Current and Future Therapies for Ulcerative Colitis

1
Current and Future Therapies for Ulcerative
Colitis

• Stephen B. Hanauer, MD
• Professor of Medicine and Clinical Pharmacology
• University of Chicago

2
Premise and Preview

• In Most Clinical Scenarios of Ulcerative Colitis
  and Crohns Disease
• Therapy is Sequential

3
Goals of Therapy for Ulcerative Colitis

• Inducing remission
• Mucosal Healing
• Maintaining remission
• Maintaining patients quality of life
• Surgical intervention (selection ofoptimal time
  for surgery)

4
Therapeutic Pyramid for Active UC
Cyclosporine
AZA/6-MP
Oral Steroids
5
Ulcerative Colitis Induction of Remission

• Mild Disease
• Aminosalicylate
• Topical Therapy (Distal Disease)
• Oral Therapy (Extensive Disease)

6
Sulfasalazine Analogues
7
Aminosalicylates

• Sulfasalazine
• Sulfapyridine5-ASA
• Olsalazine
• 5-ASA Dimer
• Balsalazide
• 5-ASAInert carrier
• Mesalamine
• Asacol
• pH-Release
• Pentasa
• Time-Release

8
Oral 5-ASA Release Sites
Pentasa
Mesalamine in microgranules
9
Sulfasalazine Dose/Toxicity
100
RESPONSE
TOXICITY
1G 2G 3G 4G
10
Aminosalicylate Dosing for Reduction of
Signs/Symptoms
Dose-Response w/o Intolerance
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Severe-Fulminant Ulcerative Colitis

• Oral Feeding Parenteral Support
• Empiric Antibiotics
• IV Steroids
• Intermittent vs. Continuous Dosing(?)
• Dose (?)
• Cyclosporine
• Dose (?)
• Maintenance

12
Severe-Fulminant Ulcerative Colitis

• Short-term Prognosis
• 60 Symptom Free by 5 Days
• 25 Colectomy
• Assess Improvement by 5-7 Days
• 85 Colectomy if gt 8 BM/D or CRPgt45

TRAVIS, GUT 38905,96
13
Cyclosporine for Severe UC
14
Maintenance Therapies for Ulcerative Colitis

• Aminosalicylates
• Azathioprine/6-MP
• Cigarettes (Nicotine?)
• Probiotics (?)

15
Combined Oral Topical Mesalamine for
Maintenance of Distal UC
DAlbasio Am J Gastro 1997
16
Mesalamine Maintenance Therapy

• Conclusions
• Aminosalicylate Dose-Response
• Optimal Maintenance Dose is Same as Inductive
  Dose
• Long-term Topical Dosing May be Necessary for
  Distal Disease

17
Immunomodulators for UC Maintenance

• Azathioprine/6-Mercaptopurine
• Steroid-dependent
• Despite Optimal 5-ASA (Oral Topical)
• 5-ASA Allergic
• Post-Cyclosporine
• Dose/Duration Untested
• Requisite 5-ASA Uncertain

18
UC Maintenance with AzathioprineControlled data
1yr Remissions

• Jewell (Gut 1974)
• AZA 2.5 mg/kg (n40) PLCBO (n40)
• Hawthorne (BMJ, 1992)
• AZA (x 100mg) (n33) PLCBO (n34)
• withdrawal trial

(p0.04)
(pns)
Jewell Hawthorne
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UC Maintenance Aza/6-MPUncontrolled Remission
data
(n26)

• George (AmJGastro,96)
• 105 retrospective pts treated with 6-MP
• Ardizzone (J.Clin.Gastro97)
• 56 retrospective pts treated AZA 2mg/kg
• Remission off steroids

(n35)
(n53)

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Maintenance of Remission after Severe Ulcerative
Colitis

• Author F/U (mos.) Remission
• Truelove 26 38
• Janerot 12 50
• Meyers 12 71
• Lichtiger 6 64
• Hanauer 24 40

21
Avoidance of Colectomy After CysA Induction
Probability of Avoiding Colectomy
Cohen, Stein, Hanauer. Am J Gastroenterol
199994(6)1587-1592
22
Comments on Maintenance of Remission for
Ulcerative Colitis

• Steroids are Ineffective
• Steroid-Dependence vs. Maintenance
• Aminosalicylate Dose-Response
• Optimal Maintenance Dose is Same as Inductive
  Dose
• Topical Dosing may be Necessary for Distal
  Disease
• Efficacy of Aminosalicylates after steroids?
• Azathioprine or 6-MP for Steroid-dependence

23
Sequential Strategies in UC

• Induction Maintenance
• Oral Aminosalicylate ? Oral Aminosalicylate
• Rectal Mesalamine ? Rectal Mesalamine
• Oral Aminosalicylate(?)
• Corticosteroids ? Oral Aminosalicylate(?)
• Cyclosporine ? AZA/6-MP 5-ASA(?)
• Ex-Smoker ? Resume Smoking (?)

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Ulcerative ColitisFuture Approaches
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Biologic Therapies

• Monoclonal Antibody
• Chimera
• Humanized
• Human
• Fab-fragment
• Fusion Proteins
• Human Recombinant
• Microbial Vector
• Antisense

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Protein Engineered Antibodies and Fusion Proteins
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ACT 2 Infliximab in Refractory UC

• 363 patients
• Refractory to (any)
• Aminosalicylate
• Steroid
• Thiopurine analogue
• Infliximab
• 0, 5mg/kg, 10mg/kg
• Week 0, 2, 6, 14, 22
• Outcome at week 30

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ACT 2 Infliximab in Refractory UCClinical
Response

Week 8 Week 30
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ACT 2 Infliximab in Refractory UCClinical
Remission

Week 8 Week 30
30
Additional Treatment Targets
Sands B, Gastro 2002118S68
31
Reversing the Therapeutic Pyramid
Severe Ulcerative Colitis?
IV Steroids Cyclosporine Anti-TNF
Risks? Costs?
Aza/6-MP
Aminosalicylates?
32
MEET THE DISEASE AT ITS FIRST STAGE

• PERSIUS A.D. 34-62

FIND THE CAUSE!