Management of Food Allergies: Beyond avoidance, what does the future hold? Stanley Fineman, MD, MBA Adjunct Associate Professor, Department of Pediatrics Emory University School of Medicine Atlanta Allergy & Asthma

Disclosures Financial: Speakers bureaus: AstraZeneca, Genetech/Novaris, Greer, Merck, MEDA, Nestle Research: Aimmune, DVB, Genentech, Stallergens, TEVA Stocks: n/a

Outline: What are our therapeutic options? What is the best way to deliver immunotherapy? Oral Immunotherapy (OIT) Sublingual Immunotherapy (SLIT) Epicutaneous Immunotherapy (EPIT) Is there a role for anti-IgE? Chinese Herbal Formula treatment What research are we doing now?

Which of these food allergy treatments are approved by the FDA and National Allergy Societies 1 – Oral desensitization/immunotherapy 2 – Sublingual immunotherapy (drops) 3 – Subcutaneous immunotherapy (shots) 4 – Anti-IgE (Xolair) with oral desensitization 5 – Chinese herbal therapy 6 – None of the above

11 subjects (14-43 yo), hx of SR to PN, + DBPC OFC to PN PN SCIT start 1:10,000 0.05 ml to max 1:100 0.5 ml over 5 days Overall systemic reactions to tx 13% 3 subjects tx w PN had neg DBPC OFC, only 1 placebo completed study – no change in OFC dose. J Allergy Clin Immunol 1992;90:256-62

J Allergy Clin Immunol 1992;90:256-62

SCIT with PN is efficacious Conclusions: SCIT with PN is efficacious Tx patients had 67-100% reduction of symptoms with OFC (8 gm-cumulative 15.86 gm) Formulation error in pharmacy: Placebo tx pt received maintenance dose of PN extract J Allergy Clin Immunol 1992;90:256-62

Key Questions? What is the preferred route for antigen administration? Can True immune tolerance be achieved through food desensitization? When should immunotherapy be started, younger or older child? How long must therapy continue to achieve permanent effect? Does immunotherapy hasten the development of immunologic tolerance in children who will ultimately outgrow a food allergy?

Therapeutic Options Use of sub-cutaneous immunotherapy. Use of anti-IgE Chinese Herbal formula Three current most commonly studied immunotherapy methods: Oral immunotherapy Sublingual immunotherapy Epicutaneous immunotherapy (EPIT)

Defining terms: Desensitization vs Tolerance Reversible state induced by short-term exposure to an allergen. Example: ASA Tolerance: Induction of disease modifying changes that will persist even after the treatment is discontinued. Sustained unresponsiveness Example: SCIT: Inhalant & venom

Challenges in OIT research Dropout rate in OIT trials is 15-20% Several studies had spontaneous resolution of food allergy in subjects getting placebo Most studies end points include reaching a target dose or passing an endpoint challenge Best outcome is ability to consume foods ad libitum What is the risk for Eosinophilic Esophagitis? Allergy Asthma Immunol Res 2013;5:3-15 J Allergy Clin Immunol 2013;131:119-27

J Allergy Clin Immunol 2014;133:318-23

Immunologic changes with immunotherapy J Allergy Clin Immunol 2014;133:318-23

OIT SLIT EPIT Daily dose 100-3000 mg 2- 8 mg 50-100 mcg (250) Side effects GI, oral-pharyngeal Oral (local) Skin (local) Desensitization Large effect Moderate effect Long-term tolerance (SU) Variable Immune modulation Significant Present J Allergy Clin Immunol 2014;133:318-23

Cow’s Milk OIT Retrospective analysis of 32 pts completing CM OIT in 2 protocols (Duke & JH) from 1.3-5.3 years 22% limited their consumption of CM due to sx 31% tolerated full servings of CM (up to 2 gm) with minimal sx Baseline characteristics: Higher baseline CM sIgE had greater likelihood of sx Those tolerating higher maintenance dose less likely to have sx Larger AST after treatment predicted greater likelihood of sx J Allergy Clin Immunol 2013;132:737-9

