Disclosures - Gi Health Foundation · • Postpartum, developed watery diarrhea, 3-4 times daily...

2

Disclosures

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continuing education activities sponsored/provided by Purdue University College of

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affiliations related to the content of the presentation or enduring material.

Full disclosure of all commercial relationships must be made in writing to the audience

prior to the activity. All additional planning committee members, staff, and reviewers of

the Gi Health Foundation and Purdue University College of Pharmacy have no

relationships to disclose.

Planning Committee Member

Julie Messick – No Relevant Relationships

Faculty

All faculty disclosures can be found in your meeting guide.

3

This program is supported

by educational grants from

American Regent

and Janssen Biotech, Inc.

5

Welcome and Introduction

Stephen B. Hanauer, MD

6

Case Presentation:

Mild to Moderate IBD


7

MEDICATION LABS PROGRESS

NOTES

OTHER

Patient Case

HISTORY

32-year-old woman

with a “longstanding”

history of GI issues

HPI

• Abdominal pain dating back to

late teens (17 years old) when she

presented for emergent

appendectomy; c/o “irregular” bowel

habits since then

• Symptoms largely resolved during

pregnancy 2 years ago

• Postpartum, developed watery

diarrhea, 3-4 times daily associated

with periumbilical abdominal pain

postprandially

PMH

• Nonerosive GERD

• Prior perianal fistula age 15

years with no recurrence

S/P fistulotomy

FH

• No family history of IBD

SH

• Smokes 1 ppd cigarettes

x 5 years

8

HISTORY

Patient Case

LABS PROGRESS

NOTES

OTHER

• Lansoprazole 30 mg once daily

• Ibuprofen prn for dysmenorrhea

MEDICATION

9

MEDICATIONS HISTORY

Patient Case

LABS PROGRESS

NOTES

OTHER

• Ferritin 20 ng/mL

• CMP normal except

albumin 3.8 g/dL

• CRP 3 mg/L (normal)

• Fecal calprotectin 338 mcg/g (high)

• Vitamin B12 500 ng/mL (normal)

• Vitamin D 15 ng/mL (low)

10.0/mm3 11 g/dL

500 x103/μL 33%

10

LABS MEDICATIONS HISTORY PROGRESS

NOTES

Patient Case

OTHER

Colonoscopic Findings

• Small AVM in the sigmoid colon

• Otherwise normal examination

• 1 cm of terminal ileum visualized;

normal in appearance

• Biopsies in colon and ileum taken

– No evidence of acute inflammation

or ulceration

– No crypt distortion

– No granulomas

11


NOTES

Patient Case

OTHER

MRI Enterography

Diffuse abnormality of the distal

and terminal ileum with wall

thickening and narrowing of

the lumen

12

Next Step?

What would you recommend next for this 32 year old female

with inflammatory ileal activity on MRE, abnormal labs,

but unremarkable colonoscopy?

A. Retrograde Double Balloon Enteroscopy with biopsy

B. Start anti-TNF therapy

C. Oral steroid tapering and start immunomodulators

D. Wireless capsule endoscopy

E. Start anti-TNF + Immunomodulator therapy

13


NOTES

Patient Case

OTHER

Retrograde double

balloon enteroscopy

Non-caseating granulomas are

present and histology consistent

with Crohn’s disease

14

MEDICATION HISTORY LABS OTHER

Patient Follow-Up: Initial Therapy

• Due to symptoms, MRE findings, elevated

calprotectin, and negative stool studies, patient

started on oral EC budesonide 9 mg x 8 weeks

– Symptom relief within a week and rapid

resolution of diarrhea

• Patient started on oral FeSO4 325 mg QD

PROGRESS

NOTES

15

Understanding Iron Deficiency

in Crohn’s Disease

David G. Binion, MD

16

Causes of Anemia in Inflammatory Bowel Disease (IBD)

Iron deficiency

Anemia of chronic disease

Vitamin B12 deficiency

Folate deficiency

Drug-induced (sulfasalazine,

thiopurines)

Hemolysis

Myelodysplastic syndrome

Aplasia (often drug-induced)

Innate hemoglobinopathies or

disorders of erythropoiesis

Co

mm

on

1

Occasio

nal1

R

are

1

Iron deficiency

1. Gasche C, et al. Inflamm Bowel Dis. 2007;13:1545-1553; 2. Kulnigg S, Gasche C. Aliment Pharmacol Ther. 2006;24:1507-1523.

Most common form of anemia

in IBD1,2

Commonly caused by intestinal

blood loss, malnutrition, and

impaired iron uptake1,2

17

Normal Distribution of Iron in Adults

Andrews NC. N Engl J Med. 1999;341:1986-1995.

18

Hepcidin is a Critical Regulator of Iron Homeostasis and is Increased in Inflammation

25-aa peptide

Principal regulator of iron absorption and distribution to tissues

Synthesized predominantly in hepatocytes

Binds to ferroportin, causes internalization and degradation

Hepcidin increased in inflammatory states

Nemeth E, Ganz T. Acta Haematol. 2009;122:78-86.

