Food Allergy Update. Dr. Oscar Lee Frick Lectureship. Hugh A Sampson, MD. April 29, 2017 AAIFNC

Transcription

1 Food Allergy Update Dr. Oscar Lee Frick Lectureship Hugh A Sampson, MD Kurt Hirschhorn Professor of Pediatrics Director, Jaffe Food Allergy Institute April 29, 2017 AAIFNC

2 Disclosures Faculty at Icahn School of Medicine at Mount Sinai (40% FTE) CSO at DBV Technologies (60% FTE) Consultant/Advisory Boards: - Allertein TherapeuQcs, LLC - UCB - Hycor Grants: NIAID, NIH and FARE

3 OUTLINE Food allergies are increasing Why? PrevenQon strategy has changed 180 o Why & what should you do? Some advances in diagnosis Current approved management Therapies on the horizon

4 2 nd Wave of Allergy Epidemic Children [1 17 yrs] in the United States ~17%% 12.5% 7.4% 3.4% 50% INCREASE IN FOOD ALLERGY 5.1% NCHS Data Brief #121; May 2013 Jackson KD et al

5 Food Anaphylaxis Admissions: Australia 18 Rate per 100,000 population ICD 9 ICD 10- AM >5 FOLD INCREASE IN ANAPHYLAXIS IN CHILDREN <4 YRS Age Year 0 to 4 5 to to to Liew WK, Williamson E, Tang MLK. JACI 2009

6 Factors Thought to Promote Allergy Maternal vitamin intake, e.g. folate Maternal smoking Maternal consumption of allergenic foods during pregnancy Caesarean section delivery Failure to initiate breastfeeding Genetic factors/family history of allergy Prenatal Perinatal Older parental age fetal epigenetic modification through maternal exposure to these factors Factors associated with the hygiene hypothesis e.g. Smaller family size Infant dietary factors e.g. Later introduction of allergenic foods ImmunizaBons Postnatal Lack of vitamin D (sunlight) Direct infant exposure Exposure to tobacco smoke + other environmental pollutants Modified from Allen K & Koplin J. Epidemiology of Food Allergy. In Burks, James, Eigenmann et al. (Eds), Food Allergy 1e.2011.

7 Past PrevenQon RaQonale Strict avoidance of food allergens unql infant s immune system matures will prevent development of food allergy - but unrealized contaminaqon & environmental exposure - & high levels of environmental exposure to peanut during infancy promote sensiqzaqon (Fox AT et al. JACI 2009;123:417-23) - early oral exposure may actually promote tolerance - Peanut allergy in Israel 1/10 th prevalence compared to UK (du Toit JACI 2008; 122:984) - Milk allergy in Israel - followed ~13,000 infants; 381 (2.9%) developed CMA (Katz Y et al. JACI 2010; 126:77-82)

8 Dual AnQgen Exposure: Lack Hypothesis 8

9 Du Toit G et al. NEJM 2015; 372: LEAP Trial Design IntervenQon grp: SPT- PosiQve Stratum (n=47) n=319 IntervenQon grp: SPT- NegaQve Stratum (n=272) Recruitment: n = 640 infants with severe eczema and/or egg allergy Control Grp: SPT- PosiQve Stratum (n=51) n=321 Age at Control Grp: SPT- NegaQve Stratum (n=270) clinic visits: 4-11 months 12 months 30 months 60 months

10 LEAP Outcome: IntenQon- to- Treat Analysis 86% RelaQve ReducQon 70% RelaQve ReducQon 81% RelaQve ReducQon Du Toit G et al. NEJM 2015; 372:

11 LEAP- On Study Design Enrolled 556 of 628 subjects compleqng 1 o trial Adherence during 1 yr eliminaqon: Avoidance Grp 90.4% ConsumpQon Grp 69.3% No difference in peanut allergy auer 1 yr eliminaqon Du Toit G et al. NEJM :

12 QuesQons Raised by LEAP Is it necessary to give 2 g PN protein 3x s/wk? (6g/wk) - Israeli infants ingest about 2 g peanut protein/ week Is it necessary to conqnue dosing unql age 5 years? - Would ad lib dosing auer 1 or 2 years be sufficient as long as peanut was ingested at least weekly? What is the risk of poor compliance or early terminaqon? Will this early introducqon apply to other foods?

