Diet Isn t Working, We Need to Do Something Else

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1 Diet Isn t Working, We Need to Do Something Else Ciarán P Kelly, MD Celiac Center Beth Israel Deaconess Medical Center & Celiac Program Harvard Medical School Boston Gluten Free Diet (GFD) Very good but far from perfect GFD a major breakthrough in therapy: Has improved countless lives Is generally effective in most patients Is generally safe for long term therapy Potential for nutritional deficiencies Tolerability varies Difficult to maintain 2 Rubio-Tapia et al. ACG Clinical Guidelines. Am J Gastroenterol 2013;108:

2 Do we need non-dietary treatments for Celiac Disease? Limitations of the GFD: Many (most) suffer episodic symptom recurrences ~10% chronically non-responsive to GFD 1 to 2% Refractory celiac disease ~ 30% of adults on GFD for 5 years have ongoing partial villous atrophy on biopsy 3 Rubio-Tapia et al. ACG Clinical Guidelines. Am J Gastroenterol 2013;108: Non-responsive Celiac Disease Ongoing symptoms, signs or lab. abnormalities consistent with active CD despite > 6 (or 12?) months of GFD 10% of celiac disease patients WHY? Not celiac disease Not really on a gluten free diet Not just celiac disease (second diagnosis) Not gluten sensitive (refractory) Rubio-Tapia et al. ACG Clinical Guidelines. Am J Gastroenterol 2013;108:

phase 5 Complete Intestinal Healing is Not Uniform on GFD Normal Abnormal 2/3 have ongoing villous

3 80% of Celiac Disease subjects in a recent study reported symptoms on the GFD 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% CLIN (Alba) n= 338 One week reporting period during placebo run-in phase 5 Complete Intestinal Healing is Not Uniform on GFD Normal Abnormal 2/3 have ongoing villous atrophy after 2 years on GFD 1/3 have ongoing villous atrophy after 5 years on GFD Rubio-Tapia AJG

A strict GFD is difficult to maintain 7 At social events For food

Take-out For the elderly For the illiterate For those with mental or

Sanders JGLD 2011 70% of Celiac Disease Subjects Have Known Gluten

consumption (n=269) Hall NJ, Rubin GP, Charnock A, Intentional and

4 A strict GFD is difficult to maintain 7 At social events For food prepared outside the home When traveling In restaurants & cafeterias Take-out For the elderly For the illiterate For those with mental or psychological impairment For those of limited means (expensive) Sanders JGLD % of Celiac Disease Subjects Have Known Gluten Exposures on GFD Reported intentional and inadvertent gluten consumption (n=269) Hall NJ, Rubin GP, Charnock A, Intentional and Inadvertent Non Adherence in Adult Coeliac Disease. A Cross-Sectional Survey Appetite 68:56-62,

Gluten where will it hide next? Toothpaste Envelope gum Lipstick Candy Flavorings Medications Vitamins i & supplements Safe gluten-free grains Thompson et al.

5 Gluten where will it hide next? Toothpaste Envelope gum Lipstick Candy Flavorings Medications Vitamins i & supplements Safe gluten-free grains Thompson et al. J Am Diet Assoc 2010;110:937 Low satisfaction with the GFD amongst patients with Celiac disease 10 42% 35% 23% Very poor Poor Average Good Excellent Satisfaction with GFD Sanders JGLD

9 Perceived Treatment Burden 23.5* 21.3* 56.4 41.7 38.4 31.9 40.

6 Perceived treatment burden of GFD is very high Renal disease on Hemodialysis = 56.4 Celiac disease = 44.9 Higher than: Insulin dependent diabetes Congestive heart failure Inflammatory bowel disease Irritable bowel syndrome Hypertension GERD VAS Treatment Burden Perceived Treatment Burden 23.5* 21.3* VAS: 0 = Very easy 100 = Very difficult Shah et al Am J Gastroenterol 2014 in press CD HTN GERD ESRD DM CHF IBD IBS *Compared with CD, p<0.001 Feelings of Social Isolation associated with following the GFD 12 Patient responses regarding: Social isolation Burden of requesting and explaining GFD Interferes with social interactions (we can t invite him/her needs a special diet) Market Research, Alba Therapeutics & Double Helix Homework 1: What having celiac disease means to you? 6