19

Hepcidin: The Master Regulator of Iron Absorption

Ferroportin

Fe2+


20


Ferroportin Hepcidin


21


Ferroportin Hepcidin

↓Hepcidin

Iron export

through

ferroportin

↑Hepcidin

Ferroportin

degradation:

Iron locked in cell


22

Hepcidin Levels Correlate With Presence of IBD and Disease Activity

• Patients with IBD and healthy controls (N=202)

• Median hepcidin levels higher in UC and CD patients vs

healthy controls (P<0.0001)

• Serum hepcidin positively correlated with disease activity

in UC (r=0.36, P=0.009) and C-reactive protein

[CRP (r=0.29, P=0.004)]

• Serum hepcidin negatively correlated with ferritin

(P=0.0008)

Oustamanolakis P, et al. Eur J Gastroenterol Hepatol. 2011;23:262-268.

23

Laboratory Workup of Anemia

Initial evaluation

CBC with differential

Serum ferritin

Transferrin saturation

CRP

Creatinine

Reticulocyte count

If cause of anemia

not identified

Vitamin B12

Methylmalonic acid

Folic acid

Haptoglobin

Lactate dehydrogenase

Bone marrow aspirate

CBC=Complete blood count; Hb=hemoglobin; MCH=mean corpuscular hemoglobin; MCV=mean corpuscular volume

Gasche C, et al. Inflamm Bowel Dis. 2007;13:1545-1553.

24

Normal Distribution of Iron in Adults

Andrews NC. N Engl J Med. 1999;341:1986-1995.

25

Oral Iron in IBD

• Considered standard because of

established safety profile, lower cost,

ease of administration

– May be useful in patients with

inactive IBD

• Most widely used oral iron

supplements contain ferrous iron

• Optimal dose not established

Goldberg N. Clin Exp Gastroenterol. 2013;6:61-70.

26

Limitations of Oral Iron

• A significant fraction of ingested iron

remains unabsorbed1

• Intolerance due to GI side effects results in

discontinuation of up to 20% of patients2

Nausea

Vomiting

Diarrhea

Abdominal pain

Constipation

Melena-like stools

1.Goldberg N. Clin Exp Gastroenterol. 2013;6:61-70; 2. Lindgren, et al. Scand J Gastroenterol. 2009;44:838-845.

27

Case Follow-Up


28


Patient Follow-Up: 2 Weeks Later

• Worsening postprandial abdominal pain noted,

no fevers

• Stopped smoking cigarettes

• Receiving Vitamin D 50,000 units /week

• PE: Fullness in RLQ mild tenderness, no guarding

PROGRESS

NOTES

29

MEDICATIONS HISTORY

Patient Follow-Up: 2 Weeks Later

LABS PROGRESS

NOTES

OTHER

• Ferritin 25 ng/mL (increased from previous value)

• CMP normal except albumin 3.1 g/dL

• CRP 12 mg/L

• Fecal calprotectin 423 μ/g

11.0/mm3 11 g/dL

623 x103/μL 30%

30

Next Steps?

What would you recommend for treatment at this time?

A. Admit patient for parenteral steroids

B. Start anti-TNF therapy

C. Oral steroid tapering and start immunomodulators

D. Oral steroid tapering and start immunomodulators +

anti-TNF

E. Start anti-TNF + immunomodulator therapy

31

Personalizing Treatment for IBD:

Evolving Treatment Paradigms

Gary R. Lichtenstein, MD

32

240 228 216 204 192 180 168 156 144 132 120 108 96 84 72 60 48 36 24 12 0

0

20

40

60

80

100

Cu

mu

lati

ve

Pro

ba

bil

ity,

%

Patients at risk Months

2002 552 229 95 37 n=

Impact of Therapy Will Depend on Degree of Structural Damage and Speed of Progression

Inflammatory

Stricturing

Penetrating

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

33

Treating IBD Beyond Symptoms: Rationale for a Clear Management Strategy

Personalized 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

34

>30 years Age at diagnosis <30 years

Limited Anatomic involvement Extensive

No Perianal and/or severe

rectal disease Yes

Superficial Ulcers Deep

No Prior surgical resection Yes

No Stricturing and/or

penetrating behavior Yes

AGA Clinical Pathway for Crohn’s Disease: Characterizing Risk

Sandborn WJ. Gastroenterology. 2014;147:702-705.

