stopping biologics: a north american perspective? · 2016. 9. 10. · remission without biologics...
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Stopping Biologics: A North American Perspective?
Brian G. Feagan MD Professor of Medicine, Epidemiology and Biostatistics
Western Ontario Robarts Clinical Trials Inc. London, Ontario, Canada
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Financial Interest Disclosure (over the past 24 months)
Grant/Research Support Abbott, ActoGeniX, Bristol-Myers Squibb, Centocor, CombinatoRx, Elan/Biogen, Genentech, Merck, Milllennium, Novartis, Protein Design Labs, Tillotts, UCB Pharma, Wyeth,
Consultant Abbott (AbbVie), Actogenix, Albireo Pharma, Amgen, Astra Zeneca, Athersys, Avaxia Biologics Inc., Axcan, Boehringer-Ingelheim France, Bristol-Myers Squibb, Celgene, Centocor, Elan/Biogen, Ferring Pharma A/S, Genentech, GiCare Pharma, Gilead, Given Imaging Inc., GSK, Ironwood Pharma, JnJ/Janssen, Merck, Millennium, Nektar, Novonordisk, Prometheus Therapeutics and Diagnostics, Pfizer, Salix Pharma, Serono, Shire, Sigmoid Pharma, Synergy Pharma Inc., Takeda, Teva Pharma, Tillotts, UCB Pharma, Unity Pharmaceuticals, Warner-Chilcott, Wyeth, Zealand Pharm, Zyngenia
Speakers Bureau Abbott, J&J/Janssen, UCB Pharma Patent Holder Member, Scientific Advisory Board Abbott, Astra Zeneca, Celgene, Centocor Inc.,
Elan/Biogen, Merck, Novartis, Pfizer, Prometheus Laboratories, Salix Pharma, Takeda, Tillotts Pharma AG, UCB Pharma
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Topics Covered
• The value of combination therapy
• Stopping therapy: Pros vs Cons
• Lessons from RA
• Lessons from CD
• STORI
• Safety considerations
• What do I do in clinical practice?
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• Single center double-blind placebo controlled trial, n=63
• Phase 1: combined effect of prednisolone plus AZA vs placebo over 12 weeks
• Phase 2: following completion of phase 1, compared AZA vs placebo over 12 months
Candy et al. Gut 1995;37:674
Azathioprine Maintenance Therapy After Corticosteroid-Induction in Crohn's Disease
AZA 2.5 mg/kg/d Placebo
Patients on trial (%)
Months
100
80
60
40
20
0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Phase 1
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Surgery Rates for CD and the Use of Immunosuppressives over 3 Decades
Prob
abili
ty o
f Rec
eivi
ng Im
mun
osup
pres
sive
s
Cosnes J. et al. Gut 2005:54(2):237-241
Use of Immunosuppressives
0
10
20
30
40
50
60
# re
sect
ions
per
100
pat
ient
s
1978 2002 2002 1979
Surgery
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Lemann et al. Gastroenterology 2006;130:1054
Azathioprine Monotherapy vs Infliximab Plus Azathioprine in Steroid-Dependent Crohn’s Disease
Remission (CDAI<150) and off steroids (%)
AZA = Azathioprine 6-MP = 6-Mercaptopurine
38 29
75
57
0
100
Week 12 Week 24
p<0.001
p=0.003
Week 52
40
22
p=0.04
Placebo week 0, 2, 6 + AZA / 6-MP (n=58)
Infliximab 5 mg/kg week 0, 2, 6 + AZA / 6-MP (n=57)
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D’Haens et al. Lancet 2008:371:660
Early Combination Therapy vs Conventional Management of Crohn’s Disease
Early combined (n=65)
Conventional therapy (n=64)
Patients in remission without steroids or surgical resection (%)
0
100
6 months 12 months
60
35.9
61.5
42.2
*p=0.0062 **p=0.0278
* **
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D’Haens et al. Lancet 2008;371:660
Early Combination Therapy vs Conventional Management of Crohn’s Disease: Complete Ulcer Disappearance
(n=26) Early combined
(n=23) Conventional therapy
**p=0.003
Patients (%)
73
30
0
100
**
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SONIC: Clinical Remission Without Corticosteroids at Week 26
30 45
57
0
20
40
60
80
100
Prop
ortio
n of
Pat
ient
s (%
)
AZA + placebo IFX + placebo IFX+ AZA
p<0.001
p=0.009 p=0.022
52/170 75/169 96/169
Colombel et al., New England J Med 2010
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Topics Covered
• The value of combination therapy
• Stopping therapy: Pros vs Cons
• Lessons from RA
• Lessons from CD
• STORI
• Safety considerations
• What do I do in clinical practice?
