Biologics: Indications and Approaches Russell D. Cohen, MD, AGAF, FACG Professor of Medicine,...
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Transcript of Biologics: Indications and Approaches Russell D. Cohen, MD, AGAF, FACG Professor of Medicine,...
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?
10
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?
IBD Biologics|
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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)
IBD Biologics|
• 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
13
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)
IBD Biologics|
• 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?
16
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?
IBD Biologics|
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FDA Indication: Infliximab 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 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
IBD Biologics|
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)
IBD Biologics|
• 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
20
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?
IBD Biologics|
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Combination Therapy: Superior Efficacy in Crohn’s
IBD Biologics| 21
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
IBD Biologics|
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?
24
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
IBD Biologics
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Natalizumab: Dosing (CD)
IBD Biologics|
• 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?
27
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 ?
IBD Biologics|
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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
IBD Biologics
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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 ?
IBD Biologics|
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Vedolizumab Blocks α4β7 Integrin
|
Lanzarotto F, et al. Drugs. 2006;66(9):1179-1189.
Anti-a4
MAdCAM-1
a4b1 a4b7
T cell
InflammatoryCytokines
IBD Biologics
33
Vedolizumab: Induction in UC
|
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
IBD Biologics
34
Vedolizumab: Maintenance in UC
|
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
IBD Biologics
35
Vedolizumab: Induction in Crohn’s
|
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
IBD Biologics
36
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
IBD Biologics
37
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
38
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 !
39