13 Perkin MR et al. NEJM : Clinical ReacQvity EAT Trial 1,162 infants enrolled in the trial (median age = 3.4 months) Randomized to early introducqon of milk, egg, peanut, fish, wheat & sesame (567) or standard feeding (595) Overall, by ITT analysis, there was no significant difference in food allergy or SPTs between groups Adherence Early feeding: 42.8%; Standard: 92.9%

14 Hen s Egg Allergy Prevention Screened 406 unselected infants 4 6 mos of age - Blinded RCT: egg or placebo to 12 mo of age - Outcome: egg sensiqzaqon or allergic reacqvity at 1 yr - 11 anaphylacqc reacqons during screening OFC n = 406 screened 17 underwent OFC n = 383 nonsensitized Conclusion: early introducqon not protecqve Bellach et al. JACI 2016 e-pub

15 Prevalence of Food and Skin Allergies in the Pediatric PopulaQon [1 17 years] in the United States 2 nd Wave of Allergy Epidemic ~17%% 70% INCREASE IN OVERALL ATOPIC DERMATITIS! 12.5% 7.4% 3.4% 5.1% NCHS Data Brief #121; May 2013 Jackson KD et al

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17 Enhancement of Skin Barrier to Prevent Atopic DermaQQs ProtecQon of the skin barrier + aggressive treatment of inflammaqon to prevent sensiqzaqon Decrease use of bathing, soaps & anqmicrobials Limit allergen contact exposure Treat inflammaqon aggressively

18 Decreased Bathing to Prevent Skin IrritaQon & Eczema Higher frequency of bathing, showering and wiping of the child s hands and face in children aged 15 months was associated with an increased risk of severe AD and wheezing at months. Sherriff A et al. Arch Dis Child. 2002;87(1):26 Increased frequency of bathing was associated with impaired skin barrier (measured by increased TEWL) - increased risk by ~5- fold with daily bathing Marrs T et al A. Clin Exp Allergy 2014

19 Aggressive Management of Eczema Daily emollient applicaqon by 3 wks of age decreased eczema by ~50% Simpson EL et al JACI 2014;134:818 Children treated vigorously for eczema with topical steroids under 5 months of age versus 5-12 months of age had a 50% reducqon in food allergy. Yomase et al. JACI 2015 (abstr.) Need to eliminate skin inflammaqon è sensiqzaqon of allergens interacqng with the skin vs tolerance

20 Managing Food Allergy & Food- induced Anaphylaxis Appropriate diagnosis of specific food allergy EducaQon - strict avoidance of food allregen - learn to read food labels & recognize high risk situaqons - early signs of an allergic / anaphylacqc reacqon Provide emergency treatment plans in wriqng - FARE website: Provide self- Injectable epinephrine & liquid anqhistamine InstrucQons to go to a medical facility

21 Diagnosing Food Allergy NIAID Guideline 11: Expert Panel recommends using oral food challenges for diagnosing food allergy. The DBPCFC is the gold standard Single- blind & open food challenge may be considered diagnosqc in clinical se}ngs Skin tests and in vitro IgE blood tests alone can never be considered diagnosqc NIAID Expert Panel. J Allergy Clin Immunol. 2010; 126(6 Suppl):S1-58.

22 PredicQve Value of PSTs Comparison of PST results & the outcome of 120 oral milk challenges - 37% posiqve Wheal > 95% PPV Milk > 8 mm Egg > 7 mm Peanut > 8 mm Sporik R et al. Clin Exp Allergy, 2000; 30:

23 PredicQve Value of Food- specific IgE Probability 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% IgE AnBbody ConcentraBon (ku A /L) UniCAP TM Egg white Logit model using log(ku A /L) Allergen Decision Pt (ku A /L) Egg 7 (< 2 yrs of age)+ 2 Milk 15 (< 1yr of age)++ 5 Peanut 14 Soy 30 Wheat 26 Tree nuts Sampson HA JACI 2001; 107: Boyano MT, et al. Clin Exp Allergy 2001; 31: Garcia- Ara C, et al. JACI 2001; 107: Clark AT, Ewan P. Clin Exp Allergy 2003; 33: Maloney J et al. JACI 2008; 122:145-5.

24 Allergen Component Resolved DiagnosQcs in Food Allergy PR- 10 Profilin Pollen crossreactive components* LTP Pollen non-cross-reactive components** Peanut Ara h 8 Ara h 9 Ara h 1; Ara h 2; Ara h 3 Ara h 5 Arah 4; Ara h 6; Ara h 7 Hazelnut Cor a 1 Cor a 8 Cor a 9 Cor a 2 Cor a 14 Soybean Gly m 4 Gly m 1 Gly m 5 Gly m 8 Gly m 3 Gly m 6 Wheat Tri a 12 Tri a 14 Tri a 19 (ω-5 gliadin) Tri a 21 - alfa gliadin Tri a 26 - HMW glutenin Tri a 28 - AAI dimer 0.19 Anaphylaxis risk *Birch tree pollen, Timothy grass pollen for wheat ** Storage seed proteins, albumins and globulins