Cow’s Milk OIT J Allergy Clin Immunol 2013;132:737-9

Cow’s Milk OIT Conclusions: CM is difficult since it is consumed at various times of day vs PN Many young children with CM allergy ‘outgrow’ their sensitivity by 3 yo Numbers vary: 19% by 3 yo; 42% by 8 yo Children with greater sensitivity more likely to have reactions during OIT J Allergy Clin Immunol 2013;132:737-9

57 subjects (7-32 yo) cow’s milk allergy DBPC with up to 2 gm of CM on screening Tx with omalizumab or PL for 4 months prior to open label cow’s milk OIT escalation up to 40 weeks and through maintenance of 28 month. At 28 mo OFC up to 10 gm, then continued OIT off OM for 8 weeks then off OIT for 8 weeks, then OFC at month 32 to assess SU J Allergy Clin Immunol 2016;137:1103-10

J Allergy Clin Immunol 2016;137:1103-10

J Allergy Clin Immunol 2016;137:1103-10

Only 48% in OM group and 35% in PL had SU after 8 weeks stopping MOIT Conclusions: Using omalizumab with MOIT improved safety, did not significantly impact efficacy Most subjects (89% in OM and 71% in PL) could be desensitized to high dose (10 gm) of cow’s milk over 24 months Only 48% in OM group and 35% in PL had SU after 8 weeks stopping MOIT J Allergy Clin Immunol 2016;137:1103-10

DBPC, 55 children (5-11 yo), 40 OIT, 15 PL Oral food challenge at 10 mo and 22 mo N Engl J Med 2012;367:233-43

DBPC, 55 children (5-11 yo), 40 OIT, 15 PL Hx of sx < 2hr after ingestion and sIgE >5kU/L (children <6yo) or >12kU/L (for children >5 yo) OFC at 10 mo (5 gm) and at 22 mo (10 gm) Baseline characteristics: Placebo OIT Total IgE 1060 1095 Egg sIgE 25.7 10.3 AST wheal 13.0 10.5 N Engl J Med 2012;367:233-43

40 assigned to egg OIT (5 withdrew) Initial escalation up to 2 gm daily maintenance 35 OFC at 10 mo, max dose of 5 gm (30 passed) 34 OFC at 24 mo, max dose of 10 gm (11 passed) At 34 mo 10 pts reported no sx (1 lost to fu) 15 pts assigned to placebo 13 OFC at 10 mo, none passed. (1 had OFC at 22 mo also didn’t pass). N Engl J Med 2012;367:233-43

High rate (78%) of AE, although most mild to moderate Conclusions: OIT can desensitize a high proportion (75%) of children with egg allergy High rate (78%) of AE, although most mild to moderate 20% of children in placebo group had AE 15% of subjects did not complete OIT Roughly 1/3 of subjects completing OIT could eat egg ad libitum at 36 mo N Engl J Med 2012;367:233-43

Egg OIT review of recent trials Cochran Database Review of 4 trials of egg OIT RCT with total of 167 pts (OIT 100; control 67) One study PL control other 3 dietary avoidance 39% of OIT pts able to tolerate full serving of egg vs 11.9% of controls 46% of OIT could ingest partial serving (1 gm – 7.5 gm) 69% had mild-severe AE during OIT 5 of 100 receiving OIT required epinephrine Authors conclusion: small studies, quality of evidence was low OIT can desensitize a large number off egg-allergic pts, but it is unknown if long-term tolerance develops Cochran Database Syst Rev 2014;11: CD010638

Egg OIT review of recent trials… Cochran Database Review of 4 trials of egg OIT Authors Conclusions: Evidence suggests that OIT can desensitize a large number of egg-allergic pts, although it is unknown whether long-term tolerance develops. Major difficulty is frequency of AEs Use of epinephrine during OIT is infrequent No standardized protocols Recommend guidelines prior to incorporating desensitization into clinical practice Authors conclusion: small studies, quality of evidence was low OIT can desensitize a large number off egg-allergic pts, but it is unknown if long-term tolerance develops Cochran Database Syst Rev 2014;11: CD010638

Peanut OIT Studies J Allergy Clin Immunol 2016;137:973-982

Non-Placebo controlled trial, open label,1-16 yo 24 of 39 pts (61.5%) completed 5 yrs of OIT (up to 5 gm) 12 pts (31% ITT) able to consume 5 gm PN and 8-10 gm of PB after stopping OIT for 4 weeks J Allergy Clin Immunol 2014;133:468-75

J Allergy Clin Immunol 2014;133:468-75

No proof that pts continue with SU Conclusions: Half of subjects with PA completed study & consumed 5 gm of PN in OFC after 1 month stopping OIT. No proof that pts continue with SU In general subjects with treatment success had less Ara h1 & 2, smaller AST, lower PNsIgE/total IgE ratios compare to treatment failures. J Allergy Clin Immunol 2014;133:468-75

Comparing immunologic parameters of subjects tx with either PN OIT or PN SLIT T1 baseline T3 blinded escalation T4 6 months maintenance T5 after 12 mo T6 OFC 6 mo later T7 OFC after stopping tx J Allergy Clin Immunol 2015;135:1283-92

Immune response for OIT > SLIT Conclusions: Both OIT and SLIT induce suppression of basophil effector functions, DC activation and Th2 cytokine responses Immune response for OIT > SLIT In many patients the suppression was temporary No consistent switch from Th2 to Th1 J Allergy Clin Immunol 2015;135:1283-92

OFC up to 300 mg PN, (mean eliciting dose: 21 mg) 40 children (9-36 mo) Hx of reaction: PNsIgE >0.35 kU/L, &/or AST >3 mm No Hx: PNsIgE>5 Avg AST 11.5 mm, Avg PNsIgE 14.4 Hx of life threatening anaphylaxis excluded OFC up to 300 mg PN, (mean eliciting dose: 21 mg) e-OIT maintenance 300 mg or 3000 mg for 30 months DBPCFC up to 5 gm, 30 passed & then no PN for 4 weeks DBPCFC up to 5 gm, 29 passed (SU) J Allergy Clin Immunol 2016;in press

J Allergy Clin Immunol 2016;in press

J Allergy Clin Immunol 2016;in press

J Allergy Clin Immunol 2016;in press

Safety Profile of OIT

J Allergy Clin Immunol 2015:135:1275-1282

Tx with FAHF-2 or placebo for 6 months 68 pts (12-45 yo), allergies to peanut, tree nut, sesame, fish &/or shellfish, confirmed w DBPCFC Tx with FAHF-2 or placebo for 6 months Food Allergy Herbal Formula-2 (FAHF-2) derived from Wu Mei Wan (extract of 9 herbs) No difference in requirement for epi to treat reactions J Allergy Clin Immunol 2015;136:962-70

A safe herbal medication Favorable in vitro immunomodulatory effects: Produced less IL-5 Greater IFN-g and IL-10 Increased Tregs Efficacy for improving tolerance to food allergens has not been demonstrated in humans 44% of subjects had poor adherence J Allergy Clin Immunol 2015;136:962-70

Oct 24, 2016: Two-Year Follow-Up Study of Viaskin Peanut Show Long-Lasting and High Levels of Desensitization to Peanut Favorable safety and high compliance were reported in OLFUS, consistent with prior results A vast majority of children continue to respond to treatment and tolerate larger doses of peanut, including patients treated with Viaskin Peanut 250 µg for up to 36 months Peanut-specific biomarkers reflect strong immunomodulation in patients After two months of treatment discontinuation, sustained responses were observed in all children who qualified for and completed a food challenge at month-26

Pediatr Clin N Amer 2015;62:1531-1549

What research are we doing now? Oral desensitization for peanut Epicutaneous peanut treatment (patch)

What does the future hold?

J Allergy Clin Immunol Pract 2014;2:91-6