Kari C. Nadeau, MD, PhD Division of Allergy, Immunology, and Rheumatology at Stanford

Transcription

1 Kari C. Nadeau, MD, PhD Division of Allergy, Immunology, and Rheumatology at Stanford

2 Describe the pathophysiology, initial evaluation & management of patients with food allergy including gastrointestinal food allergy, oral allergy syndrome and type I food allergy Identify recent advances in the field of food allergy and have some familiarity with published guidelines for managing food allergy Outline current and emerging treatment modalities for food allergic patients

3 Nothing to disclose

4 ID: 9.5 y.o. male with a history of severe food allergies, eczema, and asthma CC: Presents to PICU with hypoxic brain injury due to anaphylaxis from cow s milk ingestion Transferred to PICU from outside hospital after multiple failed resuscitations over a 3 hr period

5 On the evening of , patient accidentally drank from his sister s cup of cow s milk on the way to bed. He immediately developed emesis and became SOB; parents gave Epipen jr. to his thigh and called 911 Paramedics arrived in minutes On the scene, intubation was attempted but difficult Duration of code=1 hr. CT scan showed hypoxic injury and right uncal herniation.

6 In 2001, he presented to LPCH AAI clinic and had severe eczema and asthma. RAST tests were performed at 2001 and showed IgE > 2000, Milk> 100, Peanut>100, Egg 40.3, Soy 17.9, Wheat 20.2, Corn 26.3, Oat No known allergies to beef. He had had one prior visit to the ER for milk ingestion in He presented with hyperventilation and emesis. He was given benadryl and his symptoms improved. He was hospitalized three times in the first year of life for asthma; no intubations but did need steroids

7 Patient and family were prescribed an Epipen jr. and taught about anaphylaxis precautions Patient then began to receive care at private AI facility and was recommended 9 months prior to event to repeat RAST testing. This was not done. Over the past couple of months prior to event, parents decided to allow him to eat wheat, corn, oat, and egg products since he did not seem to have any symptoms from these foods.

8 Background Definition Clinical signs and symptoms Natural History Cow s milk, hen s egg, soy, peanut, tree nuts Diagnostic work-up Treatment Research studies and FAQs

9 Prevalence ~4% - Peanuts 3 million allergic in U.S. (~1.1%) Branum 2009 Pediatrics 124: Most common cause of visits for pediatric anaphylaxis treated in U.S. Emergency Rooms > 15% of patients/year have accidental reactions Yu 2006 J Allergy Clinical Immunology 118:

10 deaths/year reported from food allergies - Bock SA J Allergy Clinical Immunology 2001: 107 (1):

11 Food culprits (n=79) Peanut 56% Tree nut 24% Fish/shellfish 8% Milk 9% Wheat 1% Unknown 3% Mixed nuts, baked goods, cookies, candies, Ethnic food, buffets, sauces, cross-contamination Bock S.A. AAAAI meeting 2009

12 Adolescents Nut Allergy Known food allergy History of Anaphylaxis Asthma, especially those with poor control Lack of skin symptoms Denial of symptoms Concomitant intake of alcohol (which may increase absorption of food) Belief that antihistamines alone were sufficient to treat symptoms Delay or lack of administration of epinephrine However even timely injections of epinephrine do not necessarily prevent death (4 of 32 cases) Bock SA J Allergy Clinical Immunology 2001: 107 (1):

13 Can occur in minutes Due to upper or lower respiratory compromise or cardiovascular collapse Pumphrey et al. Clin Exp Allergy 30 (2000):

14 Adverse health effect arising from a specific immune response that occurs reproducibly on exposure to a given food. National Institute of Allergy and Infectious Diseases (NIAID ) Guidelines for the Diagnosis and Management of Food Allergy 2010

15 National Institute of Allergy and Infectious Diseases (NIAID ) Guidelines for the Diagnosis and Management of Food Allergy 2010

16 Signs and symptoms Percentage of cases Cutaneous >90 Urticaria and angioedema Flush Pruritus without rash 2 5 Respiratory Dyspnea, wheeze Upper airway angioedema Rhinitis Dizziness, syncope, hypotension Abdominal Nausea, vomiting, diarrhea, cramping pain Miscellaneous Headache 5 8 Substernal pain 4 6 Seizure 1 2

17 Over 170 foods have been reported to cause IgE-mediated reactions However over 90% of food allergies are caused by the following foods Milk Hen s egg Soy Wheat Peanut Tree Nuts Shellfish Fish National Institute of Allergy and Infectious Diseases (NIAID ) Guidelines for the Diagnosis and Management of Food Allergy 2010

