Novita In Tema Di Alternative Alla Dieta Aglutinata

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Charles Daniels
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School Mucosal Biology and Immunology Research Center

1 Novita In Tema Di Alternative Alla Dieta Aglutinata Alessio Fasano, M.D. W. Allan Walker Chair in Pediatric Gastroenterology and Nutrition Professor of Pediatrics Harvard Medical School Mucosal Biology and Immunology Research Center And Center for Celiac Research And Treatment Massachusetts General Hospital for Children

2 Let Thy Food Be Thy Medicine Hippocrates, 400 AD Strict gluten free diet is the only accepted treatment for celiac disease The GFD is one of the more challenging treatments we assign patients Involves avoidance of all wheat, rye and barley products Less than 50 mg of gluten (1/30th of a slice of bread) can cause significant, sustained mucosal inflammation Untreated celiac disease increases risk of malignancy, infection, and results in a 2-3 fold increase in mortality GFD

3 Patient Satisfaction with the GFD is Low Controversial in the past Better scientific data and a more diverse celiac population general acceptance Satisfaction (%) to GFD Sanders JGLD 2011

4 VAS* Perceived Importance of Treatment Visual Analogue Scale Perceived Treatment Burden CD Treatment Burden Second Only to Hemodialysis CD HTN GERD ESRD DM CHF *VAS: 0=Very Easy 100=Very Difficult IBD IBS CD HTN GERD ESRD DM CHF IBD IBS *VAS: 0=Not important at all 100=Very important Shah S, Leffler DA, AJG 2014

Many Barriers to Comply to a GFD Hidden gluten/cross contamination Medications Supplements Processed meats Frozen Vegetables Soy Sauce Seasonings Drink mixes Social and professional life

5 Many Barriers to Comply to a GFD Hidden gluten/cross contamination Medications Supplements Processed meats Frozen Vegetables Soy Sauce Seasonings Drink mixes Social and professional life Psychological well-being Impact Nutritional Content Access to gluten-free foods Health concerns Cost Label reading Leffler, AP&T 2007, Leffler et al. CGH 2009, Zarkadas J Hum Nutr Dietet 2006

Beside facing the same issues that adult CD patients experience, including risk of cross-contamination

6 CURRENT MANAGEMENT: COMPLIANCE TO THE GFD One of the most challenging issues related to the treatment of CD is proper compliance to strict gluten free diet for life. Beside facing the same issues that adult CD patients experience, including risk of cross-contamination while traveling, vacationing, eating out, etc, pediatric patients have unique challenges that make the compliance to the GFD extremely difficult

7 UNIQUE CHALLENGES FOR COMPLIANCE TO THE GFD IN PEDIATRICS Birthday parties School lunch Sleepovers Peer pressure Lack of appreciation for long term consequences for specific behavior; Transitioning to college lifestyle

NJ, Rubin GP, Charnock A, Intentional and Inadvertent Non Adherence

8 70% of Celiac Disease Subjects Have Known Gluten Exposure 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, 2013

9 Variable Rates of Mucosal Healing Adapted from Alberto Rubio-Tapia

10 Age and Persistent Villous Atrophy Aliment Pharmacol Ther. 2014;39:

11 Adult Data Serology Cannot Predict Compliance or Remission Status ttg and EMA do not correlate with dietary compliance Hopper et al. 7/16 of Adult pts on a GFD >1 year Normal ttg and EMA Persistent villous atrophy Vehadi et al. AmGastro Hopper, AD et al. ClinGastroenterol Hepatol 2008.

12 Pediatric Data 73 Patients Diagnosed with CD underwent Follow-up Biopsy 19% Never had Symptoms 79% Marsh 2 or less 49% Symptomatic 33% Marsh 3 IgA ttg + 70% IgA ttg 30% 63% Marsh 2 or less 21% Marsh 3 IgA ttg + 50% IgA ttg 50% 32% Asymptomatic 78% Marsh 2 or less 22% Marsh 3 IgA ttg + 70% IgA ttg 30%

13 Follow- Up Biopsy: According to Age + Time on GFD Age <12, < 2 years on GFD N=27 Age <12, 2 or more years on GFD N=15 Age >12, < 2 years on GFD N=21 Age >12, 2 or more years on GFD N=10 Age at Diagnosis (years) (SD) 8 (2) 6 (3) 16(3) 15(3) Gender (%F) 48% 60% 67% 60% Initial Marsh Score of 3 100% 100% 100% 100% Initial ttg positive 96% 93% 100% 90% Time on a Gluten Free Diet (months) (SD) 21(11) 75 (32) 6 years 17(9) 111 (121) 9 years 2nd Biopsy 33% 60% 57% 60% Active 2nd Biopsy 19% 27% 38% 30% 2nd Biopsy 21% 20% 28% 33%. Concordance ttg/ Followup 72% 60%. 56% 78%

14 ttg As a Marker of Mucosal Pathology At Follow-up ttg Overall Age <12 N=39 Age >12 N=31 Sensitivity 80% 81% 78% Specificity 48% 25% 62% Positive Predictive Value 78% 81% 74% Negative Predictive Value 50% 25% 67%

16 Celiac Disease: A Significant Unmet Medical Need No pharmaceutical therapy exists to treat Celiac Disease 1% of Western population ~3 Million US ~3.5 Million 5 Largest in EU ~15 Million ROW Estimated US & EU Prevalence, Consultation & Diagnosed Populations¹ 8 million Prevalence Diagnosis rates are growing significantly 6 5 Significant increase of prevalence in the US during these last 3 decades, a trend that was associated with higher comorbidity in undiagnosed patients and higher mortality²,³ Diagnosed 1 0 Diagnosed Diagnosed 2003 Diagnosed ¹ Source: NIH / CDC Celiac Disease Consensus Report, 2004 ² Catassi C, Kryszak D, et al. A.Ann Med ³ Rubio-Tapia et al, Increased Prevalence and Mortality in Undiagnosed Celiac Disease, Gastroenterology (2009 ) Jul;137(1): Consulted