Low Risk High Risk

35

Ileum and/or proximal colon,

none to minimal symptoms

Options

• Budesonide 9 mg/day with or without AZA

• Tapering course of prednisone with or

without AZA

AGA Clinical Pathway for Crohn’s Disease: Initial Treatment

Low-risk patient Moderate/high-risk patient

Options

• Anti-TNF monotherapy over no therapy

or thiopurine monotherapy

• Anti-TNF + thiopurine over thiopurine

monotherapy or anti-TNF monotherapy

• Methotrexate for patients who do not tolerate

purine analog in combination with anti-TNF Diffuse or left colon,

none to minimal symptoms

Options

• Tapering course of prednisone with or

without AZA


36

0

28.6

18.3

64.1

47.9

30.7

0

21 12.3

58.5

39

22.8

0

20

40

60

80

100

0

17 9.9

58

40

23.2

Clinical Remission in CD: Net Remission at 6 Months with TNF Antagonists

Open-label

induction

week 2

Week 30

remission

Pa

tie

nts

(%

)

ACCENT I1

Net

remission

Week 30

CHARM2

Net

remission

Week 26

Open-label

induction

week 4

Week 26

remission

Net

remission

Week 26

Open-label

induction

week 4

Week 26

remission

PRECiSE 14

Placebo Active treatment

PRECiSE 23

Infliximab

Net

remission

Week 26

Adalimumab Certolizumab pegol

18.3

29.5

1. Hanauer SB, et al. Lancet. 2002;359:1541-1550; 2. Colombel JF, et al. Gastroenterology. 2007;132:52-62;

3. Schreiber S, et al. N Engl J Med. 2007;357:239-255; 4. Sandborn WJ, et al. N Engl J Med. 2007;357:228-237.

37

Is A Treat-to-Target Approach Feasible in IBD?

Symptoms QoL

Labs CRP

Calprotectin?

Mucosal healing Hospitalizations

Surgery

Biologic (Deep remission)

Histologic remission

Disease modification

38

Working Definitions of Deep Remission

Deep remission implies resolution of inflammatory symptoms

and objective signs of inflammation

No bowel damage

or disability

Existing bowel

damage or disability

• Resolution of symptoms

• Resolution of objective

measures of inflammation

(endoscopy, imaging,

biomarkers)

• Improvement of symptoms

• Resolution of objective

measures of inflammation

(endoscopy, imaging,

biomarkers)

Colombel JF, et al. Dig Dis. 2012;30 Suppl 3:107-111.

39

Improving Initial Response to Biologics

40

The Earlier the Intervention in Crohn’s Disease

the More Effective the Therapy

Disease Duration (Years)

REACH2

SONIC3

ACCENT I5

CHARM4

Rem

issio

n a

t 1 Y

ear

(%)

0

20

40

60

80

0 1 2 3 4 5 6 7 8 9 10

SUTD1

CHARM6 subanalysis

Durations shown are median values.

1. D’Haens G, et al. Lancet 2008;371:660–67.

2. Hyams J, et al. Gastroenterology 2007;132(3):863–73.

3. Colombel JF, et al. N Engl J Med 2010;362;1383‒95.

4. Colombel JF, et al. Gastroenterology 2007;132:52–65.

5. Hanauer S, et al. Lancet 2002;359:1541–49.

6. Schreiber S, et al. Gastroenterol 2007;132(4 Suppl 2):A-147.

41

Early Aggressive Biologic Therapy versus Conventional Management of Crohn’s Disease

73

30

0

20

40

60

80

100P

ati

en

ts w

ith

no

Ulc

ers

, %

P=0.003

Complete Ulcer Disappearance at Week 104

Top-down

Therapy

(IFX + AZA)

Step-up

therapy

n=19/26 n=7/23

D’Haens G, et al. Lancet. 2008;371(9613):660-667.

42

70.8 62.5

27.3 18.2

0

20

40

60

80

100

Pati

en

ts (

%)

SES 0 SES 1–8

Remission off steroids Remission off steroids and

anti-TNF

Mucosal Healing After Therapy Predicts Improved Outcomes in Crohn’s Disease

SES=Simple Endoscopic Score.

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

43

Combination Therapy in CD: The SONIC Study

Corticosteroid-free Clinical Remission at Week 261

1. Colombel JF, et al. N Engl J Med. 2010;362:1383-1395; 2. Sandborn WJ. Gastroenterology. 2014;147:702-705.

30

44.4

56.8

0

20

40

60

80

100

P=.006

P<.001

P=.022

Azathioprine Infliximab Azathioprine +

Infliximab

Pati

en

ts (

%)

51/170 75/169 96/169

44

14.1 14

38.4

0

20

40

60

80

100

6 8 18

31 43

62

0

20

40

60

80

100

Pa

tie

nts

(%

)

No severe endoscopic lesions

Severe endoscopic lesions

Pa

tie

nts

Un

de

rgo

ing

MA

S (

%)

Complete Partial None

Degree of Mucosal Healing

1 3 8

Year of Follow-up

Mucosal Healing Reduces Risk for Colectomy in Crohn’s Disease

Risk of Colectomy According to

Severe Endoscopic Lesions1

MAS=major abdominal surgery; SEL=severe endoscopic lesions (extensive and deep ulcerations on index colonoscopy)

1. Allez M, et al. Am J Gastroenterol. 2002;97:947-953;

2. Schnitzler F, et al. Inflamm Bowel Dis. 2009;15:1295-1301.

Degree of Mucosal Healing and

Risk of Major Abdominal Surgery2

46

Case Presentation:

Moderate to Severe IBD


47

MEDICATION LABS PROGRESS

NOTES

OTHER

Patient Case 2

HISTORY

& PE

23-year-old male

HPI

• 8 weeks of progressive

abdominal pain and weight loss

Physical

• BMI 22 mg/kg2

• T 100.6º

• Pulse 105

• Tender with fullness in RLQ

Family/Social History

• No family history of IBD

• Smokes 1 ppd

cigarettes

48

MEDICATIONS HISTORY

Patient Case

LABS PROGRESS

NOTES

OTHER

• Ferritin 15 ng/mL

• CMP normal except albumin 3.1 g/dL

• CRP 25 mg/L (high)

• Vitamin B12 normal

• Vitamin D low

10.0/mm3 9 g/dL

520 x103/μL 30%

23-year-old male

49


NOTES

Patient Case

OTHER

Colonoscopic Findings

Focal area of ulceration in sigmoid. Deep ulcerations in

cecum with deformed and ulcerated ileocecal valve

MRE

Edematous ileum with mesenteric stranding and sinus

tract toward sigmoid colon

50

Managing Iron Deficiency in

Moderate to Severe Crohn’s Disease

David G. Binion, MD

51

AGA Clinical Pathway for Crohn’s Disease: Assessing Inflammatory Status

Assess inflammatory status

Assess symptoms/signs

• Fever

• Abdominal pain

• GI bleeding

• Localized tenderness

• Weight loss

• Joint pain

• Cutaneous signs

Perform clinical lab testing

• CBC

• CRP

• CMP

• Fecal calprotectin

• ESR

Select imaging modalities (if indicated)

Perform endoscopy

Identify symptoms without inflammatory

markers

Identify symptoms with inflammatory

markers*

Perform CTE or MRE

*Consider whether treatment decisions to be based on inflammatory markers vs confirming with colonoscopy.

This may depend on whether there was historically good correlation between the biomarker selected and colonoscpy in the specific patient.

CMP, complete metabolic panel; CTE, computed tomography enterography; ESR, erythrocyte sedimentation rate; MRE, magnetic resonance enterography.


52

Biomarkers Correlate Well With Endoscopic But Not Clinical Activity Indices

+ indicates significant correlation coefficients (P<.05); NS, nonsignificant correlations.

When stratified by extent, correlation coefficients were highest for colonic disease

IL-6 Calprotectin Lactoferrin CDAI SES-CD

hsCRP + + + NS +

IL-6 + + NS +

Calprotectin + + +

Lactoferrin + +

CDAI NS

CDAI=Crohn’s disease activity index; CRP=C-reactive protein; IL=interleukin; SES-CD=Simple Endoscopic Score-Crohn’s Disease.

Jones JL, et al. Clin Gastroenterol Hepatol. 2008;6:1218-1224.

53

Prevalence and Characteristics of Anemia in a Large

US Inflammatory Bowel Disease Cohort:

A 5-Year Prospective Study

50.2

17.8

53.3

17.9

44.7

17.7

0

20

40

60P

revale

nce (

%)

Severe anemia†

5-Year Prevalence of Anemia

Overall IBD (N=1826) CD (n=1,077) UC (n=744)

Anemia*

*Hb <13 g/dL in men, Hb <12 g/dL in nonpregnant women; †Hb ≤10 g/dL

Koutroubakis IE, et al. J Clin Gastroenterol. 2015 Oct 17 [Epub ahead of print].

54

Characterizing Anemia in the US IBD Population

Anemia of

chronic

disease

Types of

Anemia

17.6% 82.4% IDA or

mixed

anemia

IV iron

Oral iron

Iron Replacement

Therapy

46.6%*

( 8.7%

91.3%

*427 of 916 anemic patients were receiving iron replacement therapy.

Koutroubakis IE, et al. Clin Gastroenterol Hepatol. 2015;13(10):1760-1766.

55

13

0

8

0

17

1

11

1

28

4

12

3

0

5

10

15

20

25

30

Nu

mb

er

Phone calls ED visits GI department

visits

Hospitalizations

No anemia (n=137)

P<0.001

P<0.0001

P<0.001

P<0.0001

Anemia Duration May Serve as a Biomarker for IBD Severity

Healthcare Utilization

Anemia for 1–2 years (n=140) Anemia for ≥3 years (n=133)


56

Anemia Duration May Serve as a Biomarker for IBD Severity

No anemia (n=137) Anemia for 1–2 years (n=140) Anemia for ≥3 years (n=133)

0

10

20

30

0

20

40

60

5-y

r A

ve

rag

e C

RP

,

mg

/L (

med

ian

)

00.20.40.60.8

11.2

5-y

r A

vera

ge E

SR

,

mm

/h (

me

an

, S

D)

P<0.0001

5-y

r A

ve

rag

e U

CA

I

(me

dia

n, ra

ng

e) P<0.0001

5-y

r A

ve

rag

e S

IBD

Q

(me

dia

n, ra

ng

e)

0

20

40

60

80 P<0.001

P<0.0001

CRP ESR

UCAI SIBDQ


57

Why IV Iron in IBD?