18 Children with food allergy*: 35-71% atopic dermatitis Possible that peanut sensitization is associated with atopic dermatitis, use of peanut oil containing skin preparations, and household consumption of peanut** 33-40% allergic rhinitis 34-39% asthma * Sicherer et al. J of Allergy and Clin Immunology 2001: 108: ** Fox et al. J of Allergy and Clin Immunology 2009: 123 (2):

19 Oral pruritus, rapid onset, IgE-mediated, rarely progressive Usually fresh fruits and vegetables Heat labile: cooked forms, no reaction Cause: cross reactive proteins pollen/food Birch Ragweed Grass Pollen Apple, apricot, carrot, cherry, kiwi, plum Banana, cucumber, melon, watermelon Cherry, peach, potato, tomato Foods

20 Non-IgE-mediated, typically milk and soy induced Spectrum may include colic, constipation and occult GI blood loss Enterocolitis Enteropathy Proctitis Age Onset: Infant Infant/Toddler Newborn Duration: mo mo 9 mo-12 mo Characteristics: Failure to thrive Malabsorption Bloody stools Shock Villous atrophy Lethargy Eosinophilic Diarrhea Self limited Vomiting

21 Celiac Disease (Gluten-sensitive enteropathy) Anti-gliadin IgG, anti-endomysial IgG, IgA Villus atrophy, malabsorption, pain, associated CA Eosinophilic esophagitis, gastritis, gastroenteritis Eosinophilic infiltration Poor growth, pain, vomit, diarrhea, reflux Multiple food allergy, IgE and non-ige-mediated May affect varying regions of gut Gastrointestinal Anaphylaxis Acute vomit/diarrhea, IgE-mediated

22 Migraines Behavioral / Developmental disorders Arthritis Seizures Inflammatory bowel disease

23 Condition Symptoms Mechanism Lactose intolerance Fructose intolerance Pancreatic insufficiency Gallbladder/liver disease Food poisoning Scombroid fish poisoning Caffeine Tyramine Auriculotemporal syndrome (Frey syndrome) Gustatory rhinitis Panic disorder What is not a food allergy? Bloating, abdominal pain, diarrhea (dose-dependent) Bloating, abdominal pain, diarrhea (dose-dependent) Malabsorption Malabsorption Pain, fever, nausea, emesis, diarrhea Flushing, angioedema, hives, abdominal pain Tremors, cramps, diarrhea Migraine Facial flush in trigeminal nerve distribution associated with spicy foods Profuse watery rhinorrhea associated with spicy foods Subjective reactions, fainting upon smelling or seeing the food Lactase deficiency Fructase deficiency Deficiency of pancreatic enzymes Deficiency of liver enzymes Bacterial toxins in food In spoiled fish histidine is metabolized to histamine Pharmacologic effects of caffeine in susceptible individuals Pharmacologic effects of tyramine in susceptible individuals Neurogenic reflex, frequently associated with birth trauma to trigeminal nerve (forceps delivery) Neurogenic reflex Psychologic

24 Most children will outgrow cow s milk, egg, and wheat allergy Far fewer will outgrow peanut and tree nut allergy A high initial specific IgE against the food is associated with a lower rate of resolution of clinical allergy over time Atopic dermatitis resolution is a useful marker for onset of tolerance to food allergens Skin tests to a food can remain positive long after tolerance to a food has developed. Nevertheless, reduction in the size of the skin test wheal may be a marker for the onset of tolerance to the food allergen. National Institute of Allergy and Infectious Diseases (NIAID ) Guidelines for the Diagnosis and Management of Food Allergy 2010

25 First foreign protein introduced into infant s diet Most common food allergy in young children 2.5% of children in first two years of life 1.1% is IgE-mediated Minimal threshold dose to cause allergic reaction as low as 0.02 ml of milk (e.g. drops)

26 Cross-reactivity with cows, goat, and sheep milk secondary to homology between these proteins 90% children allergic to cow s milk will be reactive to goat s milk on oral food challenge 75% of cow s milk allergic children will tolerate extensively heated cow s milk (e.g. baked goods)

27 1-2% children Yolk considered less allergenic than white Egg white has 23 glycoproteins 70% egg allergic children may be able to ingest small amounts of egg protein in extensively heated (baked) products

28 0.4% children Belongs to legume family with peanut 88% have concomitant peanut allergy

