Cutting Edge Research for Food Allergy Sara Anvari, M.D., M.Sc. Assistant Professor of Pediatrics Baylor College of Medicine/Texas Children’s Hospital 3rd Annual Advanced Practice Provider Conference April 16, 2016 xxx00.#####.ppt 4/28/2017 12:50:07 AM

Outline Understanding Food Allergies Novel Food Allergy Investigations Sublingual and Oral Immunotherapy Epicutaneous Immunotherapy Synbiotic Treatment Trials Shrimp Allergy Study Eosinophilic Esophagitis Trials Future Directions - TCH Food Allergy Program xxx00.#####.ppt 4/28/2017

Understanding Food Allergies xxx00.#####.ppt 4/28/2017

Prevalence of Food Allergies in North America Infant/Child Adult Milk 2.5% 0.3% Egg 1.5% 0.2% Wheat/soy 0.4% Peanut 1.4% 0.6% Tree nuts 0.5% 0.8% Fish 0.1% Shellfish 2% Overall 5-8% 3-4% Boyce JA et al. JACI. 2010;126:S1-S58 Sicherer et al. JACI. 2012

How Does Food Cause an Allergic Reaction? Allergen Absorption Allergen Processing Egg Food allergen IgE mediated IgE APC Antigen Presenting Cell B cell IL-4, IL-13 T cell Non-IgE mediated Histamine Release IL-5, Eotaxin Mast cell Basophils Hives, Vomiting, Swelling, Breathing Difficulty Eos

Overview of Adverse Food Reactions J Allergy Clin Immunol. 2014 Nov;134(5):1016-25.e43. xxx00.#####.ppt 4/28/2017

Is There A Cure For Food Allergies? No effective, FDA-approved treatment Avoidance is the ONLY way to prevent an allergic reaction Epinephrine is the only therapy to treat a severe reaction xxx00.#####.ppt 4/28/2017

I. Sublingual and Oral Immunotherapy Novel Food Allergy Investigations I. Sublingual and Oral Immunotherapy xxx00.#####.ppt 4/28/2017

What is the Goal of Immunotherapy? Immune system no longer recognizes the food as harmful (Desensitization) Cease mounting an immune response to the food when it is not given daily (Tolerance) xxx00.#####.ppt 4/28/2017

Sublingual Immunotherapy Smaller doses Safer with less side effects Not as effective as oral immunotherapy Phase 2 Studies Milk, peanut, hazelnut, peach, kiwi

Efficacy of Oral vs Sublingual Immunotherapy 2000-4000 mg ~10 mg % Patients Tolerating Targeted Dose

Desensitization to Milk/Egg with Baked Goods Three-fourths of milk allergic children can tolerate baked milk Over half of egg allergic children can tolerate heated egg Nowak-Wegrzyn et al. JACI. 2008: 122:342-7. Lemon-Mulé et al. JACI. 2008:977-85 xxx00.#####.ppt 4/28/2017

LEAP AND LEAP-On Studies

Oral Immunotherapy – LEAP Study Objective: Determine if early introduction of peanut prevents peanut allergy Methods: High risk infants (severe eczema +/- egg allergy) 4-11 months old Positive skin test (≤4mm wheal) Negative skin test Randomized into (2) groups for 5 yrs: Peanut consumption Avoidance Peanut allergy was 5 times more likely to develop in children avoiding peanuts DuToit et al NEJM 2015 xxx00.#####.ppt 4/28/2017

Oral Immunotherapy – LEAP-On Study Objective: Determine the effect of peanut avoidance for 1 year after early peanut consumption Methods: High risk infants (severe eczema +/- egg allergy) 4-11 months old Positive skin test (≤4mm wheal) Negative skin test Randomized into (2) groups for 5 yrs: Peanut consumption Avoidance Peanut avoidance for 12mo after 5yrs of ingestion Prevalence of peanut allergy did not increase in the high-risk group following a 12-month period of peanut avoidance DuToit et al NEJM 2015 xxx00.#####.ppt 4/28/2017

Peanut Oral Immunotherapy Trial Initiated: July 2014 Enrolling: 15-20 patients Age: 5-16 Eligibility Hx of peanut allergy Peanut IgE >7 kU/L Positive peanut skin test Positive oral challenge to peanut No history of asthma or uncontrolled eczema No history of severe anaphylaxisd xxx00.#####.ppt 4/28/2017 12:50:07 AM

Peanut OIT Study Design Build Up Maintenance Wash Out Lab Work Lab Work Lab Work Start 12 mo. 24 mo. 36 mo. 37 mo. Skin Test Food Challenge Skin Test Skin Test Food Challenge ~20 peanuts ~1/100th peanut = 200 mg xxx00.#####.ppt 4/28/2017

Current OIT Dose Escalation Peanut Dose (mg) 20 patients screened 11 have qualified Major reason for disqualification: inability to commit to study xxx00.#####.ppt 4/28/2017

Peanut Oral Immunotherapy Skin Test Results Screen 6 mo. post-OIT Wheal Size (mm) Pt 1 Pt 2 Pt 3 Pt 4 xxx00.#####.ppt 4/28/2017

II. Epicutaneous Immunotherapy Novel Food Allergy Investigations II. Epicutaneous Immunotherapy xxx00.#####.ppt 4/28/2017

Epicutaneous Immunotherapy (Patch) Increased thresholds for allergen in mouse models Safe in humans Preliminary studies show effectiveness in humans (250mcg dose) Phase III trials underway (PEPITES) DuPont et al. JACI. 2014 DuPont et al. JACI. 2010 xxx00.#####.ppt 4/28/2017

