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1
Unconventiional Therapies: What to do when all else
fails?
Scott Plevy, MD
Associate Professor of Medicine, Microbiology & Immunology
UNC School of Medicine
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Take Home Point #1Take Home Point #1
Evaluate the patient and Evaluate the patient and figure out why conventional figure out why conventional
therapies aren’t working!therapies aren’t working!
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6-MP/AZA Non-Response6-MP/AZA Non-Response
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Clinical ScenariosClinical Scenarios
Primary AZA non-responsePrimary AZA non-response Allopurinol?Allopurinol?
Addition of AZA to anti-TNF Addition of AZA to anti-TNF failurefailure
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Xanthine Oxidase Inhibition for Preferential 6-MMP Metabolism
6-thiouric acid
6-MPHPRT
6-TGNs
XO
TPMT
6-MMP
AZA
X
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Preferential 6-MMP Metabolism Preferential 6-MMP Metabolism Allopurinol Therapy Allopurinol Therapy
Preallopurinol Postallopurinol
Sparrow MP et al. Aliment Pharmacol Ther. 2005;22:441.Allopurinol 100 mg added; 6-MP/AZA dose reducedto 25% to 50% of baseline
0
50
100
150
200
250
300
350
400
450
6-TG
0
2000
4000
6000
8000
10000
12000
6-MMP
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ProblemsProblems
Marrow suppressionMarrow suppression Primary AZA non-responsePrimary AZA non-response
Allopurinol?Allopurinol?• Not as a anti-TNF sparing strategyNot as a anti-TNF sparing strategy• Consider MTX with anti-TNFConsider MTX with anti-TNF• Perhaps after anti-TNF failure as monotherapyPerhaps after anti-TNF failure as monotherapy
Addition of AZA (or MTX) to anti-TNF Addition of AZA (or MTX) to anti-TNF failurefailure No dataNo data Too little too late?Too little too late?
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Response to Sequential TNF Response to Sequential TNF Inhibitors in Rheumatoid ArthritisInhibitors in Rheumatoid Arthritis
ThirdThird
FirstFirst
SecondSecond
Analysis time Analysis time (years)(years)
Gomez-Reino et al. Arthritis Research & Therapy. 2006;8:R29Gomez-Reino et al. Arthritis Research & Therapy. 2006;8:R29
0.000.00
0.250.25
0.500.50
0.750.75
1.001.00
00 0.50.5 11 1.51.5 22
PP=0.007=0.007
Replaced for other causesReplaced for other causes
Replaced for adverse eventsReplaced for adverse events
0.000.00
0.250.25
0.500.50
0.750.75
1.001.00
00 0.50.5 11 1.51.5 22
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Treatment Algorithm in IBD Patients With Clinical Symptoms
(Infliximab and ATI Concentrations)
1 >12 mcg/mL at 4 weeks or detectable trough level; patients should have endoscopic or radiologic imaging
Positive ATI
Change to another anti-TNF agent
Change to non-anti-TNF agent
persistent disease
Increase infliximab dose or
frequency
Change to non-
anti-TNF agent
Change to different anti-TNF
agent
Change to different anti-TNF
agent
Subtherapeutic IFX concentration1
Therapeutic IFX concentration1
Active disease on endoscopy/radiology?
Change to different anti-TNF
agent
Investigate alternate etiologies
yes no
Afif W, et al. Am J Gastroenterol 2010;105:1133-9. 9
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Indications for Surgery:Not So Unconventional
Failure of medical therapy
Recurrent obstruction
Perforation
Fistula or abscess
Hemorrhage
Growth retardation (children)
Carcinoma
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Unconventinal Unconventinal ImmunotherapiesImmunotherapies
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Cyclosporine:Cyclosporine:Limited Efficacy in Crohn’s DiseaseLimited Efficacy in Crohn’s Disease
Therapeutic gain (%)Therapeutic gain (%)
-30 -25 -20 -10 -5 0 5 10 20 30 50
Cyclosporineineffective
Cyclosporineeffective
Byrnskov (7.6 mg/kg)
Anglo/Irish (5 mg/kg)
CCRPT (4.8 mg/kg)
European Multicentre (5 mg/kg)
40
CCRPT, Canadian Crohn’s Relapse Prevention Trial Feagan et al, Inflammatory Bowel Dis 1995; 1: 335
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Cyclosporine A for IV Steroid Refractory UC: At Least There’s Evidence
Lichtiger et al, N Engl J Med 1994; 330: 1841
Steroid-resistant(n=20)
Placebo(n=9)
Cyclosporine(n=11)
Failed(n=9)
Colectomy(n=4)
Cyclosporine(n=5)
Improved(n=5)
Improved(n=9)
Failed(n=2)
Colectomy
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Tacrolimus in Refractory UC: Clinical Improvement at 2 Weeks
Cochrane Database Syst Rev. 2008 16;(3):CD007216.
