Immunosuppressive Medications and IBD: Now and What

1
Immunosuppressive Medications and IBD Now and
Whats Next

• Stephen B. Hanauer, MD
• University of Chicago

2
Indications for Immunosuppressives in IBD

• Crohns Disease
• Steroid-Sparing (Maintenance)
• Maintenance after Biologics
• Reduction of Immunogenicity
• Post-Surgical Maintenance
• Ulcerative Colitis
• Steroid-Sparing

3
Conventional approach to Induction Therapy
step-up
Anti TNF-a therapiesSurgery
Disease severity
Systemic corticosteroids
AminosalicylatesNon-systemic corticosteroids
Time

• Clinical approach to use mildest form of drug
  therapy to treat patients first
• Move to next step in non-responders

4
Step-up management approach

• Advantages
• Patients attain remission with less toxic
  therapies
• Potentially more toxic therapies reserved for
  more severe or refractory disease
• Minimizes risk of adverse events
• Cost sparing (short-term?)
• Disadvantages
• Patients have to earn most effective
  treatments
• Decrease in quality-of-life before patients
  obtain optimal therapy
• Likelihood of surgery is high
• Disease is not modified

5
IBDs are chronic, life-long

• We cannot just look at the short-term induction
  therapy

6
Long-Term Therapy for IBD is Sequential
Induction?Maintenance
7
Maintenance Therapy is Dictated by Induction
Therapy
Induction Maintenance
Aminosalicylate
Aminosalicylate
8
Maintenance Therapy is Dictated by Induction
Therapy
Induction Maintenance
Aminosalicylate (UC) Thiopurine Methotrexate (CD)
Corticosteroid
9
Maintenance Therapy is Dictated by Induction
Therapy
Induction Maintenance
Cylcosporine
Thiopurine
10
Maintenance Therapy is Dictated by Induction
Therapy
Induction Maintenance
Thiopurine (Steroid-Naïve)
Anti-TNF
Anti-TNF (Steroid-Refractory)
11
Maintenance Therapy is Dictated by Induction
Therapy
Induction Maintenance
Natalizumab
Natalizumab
12
Natural History of Disease Behavior in CD
100
90
Progression Toward Surgery
80
70
60
Penetrating
50
Cumulative Probability ()
40
Inflammatory
30
Stricturing
20
10
0
240
228
216
204
192
180
168
156
144
132
120
108
96
84
72
60
48
36
24
12
0
Months
Patients at risk
95
2002
552
229
37
N
Cosnes J et al. Inflamm Bowel Dis. 20028244.
13
Impact of Therapy will Depend on Degree of
Structural Damage Velocity of Progression
High Potential
Low Potential
100
90
80
70
60
Penetrating
50
Cumulative Probability ()
40
Inflammatory
30
Stricturing
20
10
0
240
228
216
204
192
180
168
156
144
132
120
108
96
84
72
60
48
36
24
12
0
Months
Patients at risk
95
2002
552
229
37
N
Cosnes J et al. Inflamm Bowel Dis. 20028244.
14
Difference between Early Late Intervention with
Immunosuppressants
15

16
Efficacy of AZA as Crohns Disease Maintenance
TherapyAfter Steroids in Adults

• 100

AZA 2.5 mg/kg per d Placebo
Patients Not Failing Trial
42
p0.001
7
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Duration of Trial (months)
Remission induced by prednisolone tapered over
12 wk Inclusion Patients were not steroid
dependent
Candy S, et al. Gut. 199537(4)674-678.
17
Efficacy of 6-MP as Crohns Disease Maintenance
TherapyAfter Steroids in Steroid-naïve Children
6-MP
91
Plt.007
Control
53
N55 At baseline, patients received prednisone
plus either 6-MP or placebo. Steroids were
tapered after induction of remission.
Markowitz J et al. Gastroenterology. 2000119895.
18
Dosing Considerations with Thiopurines
19
AZATHIOPRINE/6-MERCAPTOPURINE
6-methyl-mercaptopurine (6-MMP)
TPMT
IMDPH GMPS
HPRT
Azathioprine 6-mercaptopurine
Thioinosinic 6-thioguanine (AZA)
(6-MP) acid
(6-TG)
XO
6-thiouric acid
20
Distribution of Thiopurine Methyltransferase
Enzyme Activity in the Population
of Subjects/0.5 units of Activity

• 12

TPMTH TPMTH
10
8
TPMTL TPMTH
6
4
TPMTL TPMTL
2
0
0
5
10
15
20
Erythrocyte TPMT Activity (U?mL-1)
Weinshilboum. Am J Hum Genet. 1980
21
Early Evidence with Allopurinol
HEPATOXICITY
6-MMP??
HPRT,IMDPH,GMPS
??ACTIVITY
6-MP 6-TG
X0
6-thiouric
INACTIVE
Sparrow Hanauer DDW 2005
22
CONTROVERSIES REGARDING THERAPEUTIC DRUG
MONITORING

• No Prospective Data
• Time Course to AZA/6-MP Activity gt 8-12 weeks
• Sandborn I.V. Loading trial
• Mechanisms of Action of 6-MP?
• Relationship of 6-MMP to Bone Marrow ?
• Also of 6-Thioguanine to Bone Marrow ?
• Cost Effectiveness vs. Clinical Monitoring with
  WBC

23
Indications for Therapeutic Monitoring

• Primary Dosing Regimens
• Aim for target levels
• Expensive
• Assessment of Non-Responders or Elevated
  Transaminases
• Consistent with current practices
• May be more cost-effective
• Assessment of Adherence
• Pediatrics

24
SUMMARY

• Pharmacogenitic Considerations are Important for
  IBD Therapeutics
• Therapeutic Drug Monitoring May Offer
  Improvements If
• Prospectively Demonstrated
• Superior Safety and Efficacy to Clinical and
  Routine Laboratory Monitoring

25
Optimizing Dose of ThiopurinesConsider
Pharmacology TPMT Status

• TPMT Homozygotes
• Start very low (e.g. 25 mg, 2-3 times/week)
• TPMT Heterozygotes
• Start low dose (1 mg/kg)
• TPMT Normal
• Start 2.5 mg/kg
• TPMT High (abnormal LFTs, ?6MMP)
• Consider reducing dose adding allopurinol

26
Methotrexate Maintenance after Steroids in
Crohns Disease
100 90 80 70 60 50 40 30

• Multicenter, randomized, controlled trial
• 76 steroid-dependent patients
• In remission following methotrexate 25 mg IM x
  16 weeks
• Randomized to 15 mg IM or placebo x 40 weeks

n40
Remission
65
n36
Methotrexate Placebo
39
0 4 8 12 16 20 24 28
32 36 40
Weeks since randomization
Feagan B, et al. N Engl J Med 2000.
27
Yin Yang of Concomitant Immunomodulators

• All biologics are immunogenic
• Antibodies (at least to infliximab)
• Associated with acute/delayed infusion reactions
• Shorter duration of response (with episodic
  therapy)
• Immunomodulators reduce immunogenicity across all
  trials

• Yet
• No difference in short- or long-term responses to
  induction maintenance therapy
• Increase toxicity
• Serious infections
• Risk of neoplasia

28
Do Concomitant Immune-modulators Improve Efficacy
of Infliximab in CD and UC?
IMM
IMM -
Ulcerative colitis
patients
ACT I 54 wk Response
ACT I 54 wk Remission
ACT I 54 wk Hosp
ACT II 30 wk Response
ACT II 30 wk Remission
ACT II 30 wk Hosp
All p-values NS
Crohns disease
patients
ACCENT I 54 wk Response
ACCENT I 54 wk Remission
ACCENT I 54 wk Hosp
ACCENT II 54 wk Response
ACCENT II 54 wk Response
Lichtenstein GR, et al. DDW 2007. 982
29
ACCENT I II Comparable clinical outcomes /-
immunomodulators (IMM)
ACCENT I
Patients ()
OR 1.53
Response
Remission
Patients ()
ACCENT II
Maintenance of fistula closure

• Concomitant IMM in patients receiving scheduled
  maintenance IFX therapy
• does not improve clinical outcomes over 54 weeks
• should be considered optional for IBD

Lichtenstein et al, Gastroenterology 2007 132
A-146 (No. 982)
30
Concomitant Immunomodulators Do Not Improve the
Clinical Outcomes of IFX Maintenance Therapy
Clinical Remission (all PNS)
Percentage of Patients
Clinical response ACT I/IIdecrease in Mayo
score (30 and 3 points) and a decrease in
rectal bleeding score (1 or a score of 0 or 1 at
Week 8) ACCENT Iimprovement of 70 points in
CDAI score and 25 improvement in CDAI score.
Lichtenstein GR, Diamond RH, Wagner C, et al.
Gastroenterology. 2007132A-146. Abstract 982
31
CHARM Concomitant adalimumab and
immunosuppressive therapy DO NOT impact on
remission at week 56
Patients in remission ()
Placebo
100
Adalimumab 40 mg EOW, sc
Adalimumab 40 mg q-weekly, sc
50
39
37
33
13
12
0
131 136 121 39 36
36
Without IMM
With IMM
Week 56
Remission defined as CDAI lt150
Colombel et al, Gastroenterology 2007 132 52
32
PRECiSE 2 Concomitant certolizmab pegol and
immunosuppressive therapy DO NOT impact on
Clinical response at week 26
0
Patients ()
100
Certolizumab pegol (3 injections) placebo


64
61
Certolizumab pegol q-4w 400 mg, sc
39
33
0
(n86) (n87)
(n124) (n128)
With IMM
Without IMM
plt0.001 CR100
Schreiber et al, N Engl J Med 2007 357 239
33
ENACT-2 Concomitant immunosuppressive DO NOT
impact on Remission at 6 or 12 Months
P0.009 for all comparisons with placebo
Placebo
Natalizumab
(60)
(62)
(111)
(106)
(60)
(62)
(111)
(106)
- IMM
- IMM
IMM
IMM
Month 12
Month 6
Sandborn W, Colombel J-F, Enns R, et al.
Presented at DDW 2006 May 20-25, 2006 Los
Angeles, CA.
34
COMMITT MTX plus IFX in CD (1)

• Methods
• Randomized, double blind, PBO-controlled trial
• Patients with active CD on corticosteroids within
  last 6 weeks
• 11 randomization to
• IFX PBO (n63)
• IFX MTX (dose escalation 10 mg,10 mg, 20 mg,
  25 mg) (n63)
• Steroids withdrawn by Week 14 per protocol
• IFX at 0, 2, and 6 weeks then maintenance q8W
• Primary analysis time to treatment failure
• CDAI lt150, no prednisone by Week 14 and
  maintained to Week 50
• Relapse CDAI increase of 70 points

Feagan B, et al. DDW 2008 682C
35
COMMITT MTX plus IFX in CD (2)
p0.83
p0.63

• No difference in ITT analysis, duration of
  disease lt2 years, by CDAI score
• No difference in infectious AEs (58.7 MTX vs
  61.9 PBO)

Feagan B, et al. DDW 2008 682C
36
What about stopping Immunomodulators?
37
IMID Impact of Concomitant Immunosuppression on
the Outcome of Maintenance Infliximab Therapy
Week 104
Randomization (N80)
Continued IMM (n40)
Discontinued IMM (n40)
Patients treated with AZA, 6-MP, or MTX plus IFX
5 mg/kg and in clinical remission for 6 months
Percentage of patients requiring a change in IFX
dosing or who discontinued IFX
6-MP6-mercaptopurine AZAazathioprine
IFXinfliximab IMMimmunomodulator therapy with
AZA, 6-MP, or MTX MTXmethotrexate Van Assche
G, Paintaud G, Magdelaine C, et al.
Gastroenterology. 2007132A-103. Abstract 734
38
IMID Impact of Concomitant Immunosuppression on
the Outcome of Maintenance Infliximab Therapy
No need for early rescue IFX primary endpoint
Median IFX levels, Week 8 to Week 104 combined
Cumulative survival
IFX trough levels (µg)
1.0
100
plt0.005
Log Rank (Cox) 0735 Breslow 0.906
0.8
0.6
10
0.4
Continued Discontinued
0.2
1
0.0
0
0
20
40
60
80
100
Continued
Discontinued
Time (weeks)
Van Asche et al, Gastroenterology 2007 132
A-103 (No. 734)
39
Risks Associated With Long-term Use of
Immunosuppressants (AZA/6-MP)1,2

• Overall toxicity 15
• Pancreatitis 3.3
• Bone marrow depression (leukopenia) 2-5
• Allergic reactions 2
• Drug hepatitis 0.3
• Infectious complications 7.4
• Malignant neoplasm 3.1
• Opportunistic infections
• Lymphoma
• Associated with fourfold increase in risk of EBV
  () lymphoma and prior treatment with AZA/6-MP
• 1 additional lymphoma will occur every 300 to
  4,500 years after therapy with AZA or 6-MP,
  depending on patient age
• Consistent with RA reports

Lymphoma Occurrence in IBD Patients Increased in
the 8-year Period After Introduction of AZA and
6-MP
Patients ()
EBVEpstein-Barr virus
Lag time observed between AZA/6-MP treatment and
lymphoma development (median, 3.5 years)
1. Present DH, Meltzer SJ, Krumholz MP, et al.
Ann Intern Med. 1989111641-649. 2. Dayharsh
GA, Loftus EV Jr, Sandborn WJ, et al.
Gastroenterology. 200212272-77.
40
Ex from Risk Factors for Opportunistic
Infections in IBD A Case-Control Study of 100
Patients (1998-2003)
Opportunistic infections and anti-TNF therapies

Odds Ratio (95 CI) Odds Ratio (95 CI) P value
Any medication (5-ASA, AZA/6MP, Steroids, MTX, Infliximab) 3.50 (1.98-6.08) lt0.0001
5-ASA 0.98 (0.61-1.56) 0.94
Corticosteroids 3.35 (1.82-6.16) lt0.0001
AZA/6MP 3.07 (1.72-5.48) 0.0001
MTX 4.00 (0.36-4.11) 0.26
Infliximab 4.43 (1.15-17.09) 0.03
One medication 2.65 (1.45-4.82) 0.0014
Two medications 9.66 (3.3128.19) lt0.0001
Toruner M, et al. Gastroenterol. 2008.
41
Infliximab Azathioprine in Patients WithActive
Steroid Dependent Crohns Disease

• 115 pts active CD (CDAI gt150) despite treatment
  with prednisone ?10 mg/d for ?6 mo
• Stratified for pre-study use of AZA/ 6-MP for gt 6
  mo, or no prior AZA/6-MP
• All treated with AZA 2 to 3 mg/kg or 6-MP 1 to
  1.5 mg/kg
• Randomized to infliximab 5 mg/kg or placebo at 0,
  2, 6 weeks
• Steroids systematically tapered
• Primary endpoint clinical remission off
  steroids at Week 24
• No difference in outcome for AZA/6-MP treated
  and naive patients

Plt0.001
P0.003
P0.04
Lemann. Gastroenterology. 2006
42
Conventional Treatment of UC Immunomodulators

• Immunomodulators are effective for maintenance of
  remission, but not induction
• Blinded, controlled clinical trial data are
  limited compared to CD

43
AZA Withdrawal in Patients With UC Who Required
AZA to Achieve Remission
P.04
N79
Randomized controlled trial of patients who had
been receiving AZA for ?6 months
Hawthorne AB et al. BMJ. 199230520.
44
AZA vs 5-ASA for Steroid-Dependent, Active UC
P.006

N72
Defined as clinical remission (Powell-Tuck Index
Score of 0) and endoscopic remission (Baron Index
Score ? 1) plus steroid discontinuationPatients
treated with concurrent tapering dose of
steroids 0.8 g at breakfast and lunch and 1.6 g
at dinner
Ardizzone S et al. Gut. 20065547.
45
Conventional Treatment CsA

• CsA is effective for induction of remission in
  severe UC
• CsA has demonstrated little efficacy for
  maintenance of remission
• Use is limited due to significant safety concerns

46
Intravenous CsA Severe Active
Steroid-Refractory UC
Plt.001

N20 Lichtiger score lt10 points for 2
consecutive days
Lichtiger S et al. N Engl J Med. 19943301841.
47
CsA Use in Acute UC Long-Term Experience
Campbell S et al. Eur J Gastroenterol Hepatol.
20051779.
48
Avoidance of Colectomy with Azathioprine After
CYSA Induction
Probability of Avoiding Colectomy
Cohen, Stein, Hanauer. Am J Gastroenterol
199994(6)1587-1592
49
Cyclosporine as a Bridge to Azathioprine
Maintenance in UC

• Study No. CYA Initial Sustained
  Sustained Dose Response
  Response Response
• on AZA
  no AZA
• Fernandez 13 4 mg/kg IV 12/13
  7/8 1/4
• Ramkrishna 6 1-2 mg/kg IV
  5/6 4/5 0/1
• Cohen 42 4 mg/kg IV
  36/42 20/25 6/11
• Rowe 36 2.5 mg/kg IV
  26/36 7/19 5/7
• Stack 22 4 mg/kg IV
  20/22 7/10 5/10
• 
  ____ ___ ___
• 99/119(83) 45/67(67)
  17/33(51)

50
Cyclosporine Use in Acute Ulcerative Colitis
Long-Term Experience
142 patients with severe acute UC treated with IV
CyA 118 (83) responded 44 patients (31) were on
AZA, 74 (52) were started de novo At 1 year,
23/44 (52) of patients on AZA required
colectomy compared with 12/74 (16) starting AZA
Year 1 2 3 4 5 6 7
Percent without colectomy 67 57 48 41 31 16 12
Percent in remission 41 35 25 18 12 8 6
Moskowitz. Gastroenterology 2005 Abstract
51
Should Biologics be used Earlier in IBD?

• Anti-TNF is more efficacious than conventional
  therapies
• Anti-TNFs are safer than conventional therapies
  (Corticosteroids)
• May be more cost-effective (over time) than
  conventional therapies

• Conventional Therapies Induce/Maintain Remissions
  in majority of patients
• Majority of patients do not need cost/toxicity
  risks of biologics
• Long-term safety experience in children
  pregnancy
• Can we transition back to conventional immune
  modulators as in RA?

52
When to Introduce Biologics?

• The Tipping Point may be Corticosteroids?

53
Challenges of Induction?Maintenance
2008Consider the Population

• Steroid-Naïve
• Steroid-Induction?
• Thiopurine/MTX Maintenance
• Anti-TNF Induction?
• Thiopurine/MTX Maintenance

54
Challenges of Induction?Maintenance
2008Consider the Population

• Steroid-Dependent
• Thiopurine/MTX Maintenance

Failure Biologic
55
Challenges of Induction?Maintenance
2008Consider the Population

• Steroid-Refractory
• Immunosuppressive naïve
• Anti-TNF induction? Thiopurine/MTX Maintenance?

• Steroid-Refractory
• Despite Immunosuppressive
• Anti-TNF induction Maintenance
• Stop Immunosuppressive

Fail Anti-TNF Switch
Fail Switch or Natalizumab
56
SummaryImmunosuppressives in IBD

• Most Effective as Maintenance Therapies
• After Steroids
• After Biologics
• After Cyclosporine (UC)
• Early Aggressive Therapy is most effective
• Optimal Dosing for Thiopurines Remains to be
  Established
• Consider Pharmacogenomics
• Role for Methotrexate Continues to Evolve
• Cyclosporine for Severe/Fulminant UC
• Monotherapy with Biologics appears effective and
  safe