III. Synbiotic Therapy Trials Novel Food Allergy Investigations III. Synbiotic Therapy Trials xxx00.#####.ppt 4/28/2017

What are Probiotics Probiotics: “Good”/”healthy” organisms (i.e. bacteria and yeasts) that may provide health benefits when consumed Prebiotics: non-digestible “nutrition” to stimulate the growth of the healthy bacteria Synbiotics: Probiotics + Prebiotics Why is it important? Hypothesized that allergies may be due to an imbalance between “good” and “bad” bacteria Providing more “good” bacteria may help prevent the development of allergic disorders xxx00.#####.ppt 4/28/2017

Why Are Synbiotics Important? Probiotics and Peanut Oral Immunotherapy (PPOIT) 62 peanut allergic children PPOIT vs Placebo for 18 mo Underwent 2 separate oral peanut challenges Challenge #1: Desensitization 89% vs 7% Challenge #2 (after 2-5 week washout): Tolerance 82% vs 3% Preliminary Studies Suggest Probiotics May Help with Tolerance Development Tang et al, JACI 2014 xxx00.#####.ppt 4/28/2017

PRESTO Study (Prospective, Randomized Study to evaluate the Effectiveness of Synbiotics on Cow’s Milk Allergy Tolerance) Objective: Determine if synbiotic formula allows for earlier cow’s milk tolerance and reduce # of other allergies Criteria: Diagnosis of cow’s milk allergy Age < 13 months old xxx00.#####.ppt 4/28/2017 12:50:07 AM

PRESTO Study Multicenter International Trial Start Formula Start 12 mo. 24 mo. 36 mo. 6 yrs Milk Challenge Milk Challenge Milk Challenge Phone Follow-up xxx00.#####.ppt 4/28/2017

Microbiome Influences on Development of Food Allergies in Children Background: Development and prevention of allergic disorders may be regulated by the bacteria on/in our body Objective: Characterize microbiome differences between the food allergic and non-food allergic siblings Criteria: Recruitment of healthy and food allergic siblings Stool, saliva and skin samples collected at enrollment xxx00.#####.ppt 4/28/2017

IV. Shrimp Allergy Study Novel Food Allergy Investigations IV. Shrimp Allergy Study xxx00.#####.ppt 4/28/2017

Evaluating Immune Responses in Shrimp Allergic Patients Pen a 1 IgE (kU/L) Pen a 1 component testing could potentially be used as a marker to detect true shrimp allergy Shrimp Tolerant Shrimp Allergic Tuano et al, In preparation xxx00.#####.ppt 4/28/2017

V. Eosinophilic Esophagitis (EoE) Novel Food Allergy Investigations V. Eosinophilic Esophagitis (EoE) xxx00.#####.ppt 4/28/2017

What is Eosinophilic Esophagitis (EoE) Definition: Chronic, immune-mediated disease characterized by: Clinical symptoms of esophageal dysfunction Difficulty swallowing, vomiting, poor weight gain Histological eosinophil-predominant inflammation (endoscopy with biopsy) >15 eos/hpf + histopathologic findings www.community.kidswithfoodallergies.org Liacouras CA et al. JACI. 2011 xxx00.#####.ppt 4/28/2017

Standard EoE Treatment Schema EoE Diagnosis Dietary therapy Elemental Diet 4 food Elimination Diet Elimination Diet – Test directed Medical therapy Steroids Topical or Systemic Combination of Diet and Steroids Comparison Trial of Diet vs. Medication 4 Food Elimination Trial Milk, Egg, Soy and Wheat EoE Multicenter Trial

EoE Combination Therapy Seth N, Chokshi N et al. Submitted xxx00.#####.ppt 4/28/2017

Salivary Cytokines in EoE Measured EoE relevant cytokines using magnetic high-sensitivity human multiplex assays (EMD Millipore, MA) IL-4 & IL-5 could be markers of EoE detection and can be collected non-invasively via saliva Hiremath et al., Ann Allergy Asthma Immunol, 2015 xxx00.#####.ppt 4/28/2017

Future Directions for TCH Food Allergy Program xxx00.#####.ppt 4/28/2017

TCH Food Allergy Program Designated as a F. A. R. E TCH Food Allergy Program Designated as a F.A.R.E. Center for Clinical Excellence xxx00.#####.ppt 4/28/2017

Future Analyses / Studies One year interim analysis of Peanut OIT after oral challenge Phase 3 Center for Peanut OIT Phase 3 Center for Epicutaneous “Patch” Immunotherapy Phase 1 Center for Shrimp OIT Phase 1 Center for Tree nut OIT Phase 1 Center for Multi-Food OIT xxx00.#####.ppt 4/28/2017

Conclusions Partnering with the community and F.A.R.E to bring state of the art treatment and research Oral immunotherapy trials have begun and are expanding New methods for diagnosis and treatment of food allergic diseases xxx00.#####.ppt 4/28/2017

Acknowledgements IAR Chief: Dr. Jordan Orange Food Allergy Program Director: Dr. Carla Davis TCH Food Allergy Program Ms. Daisy Tran Ms. Chivon McMullen-Jackson Ms. Christina Cowperthwait Ms. Theresa Aldape Ms. Valerie Nichols Ms. Kathy Green Ms. Kathy Pitts Ms. Lin-Lin Shao EGID Clinic Dr. Anthony Olive Dr. Girish Hiremath TCH Pathology Dr. Sridevi Devaraj TCH Center for Human Immunobiology Dr. George Makedonas Ms. Andrea Grimbergen Dr. Alexandre Carisey Dr. Emily Mace Dr. Petra Netter A/I Food Allergy Fellows Dr. Karen Tuano Dr. Atoosa Kourosh Texas Children’s Research Resources Office Ms. Supriya Parikh Ms. Ann McMeans Ms. Chiemenam Amaechi Texas Children’s Clinical Research Center Child Life Specialists, Our Patients and Donors of TCH Food Allergy Program