17 The Epidemics of Celiac Disease CD prevalence (%) % % % year

18 The Yin and Yang Between Tolerance and Immune Response Leading To Chronic Inflammatory Diseases: Lesson Learned From Celiac Disease Increased Gut Permeability Immune Response Human Genome Environmental Factors Microbiome Clinic Outcome

20 active remission na Log2(f.c.) relative to healthy healthy Genetics: RNASeq Majority signatures in the active state diminished in remission, although residual signatures do exist.

21 Challenges/Caveats for Clinical Trials 1. Inclusion Criteria: CD patients on a GFD, no symptoms, normal serology, good compliance to the diet, but abnormal intestinal mucosa (persistent damage). Gray GM et al Clin Gastroenterol Hepatol Readout: Fecal Fat Catassi C. et al. Am J Clin Nutr 2007: Readout: Histopatology A. Lanzini et al DDW 2007: Readout: Histopatology Paterson B et al. Aliment Pharmacol Ther 2007: Readout: Intestinal permeability MESSAGE #1: A wash in controlling stringency and homogeneity of GFD is necessary 2. Readouts: How to evaluate Efficacy Mustalahti K et al. Eff Clin Pract Nachman F. et al. Dig Liver Dis MESSAGE #2: There is a need of metrics for short-lived clinical trials

22 Primary Endpoints For Clinical Trial in CD: FDA identified Patient Reported Outcome (PRO) as primary endpoint Histology is central to the diagnosis of celiac disease and has been linked to outcomes Villous damage is predictable and reproducible Conversely, villous recovery rates are variable Histology can be used for inclusion criteria Confirm initial diagnosis Persistent villous atrophy as cause of persistent symptoms Mucosal healing is not universal, nor is the timing uniform and predictable Histology can be used as a secondary qualitative endpoint Lack of worsening Stable or improved VH/CD ratio

stools Gastrointestinal Symptoms* Diarrhea/ Loose Stools Nausea Headache Tiredness NonGastrointestinal Symptoms

23 Validated Celiac Disease Patient Reported Outcome CD PRO Daily, Likert Scale 0 10 CeD Symptoms CeD Symptom Domains Overall CeD GI Symptom Experience Abdominal cramping Abdominal pain Bloating Abdominal Symptoms Gas Diarrhea Loose stools Gastrointestinal Symptoms* Diarrhea/ Loose Stools Nausea Headache Tiredness NonGastrointestinal Symptoms *Overall gastrointestinal symptoms are assessed as: Symptomatic Days, Improved Symptom Days, and Total GI Domain score

24 Efficacy Readout From Patient Prospective Adults: Improvement of quality of life Pediatrics: Blend with peers, being not diferent from others

26 Alternative/Integrative Approaches To The Gluten Free Diet Prevention Primary Prevention (Timing of gluten introduction) Secondary Prevention (Microbiome Modification) Alternative Treatments Development of genetically modified grains Inhibitors of tissue transglutaminase Cytokines and/or cytokine receptors inhibitors Detoxification of immunogenic gliadin peptides via oral peptidase supplementation Oral or intra-nasal celiac vaccines to induce tolerance Inhibitors of the effects of zonulin on intestinal permeability

28 Current ClinicalTrials in CD (Updated May 19th, 2018) Registered Clinical Trials: 192 Diagnosis: 60 Dietary intervention: 32 Treatment alternative To GFD: 49 Treatment: 43 NCGS: 31 Others (comorbidities, behavior, QOL): 20 Prevention: 6 (# technologies: 6) Completed: 34 Glutenases 11 Trials Nexpep Pty Nexvax2 3Trial Active: 9 Enzymatic/Polymers Alba Therapeutics 3 Trials Larazotide Alba ChemoCentryx 1 Trial CCR9 antagonist Therapeutics Glutenases Larazotide Probiotics 1 Trial 2 Trials 13 Trials 3 Trials Princess Alexandra Hospital, Brisbane, Australia Alvine Pharmaceuticals Inoculation Hookworm ALV003 N. Americanus 6 Trials 2 Trial

29 Steroids Glutenases Gut Barrier Immuno-modulators Vaccine Immuno-suppressants (Biologics) Enzyme cocktail AL V003 Failed others entering phase II Entering phase III No further development Mainly focused on IBD (too many side effects for use in CD Adjuvant late development TG2 inhibitors Pre-clinical HLA-DQ2 blockers Pre-clinical Probiotics Early stage development Gluten sequestration Entering phase II

30 Factors Influencing Drug Development Success (In Order Of Importance) Pre-Clinical Working hypothesis Good study design Good pre-clinical models recapitulating human disease Strong safety and efficacy signals Biomarkers Clinical Phase I 1. Study design 2. Proper power calculation 3. Strong safety signal 4. Economics Phase II 1. Economics 2. Proper power calculation 3. Strong safety signal + good efficacy signal (pivotal primary readout Phase III 1. Economics 2. Proper power calculation 3. Strong safety signal and efficacy signals

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New and Emerging Therapies for Gluten-Related Conditions

New and Emerging Therapies for Gluten-Related Conditions Jocelyn Silvester, MD PhD FRCPC June 11, 2017 Disclosures Funding CIHR, NIH, Canadian Celiac Association Collaboration Biomedal SG Glutenostics