Biologic Therapy in Crohn s Disease: When and How?

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 ...
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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

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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

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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!

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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

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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

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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%