Biologics: Indications and ApproachesRussell D. Cohen, MD, AGAF, FACGProfessor of Medicine, Pritzker School of Medicine

Director IBD Center

Co-Director Advanced IBD Fellowship

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Disclosures

• Speaker’s Bureau:

– Abbvie, Entera Health, Salix Pharmaceuticals, Shire PLC

• Consultant / Advisory/ Data Safety Monitoring/ Scientific Advisory Board:

– Abbvie, Cellgene, Elan Pharmaceuticals, Entera Health, Hospira, Janssen (Johnson & Johnson / Centocor), Prometheus Laboratories, Salix Pharmaceuticals, Sandoz Biopharmaceuticals, Santarus, Shire pLC, Takeda, UCB Pharma

IBD Biologics|

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“The Tale of Two Families”

IBD Biologics|

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FAMILY #1: The Anti-TNF’s

IBD Biologics|

Generic Branded Crohn’s Disease Ulcerative Colitis

Adalimumab Humira® + +

Certolizumab Cimzia® +

Golimumab Simponi® +

Infliximab Remicade® + +

FDA- Approved Therapies

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Comparison of anti-TNF Agents

IBD Biologics|

Hanauer, Rev Gastroenterol Disord 2004; 4 (supp 3): S18-24

Human recombinant receptor/Fc fusion protein

Humanized Fab’ fragment

Human recombinant

antibody

Humanized monoclonal

antibody

Chimeric monoclonal

antibody

CDR

Fc

Receptor

Constant 2

Constant 3

Mouse CDR = Complementarity-determining region Human PEG = Polyethylene glycol Certolizumab pegol

• PEG

• PEG

VL VH

CH1Ck

Fab

Infliximab CDP571 AdalimumabGolimumab

Etanercept

6IBD Biologics|

• Benefits• Work fast.• Work very well in many

patients.• Dosed only every 2 weeks –

2 months.• Contain no steroids; so have

no steroid side-effects.• Long-term safety profile

excellent.

• Drawbacks• Given IV or by shot only.• May become allergic or

ineffective if stop and then restart later.

• Internet-hype over very very rare potential risk of lymphoma and potential increased risk of skin cancers

Benefits vs. Drawbacks: Anti-TNF’s

The benefits far outweigh the extremely rare risks in the vast majority of patients.

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FDA Indication: Adalimumab in Crohn’s Disease

IBD Biologics|

Adult & Pediatric Patients• Reducing signs and symptoms• Inducing and maintaining clinical• Moderately to severely active disease who have had an

inadequate response to conventional therapy– Pediatrics: specifies “corticosteroids or immumodulators such as

azathioprine, 6-mercaptopurine, or methotrexate.”

Adult Patients• Reducing signs and symptoms and inducing clinical remission in

patients if they have also lost response to or are intolerant to infliximab http://www.rxabbvie.com/pdf/humira.pdf Accessed 11/9/2014

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FDA Indication: Adalimumab in Ulcerative Colitis

IBD Biologics|

Adult Patients• Inducing and maintaining clinical remission• Moderately to severely active disease who have had an

inadequate response to immunosuppressants• “such as corticosteroids, azathioprine, or 6-mercaptopurine

(6-MP)”• “The effectiveness of adalimumab has not been established in

patients who have lost response to or were intolerant to TNF blockers.”

http://www.rxabbvie.com/pdf/humira.pdf Accessed 11/9/2014

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Adalimumab Dosing (CD and UC)

IBD Biologics|

• Load

– Week 0: 160mg sc (syringe or pen)– Week 2: 80mg sc (syringe or pen)

• Maintenance

– Starting @ Week 4: 40mg sc every other week.

• If lose response:

– Increase to qweekly dosing.

SC ONLY• More convenient• Less compliant?• Self-Medicating?

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Adalimumab: Dosing Issues

1. Use of trough levels to optimize therapy

2. Increase dose: 40 q week or 80 q2 weeks

3. Best outcomes with combination therapy

4. ? If doses over 80mg should be used.

5. High dose loading in severe disease?

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FDA Indication: Certolizumab in Crohn’s Disease

IBD Biologics|

Adult Patients• Reducing signs and symptoms• Maintaining clinical response• Moderately to severely active disease who have had an

inadequate response to conventional therapy

http://www.cimzia.com/assets/pdf/Prescribing_Information.pdf Accessed 11/9/2014

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Certolizumab Pegol Dosing (CD)

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• Load

• Week 0: 400 mg sc• Week 2: 400 mg sc

• Maintenance

• Starting @ Week 4: 400 mg sc every 4 weeks

• If lose response:

– Give an extra dose of 400 mg 2 weeks after last dose

SC ONLY1.Lyophylized drug:Mixed and Administered by health care professional• +/- convenient• More compliant?• Less Self-Medicating?• Preferred if Medicare

2. Prefilled syringe:• More convenient

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Certolizumab Pegol: Dosing Issues

