosalicylate

Corticosteroid

Anti-TNF

Disease severity at presentation

Severe

Natalizumab

Aminosalicylate (UC)/Thiopurine/MTX (CD)

Aminosalicylate

Anti-TNF/Thiopurine/MTX (CD)

InductionMaintenance

Moderate

Mild

Step-up / sequential management approach

Perceived advantages• Patients attain remission with less toxic therapies• Potentially more toxic therapies reserved for more severe or

refractory disease• Minimises risk of adverse events• Cost sparing (short-term?)

Perceived disadvantages• Patients have to ‘earn’ most effective treatments• Decrease in quality-of-life before patients obtain optimal therapy• Likelihood of surgery may not be altered• Disease may not be modified

60% exposed to IS therapy

No Change in Surgery Rates

P values reflect non-disabling vs. disabling CDBeaugerie L et al Gastroenterology. 2006;130:650-656.

Clinical Predictors for DisablingCrohn’s Disease

• Age of onset (P=.0004)

• Small bowel disease location (P=.002)

• Perianal lesions at diagnosis (P=.01)

• Need for steroids at first flare (P=.0001)

• Current smoker (P=.09)

13

Treatment of “Early Crohn’s” Disease is More Effective than “Late Disease”

CHARM: Remission by Disease Duration with Adalimumab at Week 26

1725

14

59*

40 41**

0

10

20

30

40

50

60

70

*P = .002, **P < .001, †P = .014, ‡P = .001 all vs placebo

Schreiber S, et al. Am J Gastroenterol 105(7): 1574-1582.

Placebo All adalimumab

% R

emis

sio

n

<2 yearsN = 23, N = 39

<2-5 years N = 36, N = 57

≥ 5 yearsN = 111, N = 233

EXTEND: disease duration and deep remission* rates

PlaceboAdalimumab 40 mg eow

Pat

ien

ts i

n d

eep

rem

issi

on

* at

Wee

k 52

(%

)

0

10

30

40

33

<2 years

20

0/15

18

2 to <5 years

0/41

16

≥5 years

0/9 3/9 2/11 7/44

*Deep remission defined as clinical remission (CDAI <150) and complete mucosal healing in EXTENDp<0.001 for adalimumab vs placebo, adjusted for baseline disease duration (Cochran-Mantel-Haenszel test)All patients (n=135) received adalimumab 160/80mg induction therapy, before randomisation (n=129) to adalimumab 40mg eow or to placeboCDAI: Crohn’s disease activity index; eow: every other week

Colombel JF, et al. Gastroenterology 132:52-65: 2007

Disease duration

Do we need a target if we want to prevent disease progression in IBD?

Symptoms

Transmuralactivity

Histological activity

Biologic activity● CRP● Calprotectin

Endoscopic activity

Seve

rity

(arb

itrar

y un

its)

0Duration of disease (years)

5 10 15 20 25 30

Graph: Adapted from Kirwan JR. J Rheumatol 2001;28:881-6Photo: Copyright © American College of Rheumatology

© ACR

Rheumatoid arthritis progression

Early RA Intermediate Late InflammationDisabilityRadiographs

Similarities betweenother therapy areas and IBD?

Hypertension, type 2 diabetes and rheumatoid arthritis

• Chronic progressive diseases

• Failure to treat early and effectively can lead to serious complications and disability

• Disease management has evolved over time– Significant advances in treatment– Insights into the importance of early and optimised therapy

• Focus on a ‘treat to target’ approach to achieve‘tight control’

Treat-to-target approach has been adoptedin other therapy areas

Diabetes• <7% HbA1c

Rheumatoidarthritis• Remission• Low disease activity

Hypertension• BP: 140/90 mmHg

(135/80 mmHg for diabetic patients)

• LDL-cholesterol: 70 mg/dL (to lower incidence of cardiac events)

Treatment targets

Diabetes: ADA. Diabetes Care 2011;34(Suppl. 1):S1–98; Hypertension: ESH/ESC Task Force. Eur Heart J 2007;28:1462–536; Rheumatoid arthritis: Smolen JS, et al. Ann Rheum Dis 2010;69:631–7