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Stopping Therapy: Pros
• May not be needed for long term efficacy
• Less toxic
• More convenient
• Less costly
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Stopping Therapy: Cons
• May be less effective
• Risk of sensitization
• May not necessarily be more safe
• May lose the opportunity to change the natural history of the disease
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Topics Covered
• The value of combination therapy
• Stopping therapy: Pros vs Cons
• Lessons from RA
• Lessons from CD
• STORI
• Safety considerations
• What do I do in clinical practice ?
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The Seductive Fantasy: Long Term Remission without Biologics in Early RA
• 20 early (<12 months) poor-prognosis RA
• Randomized, double-blind controlled trial evaluating multiple regimens: MTX+PLB vs MTX+IFX – the Winner
• At 1 year, better MRI scores with no new erosions
• At 2 yrs: 1 yr after stopping IFX, 70% sustained response
Quinn et al. Arthritis Rheum 2005; 52: 27.
Clinical response at one year
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The Reality (I)
• One half of patients who were carefully monitored by a treat-to-target approach required re-introduction of treatment
• Re-introduction was unsuccessful in ~ 25% of patients
• Risk of sensitization – limited number of biologic drugs
• Can I really risk stopping in my worst patients?
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The Reality (II)
• Why should the disease go away?
• IBD results from environmental and genetic factors that you have not altered with short term therapy
• T lymphocytes are long-lived and pathogenic clones are not ablated with conventional treatments
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Topics Covered
• The value of combination therapy
• Stopping therapy: Pros vs Cons
• Lessons from RA
• Lessons from CD
• STORI
• Safety considerations
• What do I do in clinical practice?
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Months Since Randomisation!
AZA Withdrawal
Lémann M et al. Gastroenterology 2005;128:1812
Y/N*!
Placebo! 9/43!
AZA! 3/40!
Prop
ortio
n of
Pat
ient
s
in R
emis
sion
(% )
79%
92%
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AZA Withdrawal in Patients Treated With Combination Therapy
• Eighty (80) patients, 6 months treatment IFX 5 mg/kg q8+IS • Randomised (1:1) to continue or discontinue IS; 2 years follow-up • Forty-nine (49) underwent a 2 year ileo-colonoscopy
24/40 22/40 11/40 9/40 2/40 5/40
p=NS
16/25 14/23
Primary endpoint
Van Assche G et al. Gastroenterology 2008;134(7):1861-8
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Potential for Loss of Efficacy
Van Assche G et al. Gastroenterology 2008;134(7):1861-8.
After IS withdrawal:
5-15% vs 0% of patients with undetectable trough levels beyond one year
Median CRP level significantly higher (2.8 vs 1.6 mg/l; P<0.005)
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# at
risk 115 100 79 59 49 47 38 32 32 29 15
Relapse Rate after Infliximab Discontinuation
43.9% relapse at 1 year
52.2% relapse at 2 years
Louis E et al. Gastroenterology. 2012 Jan;142(1):63-70
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Predictors of Relapse
Clinical history and characteristics P value IFX frequency last 6 months 0.46
Age 0.63 Scores and biological variables P value Gender 0.22 CDAI >20 0.045
Disease duration 0.84 CDEIS ≥2 0.002
Current smoker 0.036 CDEIS >0 0.033
Previous surgery 0.07 Presence of ulcers 0.20
Disease location 0.73 ANA 0.81
A-P disease 0.17 ATI 0.39
fistula 0.12 Fecal calprotectin ≥250 microg/g 0.0001
Stricture 0.13 CRP hs ≥5 mg/l 0.0006
Previous steroid treatment 0.067 IFX trough level ≥2 micro/ml 0.25
IS naïve 0.96 ESR >16 0.16
IS type 0.12 Plt count 0.86
IS duration 0.41 WBC >6000/ml 0.08
IFX duration 0.44 Hemoglobin ≤14.5 g/dl 0.038
IFX scheduled from the start 1.00 6TGN 0.26
Louis E et al. Gastroenterology. 2012 Jan;142(1):63-70
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Predictive Model for the Time-to Relapse: Risk Factors
Louis E et al. Gastroenterology. 2012 Jan;142(1):63-70
Simplified Model: the same without steroid use, CDEIS and IFX trough levels
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Topics Covered
• The value of combination therapy
• Stopping therapy: Pros vs Cons
• Lessons from RA
• Lessons from CD
• STORI
• Safety considerations
• What do I do in clinical practice ?
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The Bottom Line on STORI
“Currently there is no good medical reason to stop IFX in patients in stable remission”
E. Louis Principal Investigator STORI, BMJ 2012
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Topics Covered
• The value of combination therapy
• Stopping therapy: Pros vs Cons
• Lessons from RA
• Lessons from CD
• STORI
• Safety considerations
• What do I do in clinical practice ?
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• Causality difficult to establish • Mayo Clinic case-control study of
opportunistic infection: – any vs no drug OR 2.6 (1.4–4.7) – infliximab OR 4.4 (1.2–17.1) – corticosteroid OR 3.4 (1.8–6.2) – azathioprine OR 3.1 (1.7–5.5) – 2 drugs OR 12.9 (4.5–37) – 3 drugs OR- infinite
Toruner et al. Gastroenterology 2008 Apr;134(4):929-36
Serious Infection in IBD: The Role of Multidrug Therapy
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AZA + placebo
n=161
IFX + placebo
n=163
IFX + AZA
n=179
Total
n=503
Mean weeks of treatment 21.1 24.1 24.8 23.4
Subjects with ≥ 1 AE, n (%) 138 (85.7%)
135 (85.3%) 156 (87.2%)
433 (86.1%)
Subjects who d/c study agent due to an AE, n (%)
37 (23%) 19 (11.7%) 25 (14.0%) 81 (16.1%)
Subjects with ≥ 1 SAE, n (%) 39 (24.2%) 26 (16.0%) 25 (14.0%) 90 (17.9%)
Subjects with ≥ 1 infection, n (%) 60 (37.3%) 58 (35.6%) 66 (36.9%) 184 (36.6%)
Subjects with ≥ 1 serious infection, n (%)
8 (5.0%) 4 (2.5%) 6 (3.4%) 18 (3.6%)
Subjects with ≥ 1 infusion rxn, n (%) 8 (5.0%) 22 (13.5%) 9 (5.0%) 39 (7.8%)
Summary of Adverse Events Through Week 30
Sandborn et al., ACG 2008 annual meeting, abstract #29
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Lichtenstein et al. Gastroenterology 2006;130:A-71 Lichtenstein et al. Gastroenterology 2007;132: A-178
Safety Data From the TREAT Registry
Cox proportional hazard regression (multivariate)
Adverse event Hazard ratio 95% CI Death
Current use of IFX Current use of AZA/6-MP/MTX Current use of GCS Current use of narcotic analgesics
1.1 0.8 2.0 2.1
0.6–1.8 0.5–1.2 1.3–3.0* 1.3–3.2†
Serious infection Current use of IFX Current use of AZA/6-MP/MTX Current use of GCS Current use of narcotic analgesics
1.4 0.9 2.0 2.2
1.0–2.1 0.6–1.3 1.4–2.9**
1.5–3.1†
6-MP = 6-mercaptopurine; AZA = azathioprine; CI = confidence interval; GCS = glucocorticoid steroids; IFX = infliximab; MTX = methotrexate
*p=0.002; **p<0.001; †p<0.0001
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A Pooled Analysis: RCTs of Infliximab in IBD
Crohn’s Disease Ulcerative Colitis All Inflammatory Bowel Diseases
Placebo Infliximab Placebo Infliximab Placebo Infliximab No. (%) pts with serious
infection 9 (5.6%) 55 (4.5%) 6 (2.4%) 26 (5.4%) 15 (3.7%) 81 (4.7%)
Incidence per 100 pt-
yrs 8.3 7.63 2.87 5.05 4.72 6.54
95% CI (3.80,15.76) (6.10,9.43) (1.05,6.24) (3.64,6.83) (2.64,7.78) (5.45,7.77)
P-value 0.547 0.085 0.427
Lichtenstein GR. Am J Gastroenterology. 2012;107(7):1051-63
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Beaugerie et al. Lancet 2009;374:1617-25
Lymphoma Risk with Thiopurines: CESAME
n =19486 exposed: 30%+14.5%
23 incident lymphomas
OR= 5.28 (2.01-13.9, p=0.0007)
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Conclusions
• Discontinuation of our most effective therapy comes at a cost of relapse
• No high quality RCTs have examined this issue in CD!
• The therapeutic index of stopping is unknown
• What do I do in practice?
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