25 Natural Course of Food Allergy 100 Percent with clinical food allergy Birth Years Following standard of care: strict food allergen avoidance

26 Immunotherapeutic Strategies to Treat Food Allergy Ongoing Human Trials: Heat-denatured food proteins Oral immunotherapy Oral immunotherapy + omalizumab Sublingual immunotherapy Epicutaneous Immunotherapy

27 Effect Heat- denaturaqon on SequenQal & ConformaQonal Epitopes of Food Proteins 1 M I L K M I L K Heat & Processing M I L K M I K L 2 Ø ~80% of young children with milk (egg) allergy outgrow their food allergy; react primarily to conformational epitopes

28 AcceleraQon of Tolerance in Children ToleraQng Baked Products Milk: Treated vs. Controls 16 x s more likely to develop full tolerance at 5 yrs compared to control; p < Egg: Treated vs. Controls ~15 x s more likely to tolerate egg at 6 years N = 57 N = 60 Kim et al. JACI 2011; 128: Leonard S et al. JACI 2012; 130:473-80

29 Oral Immunotherapy - Study Phases Dose Build-up (max 2000 mg) Home Maintenance (8 10 weeks) 2000 mg CoFAR Egg OIT trial in 56 egg allergic children (5-18 y/o) ~ months Maintenance 4 6 wks off Initial escalation day (max 50 mg) Egg Challenge (5 gm DBPC) ~44 wks Desensitization Egg Challenge (10 gm DBPC) ~12-24 mo later Tolerance Egg Challenge (10 gm DBPC) DBPCFCs to 10 gm egg protein at ~1, 2, 3 & 4 yrs iniqaqon of OIT Burks & Jones et al. NEJM 2012; 367(3):

30 Results: Oral Food Challenge Success Rates OFC Performed Response Rates Placebo Egg OIT Placebo Egg OIT 5 gm desensiqzaqon OFC (10 mo.) /15 (0%)* (n=13) 22/40 (55%)* (n=35) 10 gm desensiqzaqon OFC (22 mo.) 1*** 34 0/15 (0%)* (n=1) 30/40 (75%)* (n=34) 10 gm tolerance OFC + open egg (24 mo.) 0*** 29 0/15 (0%)** (n=0) 11/40 (27.5%)** (n=29) 10 gm tolerance OFC + open egg (~36 mo.) N/A 13 N/A 18/40 (45%) 10 gm tolerance OFC + open egg (~48 mo.) N/A 22 N/A 22/40 (55%) *p<.001; **p=.025; ***OFC performed w/ criteria met Burks & Jones et al. NEJM 2012; 367(3): ; Jones et al. JACI 2016 (epub)

31 Egg OIT: Conclusions ~15-25% of paqents will not tolerate Egg OIT Most children experience dose- related adverse reacqons - viral illness, exercise, etc. è adverse reacqons - Skin prick tests and Egg IgE - + decreased Clinical desensiqzaqon on OIT (tolerate more egg) - ~50% developed sustained unresponsiveness auer 4 yrs of therapy;? of how permanent Provokes EoE in some paqents (? 2% - 15% reported) Supported by NIH-NIAID U19AI and U0AI Burks & Jones et al. NEJM 2012; 367(3):

32 Milk OIT + Xolair Trial Start OIT Unblind Xolair Desentization OFC Stop OIT Tolerance OFC Follow Up N=76 Start Xolair Treatment (n=28) N=56 Start Xolair Placebo Treatment (n=28) OIT Escalation Phase (22-40 wk) Continue Xolair and Milk OIT Stop Xolair Placebo, Continue Milk OIT OIT Pre-OFC Maintenance Phase (15-19 mo) Stop Xolair Treatment Pass: Continue OIT Maintenance (8 wk) Fail: Stop OIT (Follow Longitudinally) Untreated Controls (n=20) Visit 1 0 wk Visit 2 16 wk (~ 4 mo) Visit 3 68 wk (~ 16 mo) Visit 4 94 wk (~ 22 mo) Visit wk (~ 28 mo) Visit wk (~ 30 mo) Visit wk (~ 32 mo) Visit wk (~ 38 mo) = Double-blind, placebo-controlled milk challenge (DBPCMC) = Blood draw for mechanistic studies, and specific IgE levels * hcg Q 2mo; CBC, chemistry, U/A Q 6 months

33 Results of 28 & 32 Months Oral Food Challenges Treatment Xolair Placebo N % N % Total Subjects Dosed Month 28: 10 gram Desensitization OFC P- value* - Success Passed OFC Failure Failed OFC Month 32: 10 gram Tolerance OFC Success Passed OFC Failure Failed OFC