29 1.1% Most common food allergy in pediatric population beyond 4 years of age Most likely to cause fatalities 21.5% chance of outgrowing peanut allergy 8% risk of recurrence

30 0.6% population allergic Walnuts 34% Cashews 20% Almonds 15% Pecan 9% Pistachio 7% Hazelnut, Brazil nut, Pine Nut, Macadamia nut < 5%

31 In recent study, 12% patients allergic to more than 1 tree nut Approximately 30-50% of peanut allergic patients have at least one tree nut allergy Approximately 9% outgrow tree nut allergy Note 14/19 patients who never ingested tree nuts but had elevated specific IgE passed the oral food challenge Of these 14 patients, 58% with specific IgE 5 passed the oral food challenge while 63% with specific IgE 2 passed the oral food challenge Fleischer DM. J Allergy Clin Immunol. 2005;116(5):

32 The severity of a reaction cannot be accurately predicted by the degree of severity of past reactions and depends on: Amount ingested Food form (cooked, raw, or processed) Co-ingestion of other foods The severity also may be influenced by The age of the patient The degree of sensitization at the time of ingestion The rapidity of absorption, based on whether The food is taken on an empty stomach The ingestion is associated with exercise The patient has other co-morbid conditions (e.g., asthma or AD )

33 1% to 20% Typically occur 8 hours after initial reaction, but up to 72 hours later Up to 25% of fatal or near-fatal food reactions There is no consensus on optimal observation time following the initial reaction; recommendations range from 4 to 24 h Minimum 4 hour observation Studies suggest that delayed administration, inadequate dosing, or a need for large doses of epinephrine are risk factors for biphasic reactions Also failure to administer corticosteroids also seems to predispose towards biphasic reaction

34 *Results from ImmunoCAP testing are not comparable to IgE levels from other assay systems such as Immunolite and Turbo-MP. Must know assay lab using. ImmunoCAP Allergy blood tests* Generally felt to be less sensitive than SPT Allergen ku A /L PPV [+] Egg 7 98 Infants 2 yr [ ] 2 95 Milk Infants 1 [ ] 5 95 Peanut Fish Soybean Wheat Tree nuts [ ] 15 95

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36 Airway, Breathing, Circulation Vital signs EpiPen Concurrently, call 911 Supine position with legs elevated (unless respiratory compromise or vomiting) Supplemental O2 Optimize organ perfusion and bronchodilates IVF Weight estimation for dosing of medications

37 What are the indications to give Epinephrine? Severe reaction Respiratory distress Swollen throat Loss of Consciousness

38 Seconds but is rapidly metabolized Effect often short-lived and repeat doses may be necessary for severe or protracted anaphylaxis (within 1-2 minutes if first one is not working)

39 10-20% of anaphylactic cases required 2 nd Epipen injection Jarvinen et al. J Allergy Clin Immunology 2008; 122:

40 Second line treatment only Not life-saving Only relieve itching and urticaria Do not relieve stridor, shortness of breath, wheezing, GI symptoms, or shock Onset of action minutes H1 and H2 antagonism superior to H1 alone

41 National Institute of Allergy and Infectious Diseases (NIAID ) Guidelines for the Diagnosis and Management of Food Allergy 2010

42 Prolonged observation is mandated At least 8-24 hours after symptoms have resolved Moderate to severe reaction Asthmatic wheezing Ingested antigen with risk of systemic absorption Previous history of biphasic response

43 Strict Avoidance of Allergenic Foods Regular growth monitoring Nutritionist Possibly decreases risk of malnutrition (e.g. Ca, Vit D) Christie et al. J Am Diet Assoc 2002; 102(11): Education on how to read labels Only 7%, 22%, and 54% of parents correctly identified labeled products containing milk, egg, and peanut respectively Joshi et al. J Allergy Clin Immunol 109(6): Food Allergen Labeling and Consumer Protection Act (FALCA) effective 2006 mandates manufacturer disclosure of the most common allergens (milk, egg, wheat, soy, peanut, tree nuts, fish, and crustacean shellfish) in plain English in the ingredient list or in a separate contains statement 17% of 20,214 products contain advisory labels Pieretti, J Allergy Clin Immunol 2009;124:337-41

