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Food Allergy Research Update. Kim Mudd , RN, MSN, CCRP Pediatric Allergy and Immunology Johns Hopkins University School of Medicine. Food Allergy - Prevalence. 6 – 8% of young children 3 – 4% of adolescents and adults At least 12 million Americans are affected

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Food Allergy Research Update

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    1. Food Allergy Research Update Kim Mudd , RN, MSN, CCRP Pediatric Allergy and Immunology Johns Hopkins University School of Medicine

    2. Food Allergy - Prevalence • 6 – 8% of young children • 3– 4% of adolescents and adults • At least 12 million Americans are affected • Prevalence similar in other developed countries although specific patterns of sensitivity vary • Prevalence appears to be rising (sharply)

    3. Food Allergy Prevalence Rates Food Young ChildrenAdults Milk 2.5% 0.5% Egg 1.3% 0.3% Peanut 1 - 2% 1.0% Tree nuts 0.4% 0.4% Fish 0.1% 0.4% Shellfish 0.1% 1 - 2% Overall6-8%3-4%

    4. Current Treatments for Food Allergy and Their Limitations • Strict avoidance • Very difficult to accomplish • Major impact on quality of life • Significant nutritional risks • Wait for the allergies to be outgrown • Peanut, tree nut, seed, fish, shellfish allergies usually lifelong • Milk, egg, wheat, soy, ? others now more persistent (~20% persist into adulthood and are often very severe) • Treat reactions when they occur • Reactions can be severe and even fatal

    5. Potential Approaches to the Treatment of Food Allergy • Anti-IgE antibodies (Xolair) • Chinese herbal formulas • Immunotherapy • intact allergen • modified allergens • peptide vaccines • mutated recombinant vaccines • homologous proteins • plasmid vaccines • Ingestion of extensively heated milk and egg

    6. Potential Approaches to the Treatment of Food Allergy • Key questions to consider: • Is it allergen specific or a more general Rx? • Is it a treatment that may reduce risk of a severe reaction, but likely need to be used continuously, or is it a potential cure? • For immunotherapy, is it transient desensitization or long term tolerance? • How safe is it? • Is it feasible for general use?

    7. Effect of Anti-IgE on Peanut Challenge (Leung et al N Engl J Med. 2003) • Trial comparing placebo to 3 doses of TNX-901 in 84 patients • Rx given by SQ injection every 4 weeks x 4 doses, peanut challenges done at baseline and 2 – 4 weeks after final dose 9 peanuts ½ peanut Dose of TNX-901

    8. Anti-IgE Therapy – Is this the answer? • Although response is variable, would at least protect most patients from reactions due to accidental exposures • Peanut allergy was studied but the treatment could be used for any food allergy (and provide relief for other atopic conditions) • But: • Must be given on a continuous basis • May not work (or be safe) if total IgE is too high • Unlikely to ever be approved for food allergy • Issues regarding safety and cost • May have its greatest value as an adjunct to immunotherapy

    9. Chinese Herbal Formulas (FAHF-1 and 2) • Herbal formulas based on ancient Chinese remedies for allergy • Appear very effective in mouse models of peanut allergy – allergic reactions on challenge, peanut IgE levels and other measures of peanut allergy were markedly reduced • First clinical trials for food allergy now underway with FAHF-2 • Phase 1 safety study completed • Phase 1/2 study now underway to further assess safety and begin to assess efficacy • May also have a role as an adjunct to immunotherapy

    10. Immunotherapy for the Treatment of Food Allergy • In food allergy, the risks of traditional immunotherapy (allergy shots) appear to far outweigh the benefits • Alternative approaches are under investigation that may change this equation • Modification of the allergens • Different routes of delivery • Oral (OIT) • Sublingual (SLIT) • Epicutaneous (EPIT)

    11. General Approach to Immunotherapy Protocols Home Maintenance x 1 – 3 years (doses 500 mg to 4000 mg) Dose Escalation: Daily Dosing with dose increases q 1-2 weeks over 6 – 9 months 6-12 Months 18+ Months Repeat Challenges (10 grams) Many studies also include a final challenge off therapy to distinguish desensitization from tolerance Screening and Baseline Challenge (1g) Initial treatment escalation day (max 50 mg)

    12. Sublingual Immunotherapy for Hazelnut Allergy (Enrique et al, JACI 116:1073, 2005) • 23 patients with varying degree of hazelnut allergy divided into active and placebo groups • “Rush” desensitization with 22/23 reaching the planned maximum dose at 4 days P=0.02 P<0.05 50% could tolerate the entire 20 g challenge

    13. Johns Hopkins Milk OIT Study (Skripak et al. J Allergy Clin Immunol2008) • First double-blind, placebo-controlled OIT trial, initiated in 2006 • Children with severe, persistent milk allergy • Dosing • Milk powder or placebo powder • Day 1 escalation from 0.4 mg to 50 mg (1/3 tsp) • Then build-up from 50 mg to 500 mg (=15 ml milk) • Primary outcome: change in threshold dose causing reaction, as determined by oral food challenge • All patients completing treatment with placebo were offered open-label active therapy

    14. Milk Dose Threshold Active (n=18) Placebo (n=7) P = 0.0003 Milk dose (mg) Skripak et al. J Allergy ClinImmunol 2008

    15. Milk Dose Threshold P = 0.003 Milk dose (mg) P = 0.0003 • FU challenge 3-17 months after open label milk protein intake: • 6 consumed 16,000mg with no symptoms • 3 consumed 16,000 mg with mild symptoms • 4 had mild symptoms at doses between 4.800 and 12,000 mg • 2 not yet re-challenged due to ongoing symptoms (but still showing increasing tolerance) • 3 were not eligible to continue this phase of the study

    16. Milk OIT Safety Measurements

    17. Adverse Reactions in Open Label Follow-Up • >2000 cumulative doses (median 148 per child) • 407 local reactions (21% of doses) • 74 gastrointestinal (3.8%) • 20 respiratory (1%) • Treatment: diphenhydramine for 68 (3.5%) reactions, albuterol in 12 (0.6%), epinephrine 6 (0.3%) • Reactions were largely unpredictable but did become less and less common over time • Some specific risk factors have emerged (exercise, URIs, menses)

    18. CoFAR Egg OIT Trial (N Engl J Med July 2012) • Design summary: • Randomized, placebo controlled • N = 55 (40 active, 15 placebo • 10 months escalation to 2000 mg, then OFC (“desensitization challenge”) • Un-blinding, 12 additional months with daily maintenance, repeat OFC • If OFC successful: stop dosing for 6 weeks, repeat OFC (“tolerance” challenge)

    19. Egg OIT Results“Desensitization” Oral Food Challenge Oral Food Challenge with 5 grams of egg white performed after ~44 wks of OIT to assess desensitization • Results Summary: Successful challenge in 0/15 on • placebo compared to 21/40 (52.5%) on egg OIT (p<.001)

    20. Egg OIT: Oral Food Challenge Results Summary • Key Results: • 75% were desensitized after 22 months of OIT • 19 out of 30 who were desensitized at 22 months lost protection after avoiding egg for 6 weeks

    21. CoFAR Peanut SLIT: Study Schematic • (Fleischer et al JACI 2013;131:119) PHASE I PHASE II Week 68 OFC – 10g 1 year on maintenance Week 44 OFC - 5g Study Unblinding Week 1-36 Dose Escalation Randomization Maintenance Peanut SLIT 1386 μg peanut protein/day Peanut SLIT Peanut SLIT N=20 Enrollment Initial OFC 2g Maintenance dose (8-28 weeks) 1386 μg peanut protein/day Placebo SLIT N=20 Placebo SLIT Maintenance Peanut SLIT 3696 μg peanut protein/day Week 1-36 Dose Escalation Week 44 OFC – 5g Crossover: 16-36 Week Buildup Peanut SLIT followed by maintenance Phase III: Continued dosing x 1 – 2 years with annual OFC Tolerance challenges if 10 gram OFC negative

    22. CoFAR Peanut SLITStudy • (Fleischer et al JACI 2013;131:119) • Design summary: • Randomized, placebo controlled, N = 40 • 2 gram peanut OFC at baseline • 10 months escalation to 1.3 mcg, then OFC (“desensitization challenge”) • Un-blinding, placebo subjects offered escalation to “high dose” SLIT (3.7 mcg) • 12 – 24 additional months with daily maintenance, repeat OFC annually • If OFC successful: stop dosing for 6 weeks, repeat OFC (“tolerance” challenge)

    23. Peanut SLIT: Oral Food Challenge Baseline to Week 44 P=0.14 P=0.008 P=0.02 • Active versus Placebo P=0.16 • 70% on peanut SLIT were responders compared with 15% on placebo (P < .001) Responders defined as tolerating 1 gram OFC or 10-fold increase in threshold over baseline

    24. Oral Food Challenge Week 68 for Peanut SLIT Subjects P = 0.008 baseline to week 68 P = 0.05 week 44 to week 68 Fleischer et al JACI 2013;131:119

    25. CoFAR Peanut SLITStudy: Safety and Study Conclusions • (Fleischer et al JACI 2013;131:119) • No significant changes were seen between the active and placebo groups • Significant within group changes from baseline were seen with active SLIT for OFC response as well as changes in peanut IgE and IgG4 • Safety overall reassuring: • Of 10,855 peanut doses, 63.1% were symptom free; excluding oral-pharyngeal symptoms, 95.2% were symptom free • Conclusion: Peanut SLIT safely induced a modest level of desensitization in a majority of subjects

    26. Johns Hopkins Milk Immunotherapy Study #2A comparison of oral and sublingual immunotherapy SLIT (Extract) OIT (Powder) • All subjects began dosing with SLIT, then randomized to further dose escalation to: • SLIT: 7 mg daily (~1/20 teaspoon) given as 5 squirts x 3 • OIT: 1000 mg (= one oz) or 2000 mg (= 2 oz)

    27. Study Schema Milk SLIT vs OIT

    28. Food Challenge Threshold At 15 mo, 10% desensitized with SLIT, 60% with OIT (p<0.001 SLIT vs. OIT)

    29. Milk SLIT vs OIT: Challenge Summary † p=0.002 SLIT vs. OIT, ‡ p=0.09 SLIT vs. OIT by χ2

    30. Milk SLIT vs OIT – Adverse Reactions • Overall reaction rates were similar in all groups (27 – 33% of all doses, escalation and maintenance) • However: • SLIT reactions were almost entirely local (oral) • While oral reactions were most common in OIT, • GI symptoms in 8 – 10% of doses • Urticaria in 4% • Lower respiratory in 2 – 3% • Multisystem reactions in 0.5 – 1% • Antihistamines were needed in 1% of SLIT doses compared to 16% of OIT doses

    31. Long-Term Follow-up of Milk OIT (Keet et al, J Allergy Clin immunol 2013) • 32 patients followed from 2 original studies • 3 – 5 years after study completion:

    32. Symptoms at Follow-up (N=32) *one patient had used epinephrine over 50 times in past 2 years

    33. OIT Follow-up: Conclusions • Although we had felt that most participants in these two milk OIT trials had had very positive outcomes, 3-5 years later only 25% consume milk without symptoms • Over time, some subjects became far more reactive than they had been early in therapy • Long term success appears to be related to ongoing milk exposure (key question: why did exposure decrease from what was recommended) • Long-term follow-up of OIT is essential • OIT for food allergy is not yet ready for clinical practice

    34. Summary of OIT and SLIT Study Results • SLIT appears to be less effective than OIT, although this could change with better delivery methods • In small studies of children with significant milk, peanut, and egg allergy, OIT appears capable of inducing significant changes in threshold for clinical reactivity • “Tolerance” is only accomplished in a minority of patients • Rates of adverse reactions are significant but likely acceptable, esp if most develop long term tolerance • Further study is clearly warranted to decrease adverse reactions and improve efficacy, including induction of long term tolerance • Should be limited to controlled, IRB / FDA approved research protocols at this time

    35. Ingestion of “Heat-Denatured” Milk or Egg • Milk (and egg) allergic children can be divided into several groups: • Group 1: Severe, more persistent, react to all forms of milk or egg • Group 2: Less severe, easier to outgrow, do not react to extensively heated (baked) products, espat lower doses • Children in group one may eventually move into group two • In those children in group 2, it may be safe to introduce milk or egg in a baked form without doing harm, and possibly helping to increase tolerance • Breaks the old dogma of strict avoidance until outgrown

    36. Present and Future Initiatives • Examples of current studies: • Comparative study of SLIT vs OIT for peanut allergy • Combination of Xolair and milk OIT • Egg oral immunotherapy vs baked egg • Epicutaneous IT for peanut allergy (peanut patch) • Wheat OIT • Peanut OIT in 1 – 3 year olds • Dissolving film for peanut SLIT • Many other studies are ongoing around the world, including new approaches being studied in animal models • Progress will be slow – partly due to funding but primarily to maximize safety – but reasonably effective Rx for severe, persistent food allergy will be developed for general use in the next 10 years