• Active disease results in

malabsorption of iron

• GI intolerance may be magnified

in patients with IBD

• Significant anemia may

require more potent treatment

58

Intravenous Iron Products: Approved Indications in the United States

1. Venofer® (iron sucrose injection) (prescribing information]. American Regent, Inc., Shirley, NY;2000; 2. Dexferrum® (iron dextran injection) [prescribing

information]. American Regent, Inc., Shirley, NY;2008; 3. Injectafer® (ferric carboxymaltose injection) [prescribing information]. American Regent, Inc.,

Shirley, NY;2013; 4. Feraheme® (ferumoxytol injection) [prescribing information]. AMAG Pharmaceuticals, Inc., Waltham, MA;2015.

Iron dextran Sodium ferric

gluconate complex Iron sucrose Ferumoxytol

Ferric

carboxymaltose

Treatment of

patients with

iron deficiency

when oral

administration is

unsatisfactory

or impossible

Treatment of iron

deficiency anemia in

adult and in pediatrics

(≥6 years of age) with

CKD receiving

hemodialysis who are

receiving supplemental

epoetin therapy

Treatment of

iron deficiency

anemia in adult

and pediatric

patients 2 years

of age or older

with CKD

Treatment of

iron deficiency

anemia in

adult patients

with CKD

Treatment of

IDA in adults

• Who have intolerance

to oral iron or have had

unsatisfactory

response to oral iron

• Who have non-dialysis

dependent CKD

59

Intravenous Iron Products: Approved Indications in the United States

Iron dextran Sodium ferric

gluconate complex Iron sucrose Ferumoxytol

Ferric

carboxymaltose

Treatment of

patients with

iron deficiency

when oral

administration is

unsatisfactory or

impossible

Treatment of iron

deficiency anemia in

adult and in pediatrics

(≥6 years of age) with

CKD receiving

hemodialysis who are

receiving supplemental

epoetin therapy

Treatment of iron

deficiency

anemia in adult

and pediatric

patients 2 years

of age or older

with CKD

Treatment of iron

deficiency

anemia in adult

patients with

CKD

Treatment of

IDA in adults

• Who have intolerance

to oral iron or have had

unsatisfactory

response to oral iron

• Who have non-dialysis

dependent CKD

1. Venofer® (iron sucrose injection) (prescribing information]. American Regent, Inc., Shirley, NY;2000; 2. Dexferrum® (iron dextran injection) [prescribing

information]. American Regent, Inc., Shirley, NY;2008; 3. Injectafer® (ferric carboxymaltose injection) [prescribing information]. American Regent, Inc.,

Shirley, NY;2013; 4. Feraheme® (ferumoxytol injection) [prescribing information]. AMAG Pharmaceuticals, Inc., Waltham, MA;2015.

60

0

10

20

30

40

50

60

70

80

Response to Intravenous vs Oral Iron

0% vs 24% AE-related discontinuation

Lindgren, et al. Scand J Gastroenterol. 2009;44:838-845.

Hb increase >2 g/dL Reached mean reference Hb

(12 or 13 g/dLl f/m)

Anemic at end of treatment

Resp

on

ders

, %

P=0.07

P=0.04 P=0.007

IV Iron sucrose (n=45) PO Iron sulfate (n=46)

61

0

20

40

60

80

100

0 2 4 8 12

Response to Intravenous vs Oral Iron

Kulnigg, et al. Am J Gastroenterol 2008;103:1182-1192.

1.5% vs 7.9% AE-related discontinuation

Ferric

carboxymaltose

(n=136)

Oral iron

(n=60)

76.5%

68.3% P=0.005

P=0.03

Re

sp

on

de

rs, %

Week

62

Hb <10 g/dL Hb >10 g/dL

Serum ferritin <100 ng/ml

IV Iron

(500 mg)

CRP elevated CRP normal

Oral Iron

30 to 50 mg per day

Intolerance

Noncompliance

Inefficacy

IV iron

(1000 – 1500 mg) IV iron

(1500 – 2000 mg)

Hb <12 g/dL (women) or <13 g/dL (men)

Serum ferritin <100 ng/mL

Proposed Algorithm for Diagnosing and Managing IDA in IBD

Adapted from Stein J, et al. Nat Rev Gastroenterol Hepatol. 2010;7:599–610.

63

Summary: IV Iron

• IV iron may be an appropriate first-line therapy in many patients with

GI disease, including those with IBD

– More rapid and complete repletion of iron stores

– Avoids gastrointestinal side effects of oral iron supplementation

• Two IV iron formulations are approved for general treatment of IDA

in the United States

– Iron dextran

– Ferric carboxymaltose

• Adverse events with IV iron can be managed

64

Case Follow-Up


65


Patient Follow-Up:

First 6 Months of Treatment

Induction prednisone attempted but flare with tapering

He is started on combination infliximab and azathioprine but

develops nausea and vomiting 3 weeks after starting azathioprine

He improves after stopping azathioprine, achieves

clinical remission, and CRP normalizes

Treated with 2 infusions of ferric carboxymaltose and

hemoglobin normalizes

After 6 months of therapy he begins to develop recurrence of

abdominal pain and night sweats

CRP is 8 mg/L (high)

PROGRESS

NOTES

66

Preventing and Managing

Loss of Response to

Anti-TNF Therapies

Corey A. Siegel, MD, MS

67

Loss of Response to Infliximab in Crohn’s Disease

0%

20%

40%

60%

80%

100%

0

50

100

150

200

250

300

350

400

450

500

550

600

650

700

750

800

Lo

ss

of-

Res

po

nse

Ra

te

Days from Index Date

2 years, 77%

Loss of response

• Health-care claims database

(1999–2005)

• Selected patients with CD receiving

infliximab maintenance therapy with

an initial response

• Loss of response inferred from:

– Upward dose adjustment

– New drug therapy for CD

– CD-related emergency room

or inpatient visits

1 year, ~50%

Wu EQ, et al. Value Health. 2008;11:820-829.

68

How to Maintain Remission with Biologics

69

Biologics – Why Monitor?

• Get it right the 1st time

– 1st biologic is our best shot

– Earlier we are successful the better

• What are we looking for?

– Not enough drug

– Antibodies

– Wrong drug class

Gisbert JP, et al. Aliment Pharmacol Ther. 2015.

70

0

1

10

100

Co

nc

en

trati

on

(µ

g/m

L) Peak

Trough

Therapeutic Windows with Biologics

2 6 14 22

Time (weeks)

71

Implications of Low Trough Levels

• Disease recurs

– No longer maintenance but re-treatment

• Development of anti-drug antibodies

– Eventual loss of response

72

What Factors Influence the Pharmacokinetics of TNF Antagonists?

Anti-drug antibodies

Low serum albumin

High baseline CRP

High baseline TNF concentration

High body mass index

Male gender

Concomitant

immunosuppressives

Decreases drug clearance

Y

Increases drug clearance

CRP=C-reactive protein

Ordàs I, et al. Clin Gastroenterol Hepatol. 2012;10:1079-1087.

73

Detectable Levels of Infliximab Are Associated

with Better Outcomes

6

32 33

82 76

88

0

20

40

60

80

100

Pati

en

ts (

%)

Clinical remission Normal CRP Endoscopic

improvement

Undetectable ≥2.0 µg/mL

P<0.001 P<0.001

P<0.001

Clinical Outcomes By Infliximab Trough Level

Maser EA, et al. Clin Gastroenterol Hepatol. 2006;4:1248-54.

74

Post-induction Infliximab Levels Predict Clinical Outcome at Week 54

17.7

82.3

39.2

60.8

0

20

40

60

80

100

Pati

en

ts,

%

Sustained response

(n=96)

No sustained response

(n=51)

Week 14 serum IFX level

<3.5 µg/mL

≥3.5 µg/mL

P=0.0042

ACCENT I

Cornillie F, et al. Gut. 2014;63: 1721-7.

75

Infliximab Trough Between Weeks 14 and 22 Predicts Sustained Response in Crohn’s Disease

• Retrospective adult cohort

• 84 patients

• IFX trough level measured at 14 or 22 weeks

• Sustained clinical response

– IFX Trough level > 3 μg/mL

• Increase in ATI

– IFX Trough level < 3 μg/mL

Bortlik M, et al. J Crohns Colitis. 2013;7:736-743. 0

.0

0.2

0

.4

0.6

0

.8

1.0

0 5 10 15 20 25 30 35

Time from IFX Start (Months)

P-value (logrank): <0.001

IFX level

>3 μg/mL

<3 μg/mL

Cu

mu

lati

ve

Pro

ba

bil

ity o

f S

us

tain

ing

in C

lin

ica

l R

es

po

ns

e

76

Vedolizumab Response and Remission Higher with Higher Trough Concentrations

Sandborn WJ, et al. New Engl J Med. 2013;369:711-721.

77

–Active Monitoring

• REactive drug monitoring: our norm.

Wait until something bad happens (e.g., loss

of response, infusion reaction) then try to fix it

• PROactive drug monitoring: optimize dosing

to maximize chance of and prevent loss

of response

78

When to Monitor?

Up for debate

REactive PROactive

Adapted from Silva-Ferreira F. et al. Inflamm Bowel Dis. 2016. 22(9):2289-2301.

79

MEDICATIONS HISTORY

Patient Case

LABS PROGRESS

NOTES

OTHER

10.0/mm3 11.1 g/dL

33%

• Infliximab trough level

is undetectable

• Anti-drug antibodies

are positive

What would

you do next?

390 x103/μL

80

Reactive Testing for Loss of Response with anti-TNF*

Symptoms suggesting loss of response

Trough levels > 5-10

Endoscopy shows active inflammation

Switch to drug with different

mode of action (non-anti-TNF)

Endoscopy shows no

inflammation

Rule out complication;

consider treating IBS symptoms

Trough levels < 5

Antibodies high

>8 µg/mL equivalents

Switch within class

No or low antibodies

<8 µg/mL equivalents

Optimize with same anti-TNF (decrease interval,

increase dose, add immunomodulator)

*Infliximab and adalimumab

Adapted from JF Colombel.

81

Increasing Dose of Infliximab in the Presence of ATI

Formation is Inferior to Changing Anti-TNF

92

17

0

20

40

60

80

100

Co

mp

lete

/pa

rtia

l R

esp

on

se

, %

Anti-TNF changed Infliximab increased

P<0.004

33

86

0

20

40

60

80

100

Patients with detectable ATI

(n=35)

P<0.016

Patients with subtherapeutic IFX

concentrations (n=69)

Complete/Partial Response

Co

mp

lete

/pa

rtia

l R

esp

on

se

, %

n=11/12 n=1/6 n=2/6 n=25/29

Afif W, et al. Am J Gastroenterol. 2010;105:1133-1139.

82

Effect of Concomitant Azathioprine or Methotrexate on Anti-drug Antibodies

ATI IFX levels

Weeks

0 10 20 30 40 50

Co

nc

en

tra

tio

n (

mc

g/m

L)

Patient 1

Start

MTX 7

6

5

4

3

2

1

0

25

20

15

10

5

0 0 10 20 30 40 50 60

Patient 3

Start

AZA

Weeks C

on

ce

ntr

ati

on

(m

cg

/mL

)

Ben-Horin S, et al. Clin Gastroenterol Hepatol. 2013; 11:444-447.

83

Prospective Therapeutic Drug Monitoring to Optimize Infliximab Maintenance Therapy in IBD

• Retrospective cohort of patients in clinical remission, single physician practice

– Infliximab dose optimization to trough concentrations 5–10 µg/mL (n=48)

– No infliximab dose optimization (n=78)

0

0

20

40

60

80

100

100 200 300 400 500 600 700

Weeks on infliximab

Pro

ba

bil

ity o

n I

nfl

ixim

ab

Optimized Not optimized

p=0.0006

0

0

20

40

60

80

100

100 200 300 400 500 600 700

Weeks on infliximab

Pro

ba

bil

ity o

n I

nfl

ixim

ab

IFXtrough <5 Not tested

p<0.0001

IFXtrough ≥5 p=0.6

Vaughn BP, et al. Inflamm Bowel Dis. 2014;20:1996–2003.

84

A Tool to Help You in the Clinic

Found at: www.BRIDGeIBD.com Accessible on all devices (smart phones, tablets and computers)

Anti-TNF Optimzier

Melmed. et al, CGH 2016.

http://www.BRIDGeIBD.com

85


Patient One-Year Follow-Up

He was treated with adalimumab induction and maintenance and

methotrexate 15 mg oral/week

After 3 months, he has worsening pain, fever and diarrhea

C. difficile is negative

Colonoscopy demonstrated persistent deep ulcers in the sigmoid,

cecum and terminal ileum

Adalimumab levels were 9 µg/mL and there were no

anti-drug antibodies

PROGRESS

NOTES

What would

you do next?

86

Unmet Needs in Crohn’s Disease:

Novel Therapeutics

William Sandborn, MD

87

The IBD Pipeline

IL-Inhibitors

Ustekinumab*

Multiple anti-IL-23 inhibitors

IL-6 inhibitors

Anti-adhesion molecules

Alicaforsen

Anti-MAdCAM

Etrolizumab

Downstream

signaling blockade

Tofacitinib

Ozanimod

Mongersen

MMP-9 inhibitor

GS-5745

Fecal transplants

*FDA approved for Crohn’s disease September 2016

MMP, matrix metalloproteinase.

Note: Several of these agents are currently approved for other indications.

Adapted from Amiot A, Peyrin-Biroulet L. Ther Adv Gastroenterol. 2015;8(2):66-82.

88

Ustekinumab for Crohn’s Disease

• Ustekinumab is a fully human IgG1k monoclonal antibody that binds the p40 subunit of IL-12 & 231

– Prevents IL-12 and IL-23 from binding IL-12Rβ1

– Inhibits IL-12 and IL-23 mediated signaling, cellular activation, and cytokine production

• Approved for moderate to severe psoriasis, psoriatic arthritis, and Crohn’s disease2

No IL-12 or IL-23

intracellular signal

1. Leung Y and Pannacione R. Gastroenterol Clin N Am. 2014;43(3):619-630;

2. STELARA® (ustekinumab) [prescribing information]. Horsham, PA: Janssen Biotech, Inc; 2016.

89

Ustekinumab in Crohn’s Disease

Indication

Adults with moderately to severely

active CD who

• failed or were intolerant to

treatment with immunomodulators

or corticosteroids, but never failed

a TNF blocker

or

• failed or were intolerant to

treatment with ≥1 TNF blockers

Dosing

Induction

Up to 55 kg

> 55 kg to 85 kg

> 85 kg

260 mg IV (2 vials)

390 mg IV (3 vials)

520 mg IV (4 vials)

Maintenance

90 mg SC every 8 weeks

STELARA® (ustekinumab) [prescribing information]. Horsham, PA: Janssen Biotech, Inc; 2016.

90

21.5 34.3 33.7

0

20

40

60

80

100

28.7

51.7 55.5

0

20

40

60

80

100

Ustekinumab in CD: Clinical Response (≥100-point CDAI Reduction) at Week 6

Placebo 130 mg ~6 mg/kg*

Ustekinumab

Pa

tie

nts

, %

n=245 n=249 n=247

P<0.001

P<0.001

Placebo 130 mg ~6 mg/kg*

Ustekinumab

UNITI-1

Patients Failing Anti-TNF Therapy

UNITI-2

Anti-TNF Naïve Patients

Pa

tie

nts

, %

*Weight-range based UST doses approximating 6 mg/kg: 260 mg (weight ≤55 kg), 390 mg (weight >55 mg and ≤85 kg), 520 mg (weight >85 kg).

Subjects who had a prohibited Crohn's disease-related surgery or had prohibited concomitant medication changes prior to designated analysis time point are

considered not to be in clinical response, regardless of their CDAI score. Subjects who had insufficient data to calculate the CDAI score at designated

analysis endpoint are considered not to be in clinical response.

Feagan BG, Sandborn WJ, et al. New Engl J Med. 2016. In press.

n=209 n=209 n=209

P=0.002

P=0.003

91

19.6 30.6

40.2

0

20

40

60

80

100

Ustekinumab in CD: Clinical Remission* (CDAI<150) at Week 8

Placebo 130 mg ~6 mg/kg†

Ustekinumab

Pa

tie

nts

, %

n=209

n=209 n=209 7.3

15.9 20.9

0

20

40

60

80

100

n=245 n=249 n=247

Placebo 130 mg ~6 mg/kg†

Ustekinumab

UNITI-1

Patients Failing Anti-TNF Therapy

UNITI-2

Anti-TNF Naïve Patients

Pa

tie

nts

, %

*Subjects who had a prohibited Crohn's disease-related surgery or had prohibited concomitant medication changes prior to Week 8 are considered

not to be in clinical remission, regardless of their CDAI score. Subjects who had insufficient data to calculate the CDAI score at Week 8 are considered

not to be in clinical remission †Weight-range based UST doses approximating 6 mg/kg: 260 mg (weight <55 kg), 390 mg (weight >55 mg and <85 kg), 520 mg (weight >85 kg).

Feagan BG, Sandborn WJ, et al. New Engl J Med. 2016. In press.

n=209

P=0.009

P<0.001

P<0.001

P=0.003

92

Ustekinumab Maintenance in CD: IM-UNITI

35.9 44.3

29.8 26

48.8 58.1

42.6 40.3

53.1 59.4

46.9 46.1

0

20

40

60

80

100

Pati

en

ts,

%

P<0.05

Clinical remission (CDAI <150)

Clinical response (≥100-point reduction in CDIA

or being in clinical remission)

Steroid-free

remission

Sustained clinical

remission (clinical remission at

Week 36, 40, and 44)

P<0.01

P<0.05

P<0.05

P<0.01

Placebo (n=131) Ustekinumab 90 mg Q12W (n=129) Ustekinumab 90 mg Q8W (n=128)

*Nominally significant

Sandborn WJ, et al. DDW 2016; Feagan BG, Sandborn WJ, et al. New Engl J Med. 2016. In press.

* * *

93

Ustekinumab Safety Profile

Placebo

(n=466)

Ustekinumab

6 mg/kg IV*

(n=470)

Vomiting

Asthenia

Acne

Pruritus

3

1

1

2

4

0.4

0.4

0.4

Placebo

(n=133)

Ustekinumab

90 mg SC Q8W

(n=131)

Nasopharyngitis

Injection site erythema

VVC/mycotic infection

Bronchitis

Pruritus

UTI

Sinusitis

8

0

1

3

2

2

2

11

5

5

5

4

4

3

Maintenance (through Week 44) Induction (through Week 8)

Common Adverse Events in Clinical Trials

*Single induction dose

UTI, urinary tract infection; VVC, vulvovaginal candidiasis

STELARA® (ustekinumab) [prescribing information]. Horsham, PA: Janssen Biotech, Inc; 2016.

94

9.5 12.2

55 65.1

0

20

40

60

80

100

Mongersen (GED-0301): Phase 2 Trial in Steroid-dependent or -resistant CD

Placebo (n=42)

10 mg/day (n=41)

40 mg/day (n=40)

160 mg/day (n=43)

Mongersen

Pati

en

ts,

%

P<0.001

P<0.001

Clinical Remission at Week 12

P<0.001

P<0.001

Monteleone G, et al. N Engl J Med. 2015;372:1104-1113.

95

Summary

• Early aggressive treatment according to

prognosis vs symptoms

• Treatment decisions based on

objective measures

• Prevent loss of response

• Assess loss of response and mechanisms

96

Thank you to our educational supporters

American Regent

and Janssen Biotech, Inc.

Disclosures - Gi Health Foundation · • Postpartum, developed watery diarrhea, 3-4 times daily...

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