7 Medications are used as adjuncts to many medically prescribed diets Hypercholesterolemia Type I diabetes mellitus Type II diabetes mellitus Gastroesophageal reflux disease Obesity (surgery) 13 Sanders JGLD 2011 Survey on interest in medical therapy for celiac disease 66% were interested Factor More interested Less Interested P= Age >50 yr 71% 60% <50 yr P=0.04 Gender Male 78% 62% Female P=0.008 Restaurant use Frequent 76% 58% Not frequent P= Satisfied with No 73% 51% Yes P= weight Concerned with Yes 77% 64% No P=0.02 cost of GFD Quality of life Lower Higher P< score Tennyson et al. Ther Adv Gastroenterol 2013;6: (of 339 surveyed) Factors NOT associated: Time since diagnosis, education level, mode of presentation or symptoms with gluten exposure 7

Ciarán P. Kelly, MD, FACG Pathogenesis of Celiac Disease & Potential Sites for Intervention Wheat Barley Rye Gluten / gliadin 1. Ingested 2. Survives digestion 3.

T cells activated Inflammation Antibody production Tissue damage Farrell & Kelly N Engl J Med 2002;346:183 Pathogenesis of Celiac Disease & Potential Sites for Intervention

Taken up by antigen Tight junction modulator Larazotide acetate presenting cells (APCs) 6. Genetically encoded DQ2 or DQ8 present 7. Presented on DQ2/8 8.

8 Ciarán P. Kelly, MD, FACG Pathogenesis of Celiac Disease & Potential Sites for Intervention Wheat Barley Rye Gluten / gliadin 1. Ingested 2. Survives digestion 3. Crosses gut lining 4. Made tastier by TTG 5. Taken up by antigen presenting cells (APCs) 6. Genetically encoded DQ2 or DQ8 present 7. Presented on DQ2/8 8. T cells activated Inflammation Antibody production Tissue damage Farrell & Kelly N Engl J Med 2002;346:183 Pathogenesis of Celiac Disease & Potential Sites for Intervention Wheat Barley Rye Gluten / gliadin 1. Ingested Gluten free diet 2. Survives digestion Glutenases 3. Crosses gut lining 4. Made tastier by TTG 5. Taken up by antigen Tight junction modulator Larazotide acetate presenting cells (APCs) 6. Genetically encoded DQ2 or DQ8 present 7. Presented on DQ2/8 8. T cells activated Inflammation Antibody production Tissue damage Induce immune tolerance / desensitization Anti-inflammatory: Steroid prednisone, budesonide Mesalamine Immune modulation AZA, anti-il-15 Farrell & Kelly N Engl J Med 2002;346:183 8

GLUTEN IN DIET Gluten Resistant to Digestion New medications being tested in celiac

substances between cells Glutenase Digestion No Gluten Reaction ALV-003 (Alvine)

Larazotide acetate (Alba) Controls tight junctions - Completed Phase 2b Diet isn t

definitive therapy Continued symptoms on GFD common Continued histologic abnormality with

maintain Many patients with celiac disease are not satisfied with treatment by the GFD

9 GLUTEN IN DIET Gluten Resistant to Digestion New medications being tested in celiac disease 17 Celiac Patient Gluten Reaction Luminal surface Enterocytes Movement of substances between cells Glutenase Digestion No Gluten Reaction ALV-003 (Alvine) Glutenase enzymes - In Phase 2b Basolateral surface Tight Junction (the gate or gasket ) Larazotide acetate (Alba) Controls tight junctions - Completed Phase 2b Diet isn t working, we need to do something else: Summary 18 GFD very valuable but not always definitive therapy Continued symptoms on GFD common Continued histologic abnormality with villous atrophy also common despite many years on GFD GFD is burdensome and difficult to maintain Many patients with celiac disease are not satisfied with treatment by the GFD would use new treatments if available Development of non-dietary therapy for celiac disease is warranted and is finally underway 9

Current Management of Celiac Disease and Identifying an Appropriate Patient Population(s) for Pharmacologic Therapies in Adult Patients

Current Management of Celiac Disease and Identifying an Appropriate Patient Population(s) for Pharmacologic Therapies in Adult Patients Joe Murray The Mayo Clinic 1 DISCLOSURES Relevant Financial Relationship(s)