44 Strict Avoidance of Allergenic Foods Nutritionist Education on how to read labels Food allergic patients assume incorrectly that terms such as shared equipment, shared facility, or may contain indicate different levels of risk. Avoid products that state may contain or manufactured on equipment 5-17% risk of significant amount of allergen in food 1.9% without declaration of allergen contained allergen - Remington et al. J Allergy Clin Immunol 2010;125 (2): AB218 - Ford et al. J Allergy Clin Immunol 2009; 123 (2): S176

45 Even when patients ask about ingredient information they may receive inaccurate information If symptoms start assume allergic reaction, call for help Bock S.A. Academy of Allergy Asthma and Immunology Annual meeting 2009

46 Food Allergy and Anaphylaxis Network ( Newsletter Website with patient handouts, educational videos and children s books

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54 Epinephrine 1 st line treatment Life-saving Majority of patients who have prescription do not carry Epinephrine Even those who carry the Epinephrine do not administer the medication when clinically indicated Only 3% of patients who died of food anaphylaxis had Epineprhine Bock et al. J Allergy Clin Immunol 2001;107:191-3 Only 21% of families demonstrate proper use Sicherer, et al. Pediatrics 105 (2000), pp

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56 Must demonstrate how to use it Have families practice Watch Training Video (EpiPen or TwinJect)

57 While administering epinephrine, call 911 Delayed administration of epinephrine has contributed to fatalities Give Epinephrine immediately, but at least within 30 minutes, of food allergic reaction Sampson et al. Engl J Med (6): All other medications, including antihistamines and corticosteroids considered adjunctive Antihistamine use most common reason cited for not using Epinephrine and may significantly increase risk of life-threatening reaction Simons et al. J Allergy Clin Immunol 2009;124:301-6

58 Liquid Zyrtec or Benadryl at all times Prefilled teaspoons are easy to transport and readily available over the counter

59 Medicalert.org laurenshope.com Inscription example: Patient s name. Allergic to peanuts, tree nuts + Asthma. Give EpiPen and call 911. Mother or father: cell phone number.

60 MMR and Varicella and influenza grown in chicken-embryo fibroblast culture and contains minimal amounts of egg protein Can be administered safely in egg-allergic patients, even those with a severe h/o allergic reaction if skin test is negative National Institute of Allergy and Infectious Diseases (NIAID ) Guidelines for the Diagnosis and Management of Food Allergy 2010

61 History: symptoms, timing, reproducibility Acute reactions vs chronic disease Diet details / symptom diary Specific causal food(s) Hidden ingredient(s) Physical examination: evaluate disease severity Identify general mechanism Allergy vs intolerance IgE versus non-ige mediated

62 Suspect IgE-mediated Prick skin tests (fresh extract if oral allergy) RAST Suspect non-ige-mediated Consider biopsy of gut, skin Suspect non-allergic, consider: Breath hydrogen Sweat test Endoscopy

63 Positive prick test or RAST Indicates presence of IgE antibody NOT clinical reactivity Negative prick test or RAST Essentially excludes IgE antibody (>95%) ID skin test with food Risk of systemic reaction & not predictive Contraindicated Unproven/experimental tests Provocation/neutralization, cytotoxic tests, applied kinesiology, hair analysis, IgG4

64 Recommended Interpretation of Food Allergen-Specific IgE levels (ku/l) Egg Milk Peanut Fish Soy Wheat Reactive if > Possibly reactive (physician challenge) Unlikely reactive if < (home challenge) * Sampson, H. Utility of food specific IgE in predicting symptomatic food allergy. JACI

65 Elimination diets (1 to 6 weeks) Eliminate suspected food(s), or Prescribe limited eat only diet, or Elemental diet Oral challenge testing (MD supervised, ER meds available) Open Single-blind Double-blind, placebo-controlled (DBPCFC)

66 Test for specific-ige antibody Negative: reintroduce food* Positive: start elimination diet Elimination diet No resolution: reintroduce food* Resolution Open / single-blind challenges to screen DBPCFC for equivocal open challenges * Unless convincing history warrants supervised challenge

67 Includes disease with unknown mechanisms Food additive allergy Elimination diets (may need elemental diet) Oral Challenges Timing/dose/approach individualized for disorder Enterocolitis syndrome can elicit shock Enteropathy / eosinophilic gastroenteritis may need prolonged feedings to develop symptoms DBPCFCs preferred May require ancillary testing (endoscopy / biopsy)

