David T. Rubin, MD, FACG
Biologic Therapy in Crohn’s Disease: When and How? David T. Rubin, MD, FACG Professor of Medicine Co-Director, Inflammatory Bowel Disease Center
@IBDMD
Disclosures (Last 24 months)
• Consultant and Grant Support: – Abbvie – Janssen – Prometheus – Takeda – UCB
ACG Board of Governors/ASGE Best Practices Course - Las Vegas, NV Copyright 2014 American College of Gastroenterology
1
David T. Rubin, MD, FACG
Biological Therapies in Crohn’s Disease • Currently available in the U.S.: – Anti-TNF: Anti TNF: • Adalimumab • Certolizumab pegol • Infliximab
– Anti-integrin • Natalizumab
• Emerging: – Anti-IL12/23: • Ustekinumab
– Anti-integrin • Vedolizumab
Optimizing anti-TNF Therapy in IBD 1. 2 2. 3. 4. 5. 6. 7. 8.
Choose the right patients T t early Treat l Load appropriately Consider combination therapy for most patients Stick to a strict maintenance schedule Dose adjust j to achieve and to maintain control Monitor for disease “drift” In the future (near?): adjust therapy proactively
ACG Board of Governors/ASGE Best Practices Course - Las Vegas, NV Copyright 2014 American College of Gastroenterology
2
David T. Rubin, MD, FACG
Anti-TNFα Agents for Crohn’s disease Infliximab
Adalimumab
Certolizumab pegol
PEGylated humanized Fab′ fragment containing 2x20 kDa PEG molecules
Monoclonal antibody = murine
= human
Anti-TNFα Agents for Crohn’s disease Infliximab
Adalimumab Fab
IgG1 Fc
PEG
PEGylated humanized Fab′ fragment containing 2x20 kDa PEG molecules
Monoclonal antibody = murine
ACG Board of Governors/ASGE Best Practices Course - Las Vegas, NV Copyright 2014 American College of Gastroenterology
Certolizumab pegol
= human
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David T. Rubin, MD, FACG
Dosing of Anti-TNFα Agents in CD
Interval Between B t Maintenance Injections (weeks)
Route
5 mg/kg (10 mg/kg in responders who lose response)
8
IV
160 mg at week 0 followed by 80 mg at week 2
40 mg
2
SC
400 mg at 0, 2, and 4 weeks
400 mg
4
SC
Agent
U.S. Approval
Induction Dosing
Infliximab1
CD lumen CD fistula UC
5 mg/kg at 0, 2, and 6 weeks
Adalimumab2
CD lumen UC
Certolizumab pegol3
CD lumen
Adult Maintenance Dose
1 REMICADE
(infliximab) Prescribing Information, August 2008, Centocor, Inc., Malvern, PA. (adalimumab) Prescribing Information, February 2008, Abbott Laboratories, North Chicago, IL. 3 CIMZIA (certolizumab pegol) Prescribing Information, April 2008, UCB, Inc., Smyrna, GA. 2 HUMIRA
When? Earlier is better!
ACG Board of Governors/ASGE Best Practices Course - Las Vegas, NV Copyright 2014 American College of Gastroenterology
4
David T. Rubin, MD, FACG
Treat beyond symptoms to reduce bowel damage and stop disease progression Stricture
Bowel damage
Inflammatory activ vity
Surgery
Fistula/abscess Stricture
Disease onset
Diagnosis Early disease
Pariente B, et al. Inflamm Bowel Dis 2011;17:1415–22
Treat beyond symptoms to reduce bowel damage and stop disease progression Stricture
Bowel damage Disease onset
Fistula/abscess Stricture
Inflammatory activ vity
Surgery
Diagnosis Early disease
Pariente B, et al. Inflamm Bowel Dis 2011;17:1415–22
ACG Board of Governors/ASGE Best Practices Course - Las Vegas, NV Copyright 2014 American College of Gastroenterology
5
David T. Rubin, MD, FACG
Treat beyond symptoms to reduce bowel damage and stop disease progression Stricture
Bowel damage
Fistula/abscess Stricture
Disease onset
Inflammatory activ vity
Surgery
Diagnosis Early disease
Pariente B, et al. Inflamm Bowel Dis 2011;17:1415–22
Treat beyond symptoms to reduce bowel damage and stop disease progression
Diigestive damage
Inflammatory activ vity
Disease onset
Diagnosis Early disease
Adapted from Pariente B, et al. Inflamm Bowel Dis 2011;17:1415–22
ACG Board of Governors/ASGE Best Practices Course - Las Vegas, NV Copyright 2014 American College of Gastroenterology
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David T. Rubin, MD, FACG
Induction Treatment with anti-TNFα Agents in Crohn’s Disease Clinical remission in anti-TNFα naïve patients (ITT) (CDAI ≤ 150) (for Targan study CDAI < 150)
REMISSION AT 4 WEEKS1,2,3
LONGER DURATION OF DISEASE
100
Targan1**
Schreiber2**
CLASSIC I3
PRECiSE 12
Patients(%)
80
*
60
*
NS
NS
25.0*
25.0*
*
*
NS
*
NS
*
48.2* 40
36.5* 28.6*
26.7* 18.2*
20 4.0
18.1
12.2
82 8.2
24.3
20.9* 10.3
0
1. Targan et al. N Engl J Med 1997;337:1029-1035. 2. UCB Data on File. 3. Hanauer et al. Gastroenterology 2006;130:323-333.
Maintenance Treatment with anti-TNF- α in CD Moderate to Severely Active IBD
Most Failing Immune modulators
ACCENT I1 Infliximab CDAI 70 & 25% reduction d ti 5mg/kg q8 54 weeks
CHARM2 Adalimumab CDAI 70 40mg eow 56 weeks
100%
100%
0%
12
54%*
43%
0
18
0%
0
6
Months IFX Placebo
63%
54% 38%
6
PRECiSE 2&33,4 Cert pegol CDAI 100 & HBI 400mg q4 80 weeks
100%
52%
0%
LONGER DURATION OF DISEASE
12
18
Months
44%*
0
6
12
18
Months
ADA
certolizumab pegol
Placebo
certolizumab pegol open label Placebo
1. Hanauer et al. Lancet 2002;359:1541-49. 2. Colombel et al. Gastroenterology 2007;132:52-65. 3. Schreiber et al. Gut 2006;55(Suppl V):A131 4. Lichtenstein et al. Gastroenterology 2007;132(Suppl 2):A502 (Abstract T1264)
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David T. Rubin, MD, FACG
Higher Remission Rates with Adalimumab and Certolizumab with Shorter Disease Duration Post-hoc analyses
70 60 50 40 30 20 10 0
All ADA
59* 41**
40 25 17
Placebo
80%
% in CDAI Response or Remission
% of patients
Placebo
All CZP
68%
70%
60%
55% 47%
50%
37.1%
40%
44%
36.4% 29.1%
30%
23.5%
20%
14
10%