Food Allergen Immunotherapy/Oral Desensitization: Closer to a Cure?

1. Food Allergen Immunotherapy/Oral Desensitization: Closer to a Cure? Wesley Burks, M.D. Kiser-Arena Professor and Chief Pediatric Allergy and Immunology Duke University Medical Center

2. FACULTY DISCLOSURE • FINANCIAL INTERESTS I have disclosed below information about all organizations and commercial interests, other than my employer, from which I or a member of my immediate family or household receive remuneration in any amount (including consulting fees, grants, honoraria, investments, etc.) or invest money which may create or be perceived as a conflict of interest. Name of Organization Nature of Relationship Allertein Minority Stockholder Dannon Co. Probiotics Advisory Board Mast Cell, Inc. Minority Stockholder McNeil Nutritionals Consultant Novartis Consultant Nutricia Expert Panel • RESEARCH INTERESTS I have disclosed below information about all organizations which support research projects for which I or a member of my immediate family or household serve as an investigator. Name of Organization Nature of Relationship National Institutes of Health Grantee Food Allergy and Anaphylaxis Network Grantee Food Allergy Initiative Grantee Food Allergy Project Grantee Wallace Research Fund Grantee

3. Background: Food Allergy • Prevalence: • 3 million school age children (3.9%) • 18% increase since 1997 Branum 2009 Pediatrics. 124:1549-55 • 7 most common food allergens in U.S. • Milk, egg, peanut, tree nuts, shellfish, soy, wheat • Peanut allergy • Prevalence ~1% • Most common cause of anaphylaxis in children presenting to the ED • Most common cause of fatal food anaphylaxis • Standard of care • Avoidance of only foods appropriately diagnosed • Self-injectable epinephrine/antihistamines Vander Leek, J Peds 2000 Bock, J Allergy Clin Immunol 2007

4. Background: Food Allergy • Accidental exposures • Incidence ~33% per year • Peanut IgE can’t predict severity • Vast majority of fatalities in patients with known allergy • ~20% of young children with peanut allergy outgrow the disease • Generally by school age • Significant adverse effect on quality of life • Greater than some other chronic diseases (i.e., type 1 diabetes) Cummings 2010 Allergy 65(8):933-945 • No proactive therapy available Fleischer 2007 Curr.Allergy Asthma Rep. 7:175-181 Skripak 2007 J Allergy Clin.Immunol. 120:1172-1177

5. Peanut Sensitization Burks AW. Lancet 2008;371,9623:1538-1546

6. Peanut Sensitization Burks AW. Lancet 2008;371,9623:1538-1546

7. Mast Cell Mediators Burks A. N Engl J Med 2008;358:79-81

8. Development of Treatment Options • Allergen non-specific • Anti-IgE – not stand alone treatment • Leung, Sampson, et al. NEJM 2003; 348:986-93 • Chinese herbal medicine – in trials now • Li, X 2003 J.Allergy Clin.Immunol. 112:159-167 • Allergen-specific • Engineered recombinant protein – reduced IgE binding • Oral immunotherapy (OIT) • Sublingual immunotherapy (SLIT) • Skripak Current Opinion In Immunology 2008,20:690-696

9. Initial Food Allergy Study Goals • Goals of treatment are two-fold • Clinical desensitization • tolerate more food before an accidental reaction • Eventual clinical tolerance • off treatment • Goals of research on food allergy treatment • Identify the mechanism(s) of the changes brought on by the treatment • Identify immunologic markers associated with the treatment

10. “Engineered” Recombinant Proteins • Identified the peanut allergens Ara h 1-3 (Arachis hypogaea) and with the gene produced peanut proteins in the laboratory • Identify IgE-binding epitopes on Ara h 1 – 3 • Substitute single amino acid within epitope • e.g. Ara h 2 – a.a. 27- 36 - DRRCQSQLER • eliminates or markedly reduced IgE binding • T cell response unchanged • Utilized the “engineered” peanut protein in a mouse model of peanut allergy – the “new” proteins worked to help prevent anaphylaxis in the peanut-allergic mice • Initial safety studies through CoFAR started in 2009 and are continuing now

11. Oral IT (OIT) swallowed with food Sublingual IT (SLIT) sublingually then swallowed Differences amount of protein, route?, digestion?, possibility of causing tolerance? Methods of Immunotherapy OIT SLIT

12. Peanut OIT Blinded Study Design Maintenance 4000 mg Dose Escalation *Food Challenge #1 (OFC 1) Desensitization Initial escalation day – 6 mg 1 peanut = 300 mg Jones et al. -AAAAI 2010

13. Peanut OIT Blinded Study Design Meet criteria for assessing tolerance Maintenance 4000 mg Off OIT 1 mo Dose Escalation *Food Challenge #1 (OFC 1) Food Challenge #2 (OFC 2) Desensitization Food Challenge #3 (OFC 3) Initial escalation day – 6 mg Tolerance 1 peanut = 300 mg Jones et al. -AAAAI 2010

14. Peanut OIT – Blinded Study • 25 subjects – 16 - active treatment; 9 - placebo • Any peanut-allergic subject – unless accompanied by significant hypotension • All subjects - maximum dose of 6 mg (initial day); 4000 mg during build-up * * * P=.008 Jones et al. -AAAAI 2010

15. Peanut OIT – Blinded Study • 25 subjects – 16 - active treatment; 9 - placebo • Any peanut-allergic subject – unless accompanied by significant hypotension • All subjects - maximum dose of 6 mg (initial day); 4000 mg during build-up * * * * * P=.008 * P=.001 Jones et al. -AAAAI 2010

16. Serum Levels of Peanut-Specific IgE and IgG4 Change with Treatment Jones et al. -AAAAI 2010 ImmunoCAP-FEIA (Phadia)

17. Serum Levels of Peanut-Specific IgE and IgG4 Change with Treatment Jones et al. -AAAAI 2010 ImmunoCAP-FEIA (Phadia)

18. Peanut OITAllergen-Specific T cells Basophil markers - %CD63 Significant change over first few months of OIT Peanut-specific CD4+CD25+Foxp3+ T cells T-Regulatory cells increased at 12 months decreased thereafter Peanut-specific cytokines Decreased – pro-allergic cytokines - IL-4, IL-5, IL-13 Increased – regulatory cytokines - IL-10, TGF-ß Breslin et al. AAAAI - 2010 Jones, Burks et al. – J Allergy Clin Immunol – August 2009

19. Permanent Tolerance Develops after 3 Years of OIT • 27 subjects - on OIT >36 months • 13/27 (48%) passed food challenges to peanuts • Off treatment • These subjects remain off OIT and ingest peanut in their diets Varshney, Jones, Burks et al. AAAAI 2010

20. Oral IT (OIT) swallowed with food Sublingual IT (SLIT) sublingually then swallowed Differences amount of protein, route?, digestion?, possibility of causing tolerance? Methods of Immunotherapy OIT SLIT

21. Sublingual Immunotherapy (SLIT) • SLIT – peanut-allergic children and adults • Initial pilot study (Duke) • Adolescents and adults Laubach, Burks, et al. J Allergy Clin Immunol 2008;121:S96 Bird et al. J Allergy Clin Immunol 2009 (2) 2nd-blinded study (Duke) - Children - Bird et al. AAAAI 2010 Kim et al. AAAAI 2010 (3) 3rd study (CoFAR-NIH) - Adolescents and adults – 3 year study

22. Immunotherapy Comparison

23. Immunotherapy for Food Allergy - Future OIT/SLIT – still investigational Studies needed to understand possible clinical benefit and mechanism randomized, blinded controlled trials – in process now optimizing pharmacokinetics targeting appropriate population(s) Determine mechanism of action of OIT/SLIT Basophils/mast cells, humoral, cellular Determine if food IT induces Desensitization without/and clinical tolerance Is desensitization only worthwhile? Goal: development of active treatment for food allergy

24. Thanks Grant support Food Allergy and Anaphylaxis Network, Food Allergy Project, Food Allergy Initiative, Gerber Foundation, NIHR01 – AI, NIHR01-NCCAM, NIH 1 UL1 RR024128-01 (DCRU), Doris and Frank Robins Family, National Peanut Board, NIAID-CoFAR Team Physicians - Stacie Jones (AR), Joe Roberts, Brian Vickery, Michael Land, Wayne Shreffler (Harvard), Hugh Sampson (Mt. Sinai) Study coordinators - Pam Steele, Jan Kamilaris, Alison Edie, Janie Hainline Fellows - Amy Scurlock, Arianna Buchanan, Krisha Palmer, Todd Green, Alison Hofmann, Pooja Varshney, Ananth Thyagarajan, Drew Bird, Edwin Kim, Stacy Chin, Stephen Boden Laboratory - Mike Kulis, PhD, Xiaoping Zhong, MD/PhD, Laurent Pons, PhD, Herman Staats, PhD DCRU/Rankin staff