More Management Options!

The newest medications for

IBD

L. Campbell Levy, MD

Assistant Professor of Medicine

Dartmouth-Hitchcock IBD Center

Crohn’s and Colitis Foundation/Dartmouth

Patient and Family IBD Symposium

May 4, 2019

• What medications do we have for IBD?

• What are our current best treatments?

• Can we do better? …with new

treatments?

Questions

Drug class Medications Brand names

5-Aminosalicylates (5-

ASAs)

Sulfasalazine Azulfidine

Mesalamine

Delzicol, Asacol HD, Apriso,

Lialda, Pentasa, Rowasa,

Canasa

Balsalazide Colazal, Giazo

Olsalazine Dipentum

AntibioticsCiprofloxacin Cipro

Metronidazole Flagyl

Corticosteroids

Prednisone

Budesonide Entocort, Uceris

Hydrocortisone Cortifoam, Cortenema

IBD Medicine Cabinet

Drug class Medications Brand names

Immunomodulators

Azathioprine Azasan, Imuran

Mercaptopurine Purinethol

Methotrexate

Biologics

Infliximab Remicade

Adalimumab Humira

Golimumab Simponi

Certolizumab pegol Cimzia

Vedolizumab Entyvio

Ustekinumab Stelara

Small molecule Tofacitinib Xeljanz

IBD Medicine Cabinet

What are our current best

treatments?

• Topical anti-inflammatory – oral or rectal

• Work within 1-2 weeks

• EXCELLENT SAFETY PROFILE

• Not effective for Crohn’s disease

Aminosalicylates (5ASA) for

mild-to-moderate UC

Take your medicines!~90% Maintain Remission

Kane S et al. Am Journ Medicine 2003;114:39-43

What about more

moderate-to-severe

disease?

ImmunomodulatorsAzathioprine/6-mercaptopurine

• Also called “immunosuppressants” or “anti-

metabolites”

• Take ~2-4 months to become effective

• Taken along with another medication (steroids,

biologics) to achieve remission

• “Steroid sparing”

• Maintain remission at one year ~50%

What are biologics?

• Proteins, not

chemicals

• Infliximab 1st;

FDA approval

1998

• Mechanism

very specific

• $$$$

Genetic blueprintReprogrammed cells make protein, reproduce in large numbers

Inserted into cells

Protein is harvested and purified

Many further processing steps

Biologic medicine

Biologic Anti-TNF Agents

• Infliximab (Remicade®), Adalimumab

(Humira®), Golimumab (Simponi®) and

Certolizumab pegol (Cimzia®) are all

anti-TNF drugs

– Remicade® Intravenous every 8 wks

– Humira® Subcutaneous injection every 2 wks

– Cimzia® Subcutaneous injection every 4 wks

– Simponi® Subcutaneous injection every 4 wks

Biologic Anti-TNF Agents

• Antibodies block

inflammatory pathway

important in IBD

• Fast acting – within 2-4 wks

• No need for steroids (… or

can wean fast!)

• Remission at 1 year ~50%

• Anti-drug Ab’s ~10-15%

• $$$$

TNF

Anti-TNF medications

Chemical receptor

Cell

Block chemicals that cause

inflammation

Adverse Events Associated with

anti-TNF Treatment

Siegel CA. The risks of biologic therapy for inflammatory bowel disease. In Bernstein, ed. The inflammatory bowel disease yearbook, volume 6. Infliximab

package insert; Vermeire Gastro 2003; Cush, Ann Rheum Dis 2005; Lenercept study group, Neurology 1999; ATTACH trial 2003

Event Estimated

Frequency

Stop therapy due to adverse event 10%

Infusion or injection site reactions 3%-20%

Drug related lupus-like reaction 1%

Serious infections 3%

Tuberculosis 0.05% (5/10,000)

Non-Hodgkin’s lymphoma (combo) 0.06% (6/10,000)

Multiple sclerosis, heart failure,

serious liver injuryCase reports only

Combination Therapy Superior in

Early Crohn’s Disease

Columbel JF et al. N Engl J Med 2010;362:1383-95.

An Anti-TNF and an

immunomodulator is the

best first treatment for

moderate-to-severe IBD

BUT… can we do better?

• 50% at one year?

• Adverse effects?

• Cost?

• Antibodies to drug?

Vedolizumab (Entyvio®)Crohn’s disease and Ulcerative Colitis

• FDA approved May 2014

• Prevents immune cell

migration to the intestine

• ~30-50% steroid-free

remission at 1 yr

• Excellent safety because

GUT SPECIFIC

• Anti-drug Ab’s less of an

issue (3-5%)

Sandborn et al. NEJM 2013;369:711-21

• Not an adequate induction agent

– Short course of corticosteroids

• Extraintestinal manifestations

Vedolizumab (Entyvio®)Crohn’s disease and Ulcerative Colitis

Ustekinumab (Stelara®)Crohn’s disease

• Approved 2016

• One IV dose then

injection every 8wk

• 30-40% steroid-

free remission

• Anti-drug Ab’s ~2-

4%

• No increased rate

of infection or

malignanciesFeagan BG et al. N Engl J Med 2016;375:1946-1960.

New Drugs Available Today!

What about cost? Where are

all the generics?

What is a Biosimilar drug?

FDA definition:

• A biological product that is highly similar to a reference

product, notwithstanding minor differences in clinically

inactive components

• No clinically meaningful differences in terms of safety,

purity, and potency

• 5 FDA approved 2017-18

Small Molecules vs Biologics

Small Molecules Biologics

Very small that have been

synthesized

Large molecules produced by living

systems

Physically stable More susceptible to degradation

Oral drugs Injected or infused

Not immunogenic Potential immunogenicity

Work inside the cell Block receptors outside the cell

Morrow T, Felcone LH. Biotechnol Healthc. 2004;1:24-26,28-29

Tofacitinib (Xeljanz®)Ulcerative Colitis

• Approved May 2018

• Small molecule (JAK inhibitor) stops signaling

cascade in the immune cell thats promotes

inflammation

• Pill twice per day

• 1 yr, steroid-free remission 40%

• No significant differences in cancers or serious

infections

– Herpes zoster (5.1% vs 0.5%)

– LDL and HDL cholesterol increase (no cardiovascular events)

Sandborn W, et al. Gastroenterology 2016;150(4 Suppl 1):S157.

Sandborn W. DDW 2017

Coming Attractions…

• More oral small molecules

– Newer JAK inhibitors

– S1P modulators (Ozanimod)

• Synthetic microbiome

alteration based on Fecal

transplant

• Many new targets

• What medications do we have for IBD?– Mild UC: Mesalamine

– Moderate-to-severe IBD: anti-TNF + 6MP/AZA

– Lots more options for individualizing therapy

• Can we do better? …with new

treatments?– Yes! Lots more options, with newer biologics,

biosimilars, and small molecules with fewer adverse

events, less “rejection”

Questions

Since the last IBD symposium… 6 more

IBD drugs FDA approved with more to

come!