68 If Specific IgE to a food > 25 ku/l., low likelihood of losing allergy Component Diagnostic Testing and Epitope Arrays are moving forward to further our knowledge and diagnostics capabilities There are no reliable predictors to determine whose food allergy will persist There are no reliable predictors to determine whose food allergy will lead to severe anaphylaxis (predicted in 50% of cases of food allergy) The gold standard to identify an offending food allergen is a double blind, placebo-controlled in vivo challenge which requires hospitalization, is costly, lengthy and can result in an anaphylactic shock Once the tests occur, there are many false positives that can lead to elimination diets in children associated with malnutrition (NY Times.2009)

69 Epitope Arrays : Development of a novel peptide microarray for large-scale epitope mapping of food allergens Serum dilution experiment (A) and peptide inhibition assay (B). Areas showing non-specific binding are indicated with black arrows. Targeted peptides, which are the peptides pre-incubated with the serum pool are indicated with red arrows for each inhibition group. Areas with possible crossinhibition based on sequence alignment are indicated with blue arrows. J Allergy Clin Immunol Aug;124(2): Lin J, et al.

70 New Diagnostic Allergy Test based on rapid assessment of blood basophil activation Stimulated by Antigen Unstimulated Expression of molecules on the cell surface (expressed by cytoplasmic compartments) for example CD203c or CD63

71 New Diagnostic Allergy Test Based on rapid assessment of blood basophil activation Non Activated-diluent Activated-allergen 20 minutes incubation Spin 300 x g 0 Breaks Plasma Leukocytes Gradient Antibodies 1. Anti-CD203c 2. Anti-CD63 3. Anti-CD HLA-DR Abs Staining RBC TIME To RESULT: ~ 1 HOUR Abs diluted in 1% BSA 0.05% NaN3 in PBS Wash, and Flow Cytometry Responses to multiple allergens can be tested at the same time (to assess which are most important in that patient) Results available within 1 hour Use the finger stick test to determine who can tolerate their next dose of food oral immunotherapy

72 Our Diagnostic Allergy Test Can Detect Allergic vs. Non-allergic Patients Non Activated basophils CD203c (MFI) Activated basophils Modified Bock's Reaction Grade A r 2 = Peanut allergic CD203c MFI Controls Modified Bock's Reaction Grade B r 2 = CD63 MFI

73 Hidden ingredients (peanut in sauces or egg rolls) Labeling issues ( spices, changes, errors) Cross contamination (shared equipment) Code words ( Natural flavor may be CMP) Seeking assistance Registered dietitian: ( Food Allergy Network ( )

74 Artificial butter flavor, butter, butter fat, buttermilk, casein, caseinates (sodium, calcium, etc.), cheese, cream, cottage cheese, curds, custard, Half&Half, hydrolysates (casein, milk, whey), lactalbumin, lactose, milk (derivatives, protein, solids, malted, condensed, evaporated, dry, whole, low-fat, non-fat, skim), nougat, pudding, rennet casein, sour cream, sour cream solids, sour milk solids, whey (delactosed, demineralized, protein concentrate), yogurt. MAY contain milk: brown sugar flavoring, natural flavoring, chocolate, caramel flavoring, high protein flour, margarine. * It is common to have a reaction to a hidden ingredient to rather than to have an allergic reaction to a previously tolerated food.

75 Soy (confirm soy IgE negative) <15% soy allergy among IgE-CMA ~50% soy allergy among non-ige CMA Cow s milk protein hydrolysates >90% tolerance in IgE-CMA Partial hydrolysates Not hypoallergenic! (ex/ Nutramigen) Elemental amino acid-based formulas Lack allergenicity (ex/ Neocate) * CMA=cow s milk allergy

76 Epinephrine: drug of choice for reactions Self-administered epinephrine readily available Train patients: indications/technique Antihistamines: secondary therapy Emergency plan in writing Schools, spouses, caregivers, mature sibs / friends Emergency identification bracelet

77 Re-evaluate for tolerance periodically Interval and decision to re-challenge: Type of food allergy Severity of previous symptoms Allergen Ancillary testing Skin prick test/rast may remain positive Reduced concentration food specific-ige encouraging

78 Aimed at high risk newborn Positive family history: biparental or parent / sib Breast feeding generally protective of allergy Wean / supplement with extensively hydrolyzed hypoallergenic protein hydrolysate Delay introduction of solid foods > 6 mo Cow milk/dairy: 6-12 months Egg: months Peanut, tree nut, seafood > mo

79 Identification of causative food Institution of elimination diet Education on food avoidance Development of action plan Prevention of other allergies