IBD Biologics|

1. Use of trough levels to optimize therapy ? (N/A)

2. Increase dose to 400 q2 weeks: effective?

3. Best outcomes with combination therapy

4. High dose loading in severe disease?

5. Choose the lyophilized version for Medicare patients (Medicare pays for injectables if administered by a health care professional)

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FDA Indication: Golimumab in UC

IBD Biologics|

Adult Patients• Inducing and maintaining clinical response• Inducing clinical remission• Achieving and sustaining clinical remission in induction

responders• Improving endoscopic appearance of the mucosa during

induction• Moderate to severe ulcerative colitis with an inadequate

response or intolerant to prior treatment or requiring continuous steroid therapy

http://www.simponi.com/shared/product/simponi/prescribing-information.pdf Accessed 11/9/2014

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Golimumab Dosing (UC)

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• Load

– Week 0: 200 mg sc (syringe or pen)– Week 2: 100 mg sc (syringe or pen)

• Maintenance

– Starting @ Week 4: 100mg sc every 4 weeks.

SC ONLY• More convenient• Less compliant?• Self-Medicating?

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Golimumab: Dosing Issues

1. Use of trough levels to optimize therapy? (N/A)

2. Increase dose?

3. Best outcomes with combination therapy (anticipated)

4. ? If doses over 200 mg should be used.

5. High dose loading in severe disease?

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FDA Indication: Infliximab in Crohn’s Disease

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Adult & Pediatric Patients• Reducing signs and symptoms• Inducing and maintaining clinical• Moderately to severely active disease who have had an

inadequate response to conventional therapyAdult Patients• Reducing the number of draining enterocutaneous and

rectovaginal fistulas• Maintaining fistula closure

http://www.remicade.com/shared/product/remicade/prescribing-information.pdf Accessed 11/9/2014

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FDA Indication: Infliximab in Ulcerative Colitis

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Adult & Pediatric Patients• Reducing signs and symptoms• Inducing and maintaining clinical remission• Moderately to severely active disease who have had an

inadequate response to conventional therapyAdult Patients• Inducing and maintaining mucosal healing• Eliminating corticosteroid use

http://www.remicade.com/shared/product/remicade/prescribing-information.pdf Accessed 11/9/2014

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Infliximab: Dosing (Crohn’s and UC)

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• Load:

• Week 0: 5mg/kg IV• Week 2: 5mg/kg IV• Week 6: 5mg/kg IV

• Maintenance:

• Starting @ Week 14: 5 mg/kg IV q 8 weeks.

• If lose response:

• Increase dose up to 10mg/kg or decrease dosing interval.

IV ONLY• Less convenient• More compliant

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Infliximab: Dosing Issues

1. Use of trough levels to optimize therapy

2. ? If should increase dose or decrease duration between infusions

3. Best outcomes with combination therapy

4. ? If doses over 10mg/kg should be used

5. Aggressive loading in severe disease?

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Combination Therapy: Superior Efficacy in Crohn’s

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P<0.001 vs. azaP=0.055 vs. ifx

P<0.001 vs. azaP=0.022 vs. ifx

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

Anti-Infliximab Antibodies:Mono: 14%Combo: 1%

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Combination Therapy: Superior Efficacy in Ulcerative Colitis

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Anti-Infliximab Antibodies:Mono: 14%Combo: 1%

Panaccione et al. Gastroenterology 2014;146:392-400 e3

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Best Outcomes With Combination Therapy(Biologics + Immunosuppressant)

|IBD: New Therapies At Last !

Infliximab + Azathioprine:Crohn’s Disease (SONIC Trial) 1

Ulcerative Colitis (UC-SUCCESS Trial) 2

1 Columbel JF et al. N Engl J Med 2010;362:1383-95.2 Panaccione et al. Gastroenterology 2014;146:392-400.

Is the same true for adalimumab?When should thiopurine be started?

Should thiopurines be at therapeutic doses?Should biologics be at therapeutic doses?

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FAMILY #2: The Anti-Integrin Antibodies

IBD Biologics|

Generic Branded Crohn’s Disease Ulcerative Colitis

Natalizumab Tysabri® +

Vedolizumab Entyvio® + +

FDA- Approved Therapies

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FDA Indication: Natalizumab in Crohn’s Disease

Adult Crohn’s Disease:

I. Inducing and Maintaining Clinical ResponseII. Inducing and Maintaining Clinical RemissionIII. Moderate – to – Severe active Crohn’s Disease

I. With evidence of inflammation

IV. Inadequate response to, or are unable to tolerate conventional CD therapies and inhibitors of TNF-α.

V. In CD, should not be used in combination with immunosuppressants or inhibitors of TNF-α.

FDA Prescribing Information : v 05/2014

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Natalizumab: Dosing (CD)

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• Verify JC virus “-”

• No Load

• Standard Dosing Regimen

• 300 mg IV every 4 weeks• No other immunomodulators allowed; taper

prednisone

• If no response or lose response:

• Stop therapy

IV ONLY“CD-TOUCH” Program• Less convenient• More compliant?

