1

Unconventiional Therapies: What to do when all else

fails?

Scott Plevy, MD

Associate Professor of Medicine, Microbiology & Immunology

UNC School of Medicine

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!

6-MP/AZA Non-Response6-MP/AZA Non-Response

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

Xanthine Oxidase Inhibition for Preferential 6-MMP Metabolism

6-thiouric acid

6-MPHPRT

6-TGNs

XO

TPMT

6-MMP

AZA

X

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

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?

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

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

Indications for Surgery:Not So Unconventional

Failure of medical therapy

Recurrent obstruction

Perforation

Fistula or abscess

Hemorrhage

Growth retardation (children)

Carcinoma

Unconventinal Unconventinal ImmunotherapiesImmunotherapies

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

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

Tacrolimus in Refractory UC: Clinical Improvement at 2 Weeks

Cochrane Database Syst Rev. 2008 16;(3):CD007216.

Tacrolimus in Refractory CD: Tacrolimus in Refractory CD: Level III EvidenceLevel III Evidence

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

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

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

ProblemsProblems

Access/Cost/CopaysAccess/Cost/Copays Adverse eventsAdverse events

Daily injectionsDaily injections Bone pain/intolerabilityBone pain/intolerability

No maintenance strategyNo maintenance strategy

An FDA approved option for An FDA approved option for severe refractory CD?severe refractory CD?

BrainBone marrow Gut

MadCAM-1

a4b7

VCAM-1

a4b1

endothelium

leukocyte

integrins

addressins

natalizumab

Vedolizumab, rhuMab-beta7

natalizumab

PF-00547659

Kidney, Skin

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

• 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

Off label therapies in late Off label therapies in late phase IBD studiesphase IBD studies

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

Sandborn W, et al. N Eng J Med. 2012; 367:1519-1528.

Ustekinumab induction and maintenance therapy in refractory Crohn's disease

Problems• Access/Cost/Copays

• Doses approved in psoriasis are likely to be far lower with less frequent administration than will be effective in CD

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

Sandborn WJ, et al. N Engl J Med. 2012;367:616-624.

Tofacitinib in Active Ulcerative Colitis

Problems• Access/Cost/Copays• Adverse events

– Immunosuppression– Lipid abnormalities

• No efficacy signal in CD

What our patients want us to What our patients want us to tell them workstell them works

Balance between detrimental and beneficial gut bacteria

Injurious Pro-inflammatory

Lactobacillus sp.Bifidobacterium sp.

Non-pathogenic E. coliSaccharomyces boulardii

Bacteroides thetaiotaomicron

ProtectiveProbiotic

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.

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.

Take Home Point #2Take Home Point #2

Consider Clinical TrialsConsider Clinical Trials

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

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!