80 History and physical paramount IgE & non-ige mediated conditions exist Diagnosis by elimination and challenge Avoidance/education/preparation for emergencies are current therapies Periodic re-challenge to monitor tolerance as indicated by history, allergen, and level of food specific-ige

81 Review several new forms of allergen immunotherapy Discuss positive and negative findings of their use in clinical trials and argument if they might become available in the future Discuss the usefulness of immunotherapy in food allergy and the current status of these investigations

82 Recombinant anti-ige antibody (Stanford) Gene (naked DNA) immunization with CPG repeats (Johns Hopkins) Sublingual Immunotherapy (Stanford) Oral Immunotherapy (Stanford) Hypo-allergenic formulas (Stanford) Probiotics (UCSF)

83 Background BACKGROUND There is no effective, FDA-approved treatment for food allergy, except to avoid the offending foods and to have ready access to self-injectable epinephrine. Recently, oral desensitization has been used to treat patients with food allergy; the process is slow and associated with frequent allergic reactions.

84 OIT (multi or single) yrs Milk, Wheat, Egg, Peanut, Tree Nut, Sesame Seed, and/or Soy Recombinant anti-ige antibody + OIT yrs Sublingual Immunotherapy (peanut only) yrs Skin patch (peanut only) yrs Chinese Herbal Medicine yrs Recombinant/Engineered protein allergens Peanut OIT- 12 mo to 48 mo Lactobacillus (genetically modified)---phase I Denatured/baked milk vs non baked milk yrs Highly cooked egg vs less cooked egg yrs

85 Oral Immunotherapy Study Design Provided by Dr. Wesley Burks of Duke University

86 * Inclusion Criteria: Age >4 yrs age Symptomatic food allergy sensitivity include positive skin prick testing (greater tha n 8 mm) and specific IgE > 7 ku/l. Medically documented history of near fatal reaction to food ingestion Positive DBPCFC Allowed to take antihistamines, asthma meds, and nasal steroid s as indicated for symptomatic control of atopic conditions Exclusion Criteria: No significant organ system disease Failure to comply with training for allergy reactions FEV1 or PEF is <80% predicted with or without meds Subjects taking oral, IM,IV steroids, beta blockers. * Similar to Duke and Arkansas

87 Screening period is very important Preliminary Dosing Visit: Incremental escalating doses of fod flour given orally as tolerated to a max of the top dose of allergen of 6 mg (as per Duke and Arkansas protocol). Up dosing visits weekly to MTD (awareness of symptoms) Treatment Course: Top dose ( maintenance dose ) self administered daily for minimum of 12 months Blood samples minimally should be collected at baseline, 6 months, 12 months, continuing

88 Role of Adjunctive therapy in OIT: Use of Anti IgE in reported studies as example AAAAI, 2011 Savage, et al. Omalizumab In Peanut Allergy: Effects On The Basophil, Mast Cell, And Food Challenge Response N=10 Peanut-allergic adults with 6 mos of omalizumab. At a median of 5 weeks, a DBPCPC was performed in 9 subjects. Results: There was a significant increase in the mean dose of peanut protein tolerated (DPP, 212 mg to 6,010 mg,p<0.01) AAAAI, 2011 Pena-Peloche, et al. Treatment Of Severe And Persistent Food Allergy With Omalizumab Milk and egg allergic children underwent 16 weeks of omalizumab. Out of seven patients, 2 patients showed improvement on food challenge, 3 patients went forward with OIT. JACI, 2011 Sampson, et al. A phase II, randomized, double-blind, parallel-group, placebo-controlled oral food challenge trial of Xolair (omalizumab) in peanut allergy subjects reached primary endpoint (n=9 Xolair and n=5 placebo) and comparing change from baseline in maximum tolerable peanut dose after 24 wks of treatment, there appeared to be a greater shift in peanut tolerability in subjects treated with omalizumab (44%) vs placebo (20%). NEJM, 2003 Leung, D. et al. Effect of anti-ige therapy in patients with peanut allergy A double-blind, randomized, dose-ranging trial in 84 patients. A 450-mg dose of TNX-901 increased the threshold of sensitivity to peanut on oral food challenge from 0.5 to 9 peanuts. Allergy Asthma Proc Rafi, et al. Effects of omalizumab in patients with food allergy. Assessed the efficacy of omalizumab in 22 patients with persistent asthma and concomitant IgEmediated food allergy with improvement on reexposure to sensitized foods.