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Natalizumab: Dosing Issues

1. Verify JC virus “-” prior to starting

2. Recheck JC virus q6-12 months

- Stop therapy if converts to JC “+”3. Verify drug working by month 6; otherwise stop.

4. Can check drug level if ? of low level / likely antibodies

5. If JC virus status “-” should one be “allowed to”:

• Use concomitant immunomodulators?• Dose increase ?

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FDA Indication: Vedolizumab in Crohn’s Disease

Adult Crohn’s Disease:

I. Moderate – to – Severe active Crohn’s DiseaseII. Inadequate response with, lost response to, or intolerant to either

a. Anti- TNF blockerb. Immunomodulatorc. Corticosteroids (or dependent)

III. Outcomes:a. Achieving clinical responseb. Achieving clinical remissionc. Achieving corticosteroid-free remission

FDA Prescribing Information : v 05/2014

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FDA Indication: Vedolizumab in

Ulcerative Colitis

Adult Ulcerative Colitis:

I. Moderate – to – Severe active UCII. Inadequate response with, lost response to, or intolerant to either

a. Anti- TNF blockerb. Immunomodulatorc. Corticosteroids (or dependent)

III. Outcomes:a. Inducing and maintaining clinical responseb. Inducing and maintaining clinical remissionc. Improving endoscopic appearance of the mucosad. Achieving corticosteroid-free remission

|IBD Biologics

FDA Prescribing Information : v 05/2014

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Vedolizumab: Dosing (Crohn’s and UC)

IBD Biologics|

• Load:

• Week 0: 300 mg IV• Week 2: 300 mg IV• Week 6: 300 mg IV

• Maintenance:

• Starting @ Week 14: 300 mg IV q 8 weeks.

IV ONLY• Less convenient• More compliant

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Vedolizumab: Dosing Issues

1. Use of trough levels to optimize therapy ? (N/A)

2. Decrease time between maintenance infusions to q4 weeks if needed?

3. Best outcomes with combination therapy ?

4. Overlap with other induction agents

• Steroids √• Calcineurin inhibitors ?• Anti-TNF’s ?

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Vedolizumab Blocks α4β7 Integrin

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Lanzarotto F, et al. Drugs. 2006;66(9):1179-1189.

Anti-a4

MAdCAM-1

a4b1 a4b7

T cell

InflammatoryCytokines

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Vedolizumab: Induction in UC

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Clinical Response Clinical Remission Mucosal Healing0%

25%

50%

75%

100%

47.1%

16.9%

40.9%

25.5%

5.4%

24.8%

VedolizumabPlacebo

P=0.001

P<0.001 P=0.001

Primary Analysis: Week 6

Feagan BG et al. N Engl J Med 2013;369(8):699-710),.

GEMINI I

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Vedolizumab: Maintenance in UC

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Clinical Response Clinical Remission Steroid-Free Remission Mucosal Healing0%

25%

50%

75%

100%

52.0%44.8% 45.2%

56.0%56.6%

41.8%

31.4%

51.6%

23.8%15.9% 13.9%

19.8%

Vedolizumab q 4wVedolizumab q 8wPlacebo

P<0.001 for either drug group vs. placebo

P = 0.01 v.

placebo

Week 52

Feagan BG et al. N Engl J Med 2013;369(8):699-710),.

GEMINI I

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Vedolizumab: Induction in Crohn’s

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Clinical Response Clinical Remission0%

25%

50%

75%

100%

31.4%

14.5%

25.7%

6.8%

VedolizumabPlaceboP = 0.23

P = 0.02

Primary Analysis: Week 6

Sandborn et al. N Engl J Med 2013;369(8):711-721.

GEMINI II

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Vedolizumab: Maintenance in Crohn’s

Clinical Response Clinical Remission Steroid-Free Remission0%

25%

50%

75%

100%

45.5%

36.4%28.8%

43.5%39.0%

31.7%30.1%

21.6%15.9%

Vedolizumab q 4wVedolizumab q 8wPlacebo

P=0.005

P=0.02

P=0.004 P<0.001

P=0.04

Week 52

Feagan BG et al. N Engl J Med 2013;369(8):699-710),.P values vs. placebo

GEMINI II

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Dosing Biologics By Trough Levels

|IBD: New Therapies At Last !

“ + ”• Higher Response Rates• Higher Endoscopic

Healing Rates• Lower Hospitalization

Rates• Lower Surgical Rates• Cost-Effective

“ – ”• Extremely Expensive• Trouble Getting

Insurance Coverage• Requires Repeat Testing• Slow Turn-Around Time• Hard to Interpret

Results from Different Labs

GI Meetings 2013-4

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Ongoing Debates With Biologics

1. Earlier Use of anti-TNF’s ?

2. Monotherapy vs. Combination therapy ?

3. Withdrawal of Therapies ?

IBD Biologics|

Answers to These Dilemmas:Tomorrow’s Program !

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