Celiac Disease and Associated Conditions Celiac Disease and the Treatments of the Future

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Celiac Disease and Associated ConditionsCeliac
Disease and the Treatments of the Future
Celiac Disease More Than a Gut Reaction Canadian
Celiac Association Calgary Chapter Calgary
October 25th 2008

• Alessio Fasano, M.D.
• Mucosal Biology Research Center and
• Center for Celiac Research
• University of Maryland School of Medicine

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Celiac Disease RoadmapWhere we are coming from?
Where are we going?
Years
2.5 M
The Human race appears on the face of hearth
Diet
Fruits, nuts, tubers Occasional meat
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Celiac Disease RoadmapWhere we are coming from?
Where are we going?
Years
Something Extraordinary Happened
2.5 M
The Human race appears on the face of hearth
Change from nomadic to settled life style
Diet
Human Evolution?
Fruits, nuts, tubers Occasional meat
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If women ruled the world?!  For those who used to
watch the caveman dragging his woman by her hair,
this would come as a surprise. However, new
theories suggest that women are, and have been,
ruling the world in their own way -)
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How The Human Race Evolved From Hunting to
Agriculture?
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How Agriculture Evolved? Serendipity 1 The Place
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How Agriculture Evolved? Serendipity 2 The Catch
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How Agriculture Evolved? Serendipity 3 The
Woman Brain in Action
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Making Bread in Egypt
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Adam and Eve in the Garden of Even
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Spreading of Agriculture and Celiac Disease
2 Catalhuyuc, The first town in the world was
built 9,000 y ago
1 Cereals domestication started 10,000 years ago
in the Fertile Crescent
INVERSE RELATIONSHIP BETWEEN CD FREQUENCY AND
LENGHT OF TIME SINCE THE INTRODUCTION OF
AGRICOLTURE ?
4 CD genes confer disadvantage in
areas of high cereal consumption
3 Agricolture slowly spread with a East-West
gradient (1 Km/y)
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Celiac Disease RoadmapWhere we are coming from?
Where are we going?
Years
2.5 M
The Human race appears on the face of hearth
Diet
Gluten free products
Fruits, nuts, tubers Occasional meat
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Celiac Disease A New Paradigm of Autoimmune
Disease Normal small bowel
Celiac Disease
Gluten
Gluten-free diet
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Associated Conditions
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Associated Conditions

• The prevalence of Celiac Disease is higher in
  patients who have the following
• Certain genetic disorders or syndromes
• Other autoimmune conditions
• Relative of a biopsy-proven celiac

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Genetic Disorders

• Down Syndrome 4-19
• Turner Syndrome 4-8
• Williams Syndrome 8.2
• IgA Deficiency 2-3
• Can complicate serologic screening

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Prevalence of Celiac Disease is Higher in Other
Autoimmune Conditions

• Type 1 Diabetes Mellitus 3.5 - 10
• Thyroiditis 4 - 8
• Arthritis 1.5 - 7.5
• Autoimmune liver diseases 6 - 8
• Sjögrens syndrome 2 - 15
• Idiopathic dilated cardiomyopathy 5.7
• IgA nephropathy 3.6

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Treatment
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Treatment

• Only treatment for celiac disease is a
  gluten-free diet (GFD)
• Strict, lifelong diet
• Avoid
• Wheat
• Rye
• Barley

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Dietary AdherenceA Common Problem

• Only 50 of Americans with a chronic illness
  adhere to their treatment regimen including
• diet
• exercise
• medication
• Dietary compliance can be the most difficult
  aspect of treatment

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Barriers to Compliance

• Social Events Not wanting to look/be different
• Support of Family and Friends Just a little
  bit it wont hurt you
• Feelings of deprivation
• Fear generated by
• inaccurate information

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The Future in CD is Coming

• Prevention
• Treatment

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Prevention
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Gluten introduction N678
Group A N345
Group B N333
6 months
12 months
18 months
24 months
30 months
36 months
Stool C Celiac S IPT zonulin
Stool C Celiac S IPT Zonulin Phone call
Stool C Celiac S IPT Zonulin Phone call
Celiac S IPT Zonulin Phone call
Celiac S IPT Zonulin Phone call
Celiac S IPT Zonulin Phone call
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Age at Gluten Introduction and Risk of CD
Development
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Alternative Treatments
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The Proper Recipe for Drug Development
Biotech Company
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Drug Development Pipeline
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Current ClinicalTrials in CD www.clinicaltrials.go
v (Updated September 18th, 2008)
Registered Clinical trials 19
Treatment alternative To GFD 11
Others (diagnosis, co-morbidities, etc) 8
Treatment 8 ( technologies 4)
Prevention 3
Active 5
Completed 3
Alvine Pharmaceuticals ALV003 2 Trials
Alba TherapeuticsAT1001 2 Trials
ChemoCentryx CCR9 antagonist 1 Trial
Princess Alexandra Hospital, Brisbane,
AustraliaInoculation Hookworm N. Americanus 1
Trial
Alba TherapeuticsAT1001 2 Trials
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Prevention Future Directions
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CCR9 Inhibitor
X
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What is so Special About Gluten?
Gluten (gliadinglutenin)
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Proline Prolyl Endopeptidases
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Peptide-Based Vaccine
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Zonulin Inhibitor
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The Paracellular Pathway
Tight junctions are a dark horse implicated in
a host of disease states, ranging from acute
injury to chronic inflammation and autoimmune
diseases
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Absorption of gluten peptides Mission Impossible
Environment
Barrier impermeable to macromolecules
Gene load
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Novel Paradigm for Autoimmunity
Autoimmune diseases involve a miscommunication
between innate and adaptive immunity

• A third key element necessary to develop
  autoimmunity is the loss of the mucosal barrier
  function, so allowing the interplay between genes
  and environment.

Fasano A. Shea-Donoue T. Nat Clin Pract
Gastroenterol Hepatol. 20052416-22
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Prove of Concept onAlternative Treatmentsof
Autoimmune Diseases
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AT-1001, the Zonulin Inhibitor
Di Pierro et al, J Biol Chem 200127619160-5.
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Clinical Trial AT1001 Phase IIaSigns and
Symptoms of Gluten Toxicity
Aggregated Groups, Intent-to-treat Population n86
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P-value Fishers Exact Test
60
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Subjects with Gluten Toxicity
p0.008
p0.001
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0
Active Treatment
Gluten Challenge
Gluten Placebo
(P/P 8mg/P)
(0.25/1/4/8mg Gluten)
Symptoms of Gluten Toxicity Dermatitis
Herpetiformis, diarrhea, elevated LFTs,
nausea gas, abdominal pain, aphthous ulcers and
dyspepsia
Leffler D. et al DDW 2008
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Drug Development Pipeline
IIa
IIb
Pivotal 1
Pivotal 2
Pre-clinical
Phase I
Phase II
Phase III
? 5 yr
? 2 yr
? 3 yr
? 4-5 yr
?15 yr
0
Product pipeline
200
100
50
20
2-3
1000
NexPep (Vaccine)
Prin. Alexandra Hospital (Hookworm)
Alvine Pharmaceuticals (ALV003)
ChemoCentryx (CCX-282-B)
Alba Therapeutics (AT1001)