89 CURRENTLY ONGOING ANTI IGE AND FOOD ORAL IMMUNOTHERAPY STUDIES - Milk OIT + omalizumab in milk allergic subjects (7-35 yrs) PI, Dr. Hugh Sampson Peanut OIT + omalizumab study in peanut allergic patients (>12 yrs) PI, Dr. Wesley Burks Peanut OIT + anti IgE in peanut allergic subjects (>18 yrs) Novartis Peanut OIT + omalizumab in peanut allergic subjects (7-25 yrs) PI, Dr. Dale T. Umetsu Multi OIT + omalizumab in tree nut, milk, egg, and/or peanut allergic subjects (4-55 yrs) PI, Dr. Kari Nadeau Source: clinicaltrials.gov

90 Mechanisms of Anti IgE Therapy IgE Anti-IgE Anti-IgE FcεRI receptor Mast cell Monoclonal anti-ige antibodies, like omalizumab, selectively bind to the Cɛ3 domain of IgE with high affinity. Each IgE molecule has two antigenic sites for anti-ige, and so can be bound by two drug molecules simultaneously. These form small, soluble, biologically inert IgE/anti-IgE complexes that are easily cleared from the circulation.

91 Possible historical comparisons: Cow s milk OIT with no omalizumab Anti IgE Studies in Food Allergy at Stanford (example) Study Patient Population Methods Results Yu et al. (2009) 5 pts (5-25 yrs) with peanut allergy; positive peanut SPT ( 8mm wheal) or serumspecific IgE (peanut IgE 15kUa/L) Pilot study using omalizumab every 2-4 wks (dosing based on wgt/ige level per product insert); no placebo Free IgE anti-peanut decreased (from mean of kua/l to 5.9 kua/l) within 4-12 wks of treatment. One pt developed a negative peanut SPT at 4 wks and was able to tolerate 5 gms of peanut in DBPCFC. Iyengar et al. (2008) 8 patients (4-22 yrs) with food allergy and severe refractory AD Pilot phase I study using higher dosing frequency of omalizumab for higher IgE levels (<3,000 IU/ml; mean=1,068 IU/ml) and 1:1 placebo Clinical effect not markedly different (likely due to very high serum total IgE); TARC, TSLP, and OX40 ligand reduced (60-80% in 3/4 pts; 50-75% and 70-80% in 4/4 pts, respectively) and IL-10 levels increased % in treatment group Nadeau et al (2011) 11 children (7-17 years) with cow s milk allergy; milk-specific IgE (median 50; range kua/l), positive milk SPT (median 20/50 mm; range, 11-45/20-52 mm), Pilot phase I study using omalizumab (starting 9 wks before) rapid oral milk desensitization to 1000-mg; wkly dose increase over next 7-12 wks 9/10 patients reached 1000-mg dose during oneday desensitization period; 9/10 patients reached the max 2000 mg daily dose by wk 16; All 9 pts passed DBPCFC 8 wks after last dose (wk 24) during which cumulative dose of 7250 mg (or 220 ml milk) given. All 9 pts continued daily milk >8000 mg/day after DBPCFC; reactions (mostly local and GI) occurred at approx. 1%

92 Phase I single center study using AntiIgE Schematic with milk of Clinical oral Study: immunotherapy Study design: Baseline visit Start omalizumab (wk 0) Desensitization (1000 mg milk powder dose, 2000 mg cumulative) Weekly up dosing and continued omalizumab Maintain daily milk dose at home Off omalizumab Maintenance dose was 2000 mg DBPCFC* Week 0-9 Week 9 Week 9-16, escalation phase Week Week Home daily milk 8 oz Week Nadeau, K, Schneider, L, Hoyte, L, Borras, I, and Umetsu, D. JACI *DBPCFC=double blind placebo controlled food challenge

93 Summary of Demographics Subject Characteristics 11 patients with histories of acute reactions to uncooked and cooked milk (recruited at 2 study sites). Subjects with prior history of eosinophilic GI diseases, immunotherapy, severe asthma, and/or history of intubation were excluded. Mean age: 10 years (median 8 years). Mean skin test to milk: 22 mm wheal (median 20 mm). Mean milk specific IgE: 98 ku/l (median 50 ku/l). Mean total IgE: 701 ku/l (median 349 ku/l). Nadeau, K, Schneider, L, Hoyte, L, Borras, I, and Umetsu, D. JACI. 2011

