Nutricia Paediatric Allergy Symposium 24 th May 2016

Transcription

1 Nutricia Paediatric Allergy Symposium 24 th May 2016 The speaker had sole editorial control over the content in this slide deck. Any views, opinions or recommendations expressed in the slides are solely those of the speaker and do not necessarily represent those of Nutricia.

2 Advances in immunotherapy for food allergy Nikos Papadopoulos Professor of Allergy & Paediatric Allergy University of Manchester

3 The food allergy epidemic

4 Prevalence of peanut allergy in the UK Hourihane et al, 2007 % Grundy et al, 2002 Tariq et al, 1996 Hourihane J O B et al. J Allergy Clin Immunol 2007;119:

5 Highly variable epidemiology Allergy to egg in a European cohort Xepapadaki et al, submitted 2015

6 Impact on QoL and more Reduced general health perception, emotional impact, limitation of family activities Pronounced effect in severe cases Sicherer et al Ann All Asthma Immunol 2001;87:461-4 May lead to nutritional deficiencies Robbins et al J Allergy Clin Immunol 2014;134: Frequent adverse reactions

7 The natural history of food allergy varies by food and disease type

8 118/6209 infants developed CMA 86 IgE-mediated

9 Current management strategy Identification of offending food Avoidance Education for successful avoidance Treatment of reactions

10 INTERACTIVE QUESTION 1: Value of current food allergy management What do you think of the current food allergy management principles? A. Completely outdated/unacceptable B. Somehow outdated/not satisfactory C. Suboptimal but with no good alternative D. Perfectly fine

11 Less than what both patients and physicians hope for!

12 Subcutaneous immunotherapy is a well documented treatment for several IgEmediated allergic diseases Added values: long-term efficacy & possible effect on natural history Pollen Count/m (108.4) Outcome after 10 years Symptoms MAY JUNE JULY AUGUST MAY JUNE JULY AUGUST MAY JUNE JULY AUGUST IT 7 yr IT 4 yr/placebo 3 yr (from 1992) IT-naive hay fever control patients Durham SR et al.new Engl J Med 1999;341: Jacobsen et al. Allergy 62:

13 Early SC immunotherapy promising but with unacceptable level of adverse events 11 patients (14-43 yrs, moderate-severe) Rush SC IT protocol with defatted peanut flour Study terminated when a placebo patient received an active peanut full dose and died Improved challenge scores in 3 active patients High level of systemic reactions (13%) Oppenheimer et al. J Allergy Clin Immunol 1992; 90:

14 Alternative approaches Different routes of delivery Oral Sublingual Epicutaneous Intralymphatic Modified product Modified allergens Adjuvant/parallel treatments

15 Strategies for improving food immunotherapy Moran TP et al. Curr Opin Immunol 2013 )

16 The oral route

17 Typical OIT approach Wood R. JACI 2016;137:

18 Efficacy of OIT Nurmatov U et al. Br J Nutr 2013; 15: 1-11

19 Milk

20 60 children, 5-17yrs, severe reactions, high sge (>85kU/L), reacting to 0.8ml of milk or less. Randomized, not blinded 2-phase protocol: Rush for 10 days in the hospital, reaching 20ml (50 ml cumulatively in the day), then home slow increase (1ml every 2days). 1 year duration J Allergy Clin Immunol 2008; 121: 343-7

21 20 children, 9-21yrs, sige 35kU/L, reacting to <2.5 g of milk protein Initial build up day up to 1.5ml, then home dosing/increase every 1-2 weeks until 15ml (in 8 steps). Duration of maintenance 13 weeks J Allergy Clin Immunol 2008; 122:

22 Efficacy and safety J Allergy Clin Immunol 2008; 121: 343-7

23 57 subjects (7-32yrs), sige 40kU/L, reacting to 10-20mg 16 months treatment with omalizumab (blinded) Open label OIT after week 4.5 of omalizumab Initial updosing: up to at least 2.1mg of milk at visit 1 and 9mg at visit 2 Daily maintenance and dose escalation q 2 weeks, reaching at least 520mg (~15ml) (goal g) Duration weeks Unblinding at 12 months, omalizