IBD Medical Therapies

Mark Flasar, M.D., M.S.Assistant Professor of Medicine

Div. of Gastroenterology & HepatologyUniversity of Maryland Medical Center

1 April 2009

IBD Therapy

• Medical Treatment Goals– To make you well (remission)– To keep you well (maintenance)– To improve your quality of life– Avoid side effects

• Short term• Long term

– Don’t break the bank!

Balancing……

Effectiveness

Cost

Side Effects

Quality of life…

Adherence

“Same, but Same… Same, but Different”

Important Questions to Consider Before Beginning Treatment

• Are the symptoms consistent with IBD?– Infections (C. difficile)– Irritable bowel syndrome– Other forms of colitis

• Where is the disease located?• How severe are the symptoms?• Are other factors present?

– NSAIDs– Lactose Intolerance

IBD Therapy

• Induction • Maintenance

SurgeryClinical Trials

anti-TNF

Systemic Steroids 6-MP/AZA/MTX

anti-TNF (early intervention??)

anti-TNF CyA Surgery GI Rest Systemic Steroids

Topical/rapidly metabolized steroids

5-ASA Antibiotics Alternative Rx

SUPPOSITORIES ENEMAS

PILLSSYSTEMIC

THERAPIES

Topical/rapidly metabolized steroids

5-ASA Antibiotics Alternative Rx

Aminosalicylates (5-ASA)

– First on the block– Inexpensive– Works for some with

mild colon disease– Side effects (10-45%)– Contains SULFA

•Pill, enema, suppository forms- Mild-moderate colon UC

•Sulfasalazine (Azulfidine)

5-ASA….”the next generation”

• ‘Targeted’ delivery• Mesalamine

– Asacol, Pentasa– Lialda– Apriso

• Olsalazine (Dipentum)• Balsalazide (Colazal)

• Less side effects (15%)• Dose frequency

5-ASA Pills

+++++Cost

++++Side effects

+

+/-

++

-

Crohn’s disease active

Colon

Small bowel

++++++++UC (active, maintenance)

MesalamineSulfasalazine

Antibiotics

• Post-op prevention after surgery• Crohn’s limited to the colon• Perianal Crohn’s

– Cipro– Flagyl– Rifaximin– Amoxacillin/CA

• Side effects

Systemic Steroids 6-MP/AZA/MTX

anti-TNF (early intervention??)

Topical/rapidly metabolized steroids

5-ASA Antibiotics Alternative Rx

Steroids • Used since 1950’s• IV, pill, enema forms

– Solu-Medrol– Hydrocortisone– PREDNISONE

• VERY effective (2/3)– Moderate-severe

disease– Remission ONLY

• VERY cheap

Short and Long Term Response to Prednisone

Steroids• Does not prevent flares• Almost 1/3 patients will

not respond• More than 1/3 will be

unable to come off without a flare

• SIDE EFFECTS– You could write a book!

“Fancy” Prednisone

• Controlled-release Budesonide (Entocort)– Locally-acting, slowly-released steroid– Absorbed by gut, 80-90% cleared by liver

• 10-20% of drug enters circulation

– For Crohn’s in the ileum/upper colon– All the potential for prednisone side effects

• Much less frequent• Much less severe

Immunomodulators

• Remission (slow)– MTX in CD – 6-MP/AZA in CD and UC

• ‘Steroid sparing’ in both by both • Prevents flares by both

– 6-MP/Azathioprine (CD and UC)– MTX (CD alone)

• ? Biologic “helper”

SurgeryClinical Trials

anti-TNF

Systemic Steroids 6-MP/AZA/MTX

anti-TNF (early intervention??)

anti-TNF CyA Surgery GI Rest Systemic Steroids

Topical/rapidly metabolized steroids

5-ASA Antibiotics Alternative Rx

Anti-TNF Biologic Agents

Infliximab

Chimeric

75% human IgG1 isotype

Certolizumabpegol

PegylatedHumanized

FAb’ fragment

95% human

Adalimumab

Fully Human

100% human IgG1 isotype

VL VH

CH1Cκ

PEG PEG

Mouse

Biologic Therapy

• All block key players of IBD inflammation• Infliximab (Remicade)

– 3-hour IV treatments; lifelong*• Mod-severe CD/UC (2/3 respond, 1/3 remission)• Prevents flares (1/3 at 1 year)

• Adalimumab (Humira): CD only– Weekly injections (patient-given)

• Certulizumab pegol (Cimzia): CD only– Monthly injections

Biologic Therapy

– 75% human, 25% mouse protein• Allergies possible• Infection (‘awaken’ old TB, blood, overall)• Lymphoma?

– 1/3 of patients will need higher doses– 1/3 of patients lose response

20-30%, serious in 3-4%

12%

Biologics

Anti-Integrins

Crohn’s Disease Treatment AlgorithmCrohn’s Disease

Steroids

Prior AZA

Yes

OR

6 months

IFX monotherapy

IFX + AZA

No

?

IFX monotherapy

Sandborn, WJ et al. ACG 2008.

Corticosteroid-Free Clinical Remission at Week 26

30.6%

44.4%

56.8%

0

20

40

60

80

100

Pro

po

rtio

n o

f P

atie

nts

(%

)

AZA + placebo IFX + placebo IFX+ AZA

52/170 75/169 96/169

Sandborn, WJ et al. ACG 2008.

Crohn’s Disease Treatment AlgorithmCrohn’s Disease

Steroids

Prior AZA

Yes

OR

6 months

IFX monotherapy

IFX + AZA

No

OR IFX + AZA

6 months

IFX monotherapy

? AZA ? IFX ? IFX + AZA

IFX monotherapy

Sandborn, WJ et al. ACG 2008.

Step-up vs Top-down Approach

Hommes D, Baert F, van Assche G, et al. Gastroenterology. 2006;130(suppl 2):A108-A109.

Odds of…

• Dating a millionaire: 215 to 1• Becoming a pro athlete: 22,000 to 1• Winning an academy award: 11,500 to 1• Dying from an injury in the next year:

1,820 to 1• Getting the flu this year: 10 to 1• Getting breast cancer: 9 to 1• Getting prostate cancer: 6 to 1

Thank You

Top down versus step up: Results

0

10

20

30

40

50

60

70

80

90

100

0 26 52 78 104

Step up Top down

CDAI <150 AND no steroids AND no surgery

Weeks

Pat

ien

ts (

%)

0

10

20

30

40

50

60

70

80

90

100

0 26 52 78 104

Step up Top down

Proportion of pts on immunosuppressants

* **

*p<0.01**p<0.05

Weeks

Pat

ien

ts (

%)

*

D'Haens G, Baert F, van Assche G, et al. Lancet 2008

Results: IMID

Van Assche G, et al. Gastroenterology 2008

0 20 40 60 80 100

0.0

0.2

0.4

0.6

0.8

1.0

Time (weeks)

Cu

mu

lati

ve s

urv

ival

Log Rank (Cox): 0735; Breslow: 0.906

p<0.005

0

1

10

100

Continued DiscontinuedIF

X t

rou

gh

leve

ls (

μg

)

Median IFX levels, Week 8 to Week 104 combined

No need for early ‘rescue’ IFX: primary endpoint

CONTINUED

DISCONTINUED

Serious Adverse Events in Crohn’s Disease Clinical Trials

0.16Tuberculosis (TB)5.81Serious Infections

0.16Demyelinating Diseases0.11Lymphoma

0.05SLE/Lupus-like Syndrome

HUMIRA CD trials as of Aug 14, 2006 (n=1459)

1859.1 PY

Serious Adverse Events (per 100 Patient Years [PY))

Data on file, Abbott Laboratories

Safety of infliximab and other Crohn’s disease therapies – TREAT Registry

Data

1.4–3.7*2.2Current use of corticosteroids

0.5–1.20.8Current use of 6-MP/AZA/MTX

1.6–4.3**2.6Current use of narcotic analgesics

0.6–1.81.1Current use of IFX

95% CIHazard ratio

*p=0.001; **p<0.001

Mortality (Multivariate)

1.9–4.0†2.7Current use narcotic analgesics

1.4–2.9†2.0Current use of corticosteroids

0.6–1.30.9Current use of 6-MP/AZA/MTX

0.9–2.11.4Current use of IFX

95% CIHazard ratio

Serious infections (Multivariate)

†p<0.0001

Lichtenstein GR, et al. Clin Gastroenterol Hepatol. 2006;4:621–630.

Risk factors for opportunistic infections in IBD: a case-control study (100 cases,

1983-2003)

0.0003Infinite6MP/AZA – IFX – steroids

0.711.6 (0.1–18.7)6MP/AZA – IFX

<0.000115.7(4.1–59.5)6MP/AZA – steroids

0.0711.2 (0.8–153.3)IFX alone

0.0152.5 (1.2–5.1)6MP/AZA alone

0.0372.2 (1.1–4.8)Steroids alone

Overall p<0.0001

Infinite3 medications

<0.00019.7 (3.3–28.2)2 medications

0.00142.7 (1.5–4.8)1 medication

p valueOdds Ratio (95% CI)

Toruner M, et al. DDW 2006, Los Angeles. Abstract #489

Combined use of ımmunosuppressive drugs ıncreased risk of opportunistic ınfections

What is Hepatosplenic T-cell Lymphoma?

• γδ T lymphocytes represent a normal subset of T cells with cytotoxic functions

• γδ T-cell lymphoma (HSγδTCL) described in 1990, and HSαβTCL reported in 2000

• Tend to be young, reported in ages 12-58• Many (but not all) on chronic immunosuppression• Clinical presentation: hepatosplenomegaly; cytopenias; “B”

symptoms; no lymphadenopathy• Diagnosis made on biopsy of liver, spleen or bone marrow• Treatment with multi-agent chemotherapy (CHOP-like)• Median survival 16 months, almost universally fatal

Belhadj et al. Blood 2003;102:4261-4269.