Potential wider implications of aadopting a treat-to-target approach

• Treatment algorithms are based on treatment targets– e.g. achieve ‘absence of disease activity’ in 3–6 months in RA

• Frequent monitoring is recommended so that treatment can be optimised– e.g. HbA1c monitoring every 3 months in patients with diabetes

• Modification of the target for high-risk patient groups– e.g. lower blood-pressure target of 130/80 mmHg in patients with both

hypertension and type 2 diabetes– Risk of ‘tight target’ in ICU setting

• Early disease states are recognised– e.g. pre-hypertension, pre-diabetes

Diabetes: ADA. Diabetes Care 2011;34(Suppl. 1):S1–98; Hypertension: ESH/ESC Task Force. Eur Heart J 2007;28:1462–536; Rheumatoid arthritis: Smolen JS, et al. Ann Rheum Dis 2010;69:631–7

Potential benefits of treating to targetin rheumatoid arthritis patients

• Targeted treatment reduces disease activity more than usual care1–7

• TICORA study (n=111): outcome measures were significantly better with intensive management than with routine care 2

1. Fransen J, et al. Ann Rheum Dis. 2005;64:1294–8.2. Grigor C, et al. Lancet. 2004;364:263–9.3. Stenger AA, et al. Br J Rheumatol. 1998;37:1157–63.4. Verstappen SM, et al. Ann Rheum Dis. 2007;66:1443–9.

5. Van Tuyl LH, et al. Ann Rheum Dis. 2008;67:1574–7.6. Edmonds J, et al. Ann Rheum Dis. 2007;66(Suppl. II):325.7. Symmons D, et al. Health Technol Assess 2005;9:1–78.

Intensive management

Routine care0

20

40

60

80

100

65

16Pa

tient

s in

re

mis

sion

* (%

)

*Remission was defined as disease activity score <1.6.

Intensive management

Routine care0

1

2

3

4 3.5

1.9

Mea

n re

ducti

on in

di

seas

e ac

tivity

sco

re

p<0.0001 p<0.0001

Potential benefits of treating to targetin rheumatoid arthritis patients (cont.)

• Targeted treatment slows joint damage more than usual care1–5

• Stenger, et al. study (n=228): mean radiographic progression over 2 years was significantly lower with targeted therapy than with usual care1

1. Stenger AA, et al. Br J Rheumatol. 1998;37:1157–63.2. Verstappen SM, et al. Ann Rheum Dis. 2007;66:1443–9.3. Edmonds J, et al. Ann Rheum Dis. 2007;66(Suppl. II):325

4. Van Tuyl LH, et al. Ann Rheum Dis. 2008;67:1574–7.5. Symmons D, et al. Health Technol Assess 2005;9:1–78.

Early 'aggressive' treatment

Conventional treatment

0

10

20

30

40

26

35

Mea

n ra

diog

raph

ic

prog

ress

ion

rate

p=0.03

All patients had recent onset rheumatoid arthritis (complaints <1 year at study entry)

Baseline 102 Weeks

Treatment of early RA with anti-TNF may prevent progression of structural damage

Total Sharp score = -10.5

Mucosal Healing Predicts Sustained (2-year) Clinical Remission in Early CD

Baert FJ, et al. Gastroenterology. 2010;138:463-468.

Simple endoscopic score 0 Simple endoscopic score 1-9

% o

f p

atie

nts

in

Rem

issi

on

Remission of Steroids Off Steroids and No Anti-TNF

0

10

20

30

40

50

60

70

8070.8

62.5

27.318.2

Is a treat-to-target approach feasible in IBD?

SymptomsQoL

Labs (CRP) ?

Mucosal healingHospitalisations

surgery

Biologic(Deep remission)

Disease modification

What are the components of deep remission?

• Inflammatory symptoms• Laboratory evidence of inflammation

– CRP, calprotectin, etc.• Endoscopic healing• Histologic healing (e.g. UC)• Stabilization of Imaging (structural damage)

What is disease modification in IBD?