34 Dose- related Symptoms: First 16 Months Number of Doses Omalizumab Placebo Total Doses, N 9,485 9,949 Symptom- free doses, N (%) 8,974 (94.6) 7,698 (77.4)* Respiratory symptoms N (%) 101 (1.1) 390 (3.9)* GI symptoms N (%) 128 (1.3) 482 (4.8)** Treatment required, N (%) 118 (1.2) 436 (4.4)* Epinephrine use, N (%) 1 (0.01) 17 (0.2)*** * p <0.0001; ** p <0.0005; ***p <0.01

35 Epicutaneous Immunotherapy: Epidermal Delivery System: Viaskin Dry allergenic proteins Water condensaqon under the occlusion chamber InteracQon with epidermal APCs Epidermis Dermis SKIN SolubilizaQon and epicutaneous absorpqon of allergenic proteins < 12 years 12 years

36 VIPES Phase IIb Randomized Controlled Trial Study Design and Efficacy Endpoints VIPES Phase IIb 221 straqfied paqents, 22 centers in US, Canada, France, Poland, & Netherlands Placebo 50 µg 100 µg 250 µg 250 µg M0 M12 M24 M36 M38 VIPES OLFUS- VIPES Dose- finding Open Label Follow- Up Study OLFUS- VIPES Year 1 Study PopulaQon VIPES & OLFUS Efficacy Inclusion Criteria: >6 y/o and <55 y/o o > 0.7 ku A / L peanut- specific IgE and 8 mm SPT wheal o Peanut reacqve dose at M0 300 mg peanut protein Primary endpoint ( success ) at M12, M24 and M36 o 1,000 mg reacqve dose OR o 10- fold increase over the iniqal reacqve dose Main secondary endpoints: CRD*, changes in peanut sige and sigg4 * CRD: CumulaHve ReacHve Dose at Food Challenge

37 OLFUS- VIPES Results: Children Ages 6 11 Years Change in CRD over Qme with Viaskin Peanut 250 µg Responders, % 57% 80% 83% CumulaQve ReacQve Dose (CRD) by Visit** Median (IQ), Mean Observed values 5,000 mg 4,000 mg 3,000 mg 2,000 mg 1,000 mg 1440 mg 1440 mg 36- month observaqons 61% (11/18) achieved CRD 1044 mg 39% (7/18) achieved CRD 5044 mg 444 mg 0 mg 44 mg Mean=84.5 mg 0 Months (VIPES- Baseline) n=21 Mean= mg Mean= mg Mean= mg 12 Months 24 Months 36 Months (OLFUS- Baseline) (OLFUS- Year 1) (OLFUS- Year 2) n=21 n=20* n=18* = Mean *3/21 pabents disconbnued during OLFUS- VIPES, none due to Viaskin Peanut. **Excluding missing data. Epicutaneous immunotherapy is under clinical invesqgaqon and has not been approved for markeqng within or outside the United States. 37

38 VIPES and OLFUS- VIPES Safety and tolerability profile Epinephrine related to study drug Serious Adverse Event (SAE) Withdrawal rate related to Viaskin Peanut Adverse Event profile VIPES OLFUS- VIPES N=221 N=171 No use of epinephrine related to Viaskin Peanut applicaqon No SAEs related to Viaskin Peanut 0.9% (n=2, dermaqqs) 0% Mostly local cutaneous reacqons related to applicaqon site and skin symptoms Majority were mild or moderate and managed with anqhistamines and/or topical steroids Severity and frequency decreased over Qme 38

39 OLFUS- VIPES Results: Children Ages 6 11 Years Change in immunological markers over Qme with Viaskin Peanut 250 µg Peanut- sige Peanut- sigg4 % Change IgE (Median ± IQ) % % Change IgG4 (Median ± IQ) % Months sige values (ku/l) Baseline (Month 0) M36 (OLFUS Year 2) Median Mean Months sigg4 values (mg/l) Baseline (Month 0) M36 (OLFUS Year 2) Median Mean

40 Summary of Immunotherapy in Ongoing Trials Baked- milk & egg for majority of milk- & egg- allergic children will accelerate tolerance OIT è most robust desensiqzaqon to food allergens, but high adverse reacqon rate &? sustainability - omalizumab è i adverse reacqon rate SLIT è modest desensiqzaqon, but low adverse reacqon rate & poor compliance;? sustainability EPIT (PN Viakskin ) è modest desensiqzaqon in 1 st year, substanqally beƒer auer 2 nd year; low adverse reacqon rate & possibly more sustainable

41 Thank You QuesQons?