94 Results Efficacy Results One-day desensitization to 1,000 mg (cumulative dose=2,000 mg of milk) 7 out of 11 patients passed. One drop out after first day of desensitization. After up to 7-11 additional wks, 9 out of 10 subjects reached an oral daily dose of 2,000 mg (primary endpoint) At wks, DBPCFC to 3,000 mg (cumulative dose 7,200 mg) 9 out of 10 patients passed. After passing DBPCFC, 9 patients began tolerating 8-12 oz milk/day (including ice cream, pizza, yogurt) the next day. Nadeau, K, Schneider, L, Hoyte, L, Borras, I, and Umetsu, D. JACI. 2011

95 Results: Overall Safety Data Safety Results Total number of subjects=11 Milk doses per child, mean (range) 209 (36-334) Symptom/treatment Total doses 2301 No. (%) of total doses No. of reactions per child, mean (range) Total reactions 41 (1.8%) 3.7 (1-7) Grade 1 (Mild) symptoms 29 (1.3%) 2.6 (1-5) On rush desensitization day 14 During weekly dose escalation phase During maintenance dosing 5 Grade 2 (Moderate) symptoms 8 (0.3%) 0.7 (0-2) On rush desensitization day 5 During weekly dose escalation phase During maintenance dosing 2 Grade 3 (Severe) symptoms 4* (0.1%) 0.3 (0-1) On rush desensitization day 2 During weekly dose escalation phase During maintenance dosing 1 Nadeau, K, Schneider, L, Hoyte, L, Borras, I, and Umetsu, D. JACI

96 Summary CLINICAL CONCLUSIONS This study is the first published study to use omalizumab in combination with oral desensitization. 9 of 11 patients with milk allergy treated with omalizumab and oral milk desensitization achieved the primary objective, and tolerated desensitization to a dose of 2,000 mg/day within 7-10 wks. The 9 patients then passed a DBPCFC, and began tolerating >240 ml (>8 oz) of milk/day in their diet. These results suggest a potential value for using omalizumab during rapid oral desensitization for food allergy. Nadeau, K, Schneider, L, Hoyte, L, Borras, I, and Umetsu, D. JACI. 2011

97 Summary SAFETY OIT: CONCLUSIONS There is no cure at the current time. Drop out rates during clinical OIT studies are 15-25% Although most reactions are mild, up to 4% have been reported to be severe (requiring epinephrine). Most allergic reactions occur during home dosing Patients and families must be frequently educated Random allergic reactions can occur 3-4 years after OIT was begun. Viral infections, temperature, other allergies, exercise, menstruation all can modulate the threshold for an allergic reaction during ingestion of food therapy Reaction medications must still be available at all times

98 Possible mechanisms of Oral Immunotherapy Incorvaia, et al. 2008, Antunez, et al. 2008, Aslam, et al 2010, Frew, 2010, Jutel, et al. 2006, Jones, et al. 2009, Adkis and Adkis, 2009 Nadeau and Umetsu, 2011

99 Why study mechanisms of OIT? Provides our field with new targets for Therapy (ie. peptide vaccine based in recognized epitopes in T cells) Diagnostics (ie. basophil activation) Prognostics (ie. following epitope arrays and inhibitory assays) Identifies predictive biomarkers in samples for successful and safe clinical outcomes (ie. Treg epigenetics? Basophil threshold studies?) Defines biological parameters for improved, customized, patient-focused therapy (dose amount, dose frequency, initiation and termination of therapy, adverse event frequency)

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101 OIT Study Summary Results OIT could be promising HOWEVER It must be considered experimental and in its early phases There is still much to learn as to dosing and frequency and length of time on therapy SAFETY is paramount Work with appropriate regulatory agencies and institutional boards Trained staff should perform DBPCFCs and DEs in a hospital setting Patients and their families must be trained and frequently retrained Constant (i.e. 24/7) availability of trained staff, short term and long term follow up are important. OIT IS NOT READY FOR CLINIC USE

102 Identification of causative food Institution of elimination diet Education on food avoidance Development of action plan Prevention of other allergies

103 History and physical paramount IgE & non-ige mediated conditions exist Diagnosis by elimination and challenge Avoidance/education/preparation for emergencies are current therapies Periodic re-challenge to monitor tolerance as indicated by history, allergen, and level of food specific-ige

104 Stanford Alliance For Food Allergy Research Funded By:

105 Seeking Clinical Trials and Mechanistic Assays of Immune Tolerance in Allergy and Asthma The ITN provides: Funding for innovative research Collaborative scientific exchange Public education and involvement Partnership opportunities Submit your proposal:

106 Any questions? Contact