• Symptom resolution– Stabilised QoL and PRO

• Reduced disease/therapy complications– Structural damage– EIMs– Neoplasia

• Reduced disability• Improved pharmacoeconomics

– Direct/indirect costs

240228216204192180168156144132120108968472604836241200

10

20

30

40

50

60

70

80

90

100

Cum

ulati

ve p

roba

bilit

y (%

)

Patients at risk: Months

2002 552 229 95 37N =

Penetrating

StricturingInflammatory

Impact of therapy will depend on degree of structural damage and speed of

progression

Cosnes J et al. Inflamm Bowel Dis. 2002;8:244-250.

Summary

• Current therapeutic strategies for IBD do not modify long-term sequelae– Therapies based on symptoms not prognosis

• Similar to other chronic diseases treating to prognostic markers can improve long-term outcomes

• Prospective studies are needed to confirm: – Prognostic criteria– Relevance of individual (composite) targets– Impact on long-term outcomes (benefits/risks) – Socioeconomic values of targeted approach

Goals of therapy

Current• Induce

(clinical) remission• Maintain

(clinical) remission• Prevent complications

– Therapy• Optimise timing of surgery

Future goals• Disease modification

– Prevent disease progression & complications• Neoplasia• Strictures / fistulae• Surgery• Disability

• Pharmacoeconomics– Direct / indirect costs

Response

Remission

Deep remission

Goal Clinical Parameters

Improved symptoms

No symptoms

Normal labs

Mucosal healing

Outcomes

Improved QoL

Decreased hospitalisation

Avoidance of surgery

SUSTAINED

Minimal/no disability

Normal endoscopy

QoL=quality of lifeModified from Panaccione R. Presented at: European Crohn’s and Colitis Organization (ECCO) Fifth Annual Congress. Prague, Czech Republic; February 2010

Evolving Goals of Therapy for IBD:Sustained Deep Remission

32

Maintenance with Biologics will be Optimized by Pharmacology & Determination of Trough Levels

Factors that Influence the PK of TNF Antagonists

Impact on TNF antagonist PK

Presence of ADAs Decreases drug concentration Increases clearanceWorse clinical outcomes

Concomitant use of immunosuppressives Reduces ADA formationIncreases drug concentrationDecreases drug clearanceBetter clinical outcomes

Low serum albumin concentration Increases drug clearanceWorse clinical outcome

High baseline CRP concentration Increase drug clearance

High baseline TNF concentration May decrease drug concentration by increasing clearance

High body size May increase drug clearance

Sex Males have higher clearanceOrdas I et. al. Clin Gastroenterol Hepatol.

2012; 10:1079-1087. 34

Sustained Clinical Response to IFXIFX Trough Levels at the Beginning of Maintenance Therapy

35Bortlik M, et al. J Crohn’s Colitis. 2012. dx.doi.org/10.1016/j.crohns.2012.10.019.

Infliximab Concentration and Clinical Outcome in Patients With UC

• Results– The proportion of pts achieving clinical remission increased with

increasing quartiles of IFX concentrations – Similar trends were observed for clinical response and MH

Reinisch W, et al. Gastroenterology. 2012;142(5):Supp 1,S-114.

Serum IFX Concentrations (g/mL)/ Proportion of Patients (%)

1st Quartile 2nd Quartile 3rd Quartile 4th Quartile p-values

Clinical remission at Wk 8

<21.326.3

≥ 21.3-<33.037.9

≥33.0-<47.943.9

>47.943.1

p=0.0504

Clinical Remission at Wk 30

<0.1114.6

≥0.11-<2.425.0

≥2.4-<6.859.6

>6.852.1

p<0.0001

Clinical Remission at Wk 54

<1.42.1

≥1.4-<3.655

≥3.6-<8.179.0

>8.160

p=0.0066

Summary

• Personalized management for IBD depends on:

– Disease severity at presentation

– Clinical and biologic prognostic factors

– Achievement of clinical and biologic remission

– Maintenance of clinical and biologic remission

• Patient adherence

• Therapeutic monitoring

37