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Tacrolimus in Refractory CD: Tacrolimus in Refractory CD: Level III EvidenceLevel III Evidence
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ProblemsProblems
Adverse eventsAdverse events ImmunosuppressionImmunosuppression NephrotoxicityNephrotoxicity
No efficacy signal in CDNo efficacy signal in CD Stil need to think about exit Stil need to think about exit
strategiesstrategies
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Sargramostim*Sargramostim*
GM-CSFGM-CSF Hematopoietic factor that Hematopoietic factor that
stimulates cells of intestinal innate stimulates cells of intestinal innate immune systemimmune system
Modulation of the initial phase of Modulation of the initial phase of antigen processing and stimulationantigen processing and stimulation
Korzenik J et al. N Engl J Med. 2005;352:2193.*GM-CSF=granulocyte-macrophage colony-stimulating factor
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Sargramostim in moderate to Sargramostim in moderate to severe CD: n.o.v.e.l 4severe CD: n.o.v.e.l 4
286 patients mod-severe 286 patients mod-severe disease (CDAI 220–475)disease (CDAI 220–475)
Randomized 2:1 Randomized 2:1 (SS 6 (SS 6 μμg/kg:placebo)g/kg:placebo)
Primary endpoint: Primary endpoint: response ∆ CDAI 100 at response ∆ CDAI 100 at Week 8Week 8
Secondary endpoint: Secondary endpoint: CDAI remission at Wk 8CDAI remission at Wk 8
25% drop out by Week 825% drop out by Week 8
41.1
22.3
33.3
22.6
0
5
10
15
20
25
30
35
40
45
Response Remission
SS Placebo
Pat
ient
s (%
)
NS
NS
Feagan BF, et al. DDW 2007. #737
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ProblemsProblems
Access/Cost/CopaysAccess/Cost/Copays Adverse eventsAdverse events
Daily injectionsDaily injections Bone pain/intolerabilityBone pain/intolerability
No maintenance strategyNo maintenance strategy
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An FDA approved option for An FDA approved option for severe refractory CD?severe refractory CD?
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BrainBone marrow Gut
MadCAM-1
a4b7
VCAM-1
a4b1
endothelium
leukocyte
integrins
addressins
natalizumab
Vedolizumab, rhuMab-beta7
natalizumab
PF-00547659
Kidney, Skin
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30
22
55 55
18 18
50 50
0
10
20
30
40
50
60
Per
cen
t o
f P
atie
nts
Month 6 Month 12
P < 0.001 P < 0.001P = 0.005
P = 0.005
PlaceboNatalizumab
ENACT-2: Remission In Anti-TNF ENACT-2: Remission In Anti-TNF FailuresFailures
(171) (168) (33) (24) (171) (168) (33) (24)
Data on File Data on File
Failed TNF Failed TNFITT ITT
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• Use limited by risk of PML (total of 232 cases amongst 95,000 pts treated with natalizumab)
• Risk factors for PML:1) Longer duration of NAT treatment, >2 yrs2) Prior Immunosuppressant Use3) Positive Anti-JC Virus Serology (NEWEST) commercially available ELISA as of 2011
Estimated PML Risk on Natalizumab
Bloomgren G et al. New Engl J Med. 2012; 366(20):1870.
Estimated PML Risk on NAT (in multiple sclerosis)
Natalizumab Exposure
Anti-JCV Antibody (+)
No Prior ImmunosuppresionPrior
Immunosuppressant Use
1-24 mo 0.35/1000 2/1000
25-48 mo 4/1000 11/1000
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Off label therapies in late Off label therapies in late phase IBD studiesphase IBD studies
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Biology of Interleukins 12 and 23 Biology of Interleukins 12 and 23
CD4+
TCR
AntigenPresenting Cell
MHCII
Ag
StimulusTLR?
IFNg(Th1)
p40p35
IL-12
IL-12Rb1
b2
IL-23
p40p19
IL-17(Th17)IL-23R
IL-12Rb1
X
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Sandborn W, et al. N Eng J Med. 2012; 367:1519-1528.
Ustekinumab induction and maintenance therapy in refractory Crohn's disease
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Problems• Access/Cost/Copays
• Doses approved in psoriasis are likely to be far lower with less frequent administration than will be effective in CD
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Oral Janus Kinase (JK) Inhibitor:Rationale
Tofacitinib blocks phosphorylation of STAT and downstream activationJAK
αST
AT
STAT
mRNA
JAKPP
STAT
STAT
P
P
P
β γCytokine
Cytokine Effects on the immune system
IL-2 Stimulate the proliferation and differentiation of Th, Tc, B, and natural killer (NK) cells
IL-4 Induce the differentiation of Th0 to Th2Induce immunoglobulin switching
IL-7 Promote the development, proliferation and survival of T, B, and NK cells
IL-9 Stimulate intrathymic T cell development
IL-15 Promote the proliferation, cytotoxicity and cytokine production of NK cells
IL-21 Enhance T and B cell function
Sandborn W et al. DDW 2011
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Sandborn WJ, et al. N Engl J Med. 2012;367:616-624.
Tofacitinib in Active Ulcerative Colitis
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Problems• Access/Cost/Copays• Adverse events
– Immunosuppression– Lipid abnormalities
• No efficacy signal in CD
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What our patients want us to What our patients want us to tell them workstell them works
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Balance between detrimental and beneficial gut bacteria
Injurious Pro-inflammatory
Lactobacillus sp.Bifidobacterium sp.
Non-pathogenic E. coliSaccharomyces boulardii
Bacteroides thetaiotaomicron
ProtectiveProbiotic
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Probiotics in IBD: Systematic Reviews Induction in UC: 5 RCTsInduction in UC: 5 RCTs
““Conventional therapy combined with a probiotic Conventional therapy combined with a probiotic does not improve overall remission rates in does not improve overall remission rates in patients with mild to moderate ulcerative colitis”.patients with mild to moderate ulcerative colitis”.
Maintenance in UC: 6 RCTsMaintenance in UC: 6 RCTs ““The pooled relative risk was 1.37 (95% CI 0.62-The pooled relative risk was 1.37 (95% CI 0.62-
3.04, p=0.44) showing no significant difference 3.04, p=0.44) showing no significant difference between probiotic and control group”.between probiotic and control group”.
Induction in CD: 1 RCT (n=11)Induction in CD: 1 RCT (n=11) ““There is insufficient evidence to make any There is insufficient evidence to make any
conclusions”.conclusions”. Maintenance in CD: 7 small RCTsMaintenance in CD: 7 small RCTs
““There is no evidence to suggest that probiotics There is no evidence to suggest that probiotics are beneficial for the maintenance of remission in are beneficial for the maintenance of remission in CD”. CD”.
Zigra PI, et al. Neth J Med. 2007 ;65:411-8Butterworth AD et al. Cochrane Database Syst Rev. 2008 16:CD006634. Mallon P, et al. Cochrane Database Syst Rev. 2007 17:CD005573.Rolfe VE, et al. Cochrane Database Syst Rev. 2006 18:CD004826.
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Prospective study of 8 patients with Prospective study of 8 patients with chronic refractory pouchitis chronic refractory pouchitis Nasogastric administration of 30g fecesNasogastric administration of 30g feces Stool samples were also collected from patients for Stool samples were also collected from patients for
analysis of coliform sensitivities before and 4 analysis of coliform sensitivities before and 4 weeks after FMTweeks after FMT
• Pouch Disease Activity Index (PDAI) and Cleveland Pouch Disease Activity Index (PDAI) and Cleveland Global Quality of Life score (CGQoL ) were recorded Global Quality of Life score (CGQoL ) were recorded prior to FMT and four weeks afterwardsprior to FMT and four weeks afterwards
Results: no change in CGQoL or PDAIResults: no change in CGQoL or PDAI• 2 of 3 patients previously resistant to ciprofloxacin 2 of 3 patients previously resistant to ciprofloxacin
became responsivebecame responsive
Fecal Microbiota Transplant Is Not Fecal Microbiota Transplant Is Not Effective in Medically Refractory Effective in Medically Refractory
Chronic PouchitisChronic Pouchitis
Landy J, et al. Presented at DDW; May 21, 2013. Abstract 1985.
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Take Home Point #2Take Home Point #2
Consider Clinical TrialsConsider Clinical Trials
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Current Clinical Trials: Immunologic Interventions in IBD
• Cytokines– Anti-TNF
• Certolizumab pegol• Infliximab• Adalimumab• Golimumab
– Anti-IL-12/23• CNTO1275• J695
– Anti-IL-17 (AIN457)– Anti-IL-6 receptor– IL-6/STAT3 inhibitor– Jak3 inhibitor
• Other– Extracorporeal photopheresis– Human mesenchymal stem cells– Bone marrow/stem cell
transplatation– Estrogen receptor agonist – More
• Leukocyte adhesion/recruitment– Anti-a4 Integrin
• 683699– Anti-a4b7 (MLN0002)– Anti-b7– CCR9 antagonist (CCX-282B)– Anti-CXCL10 (MDX-1100)
• T cell activation– Anti-CD3
• NI-0401– Small molecules
• AEB071
• Innate Immunity– IFN-b1a– TLR3– TLR9– TSO
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ConclusionsConclusions
Evaluate the patient and figure Evaluate the patient and figure out why “common” therapies out why “common” therapies aren’t working.aren’t working.
Consider Clinical Trials.Consider Clinical Trials. Forget everything else I told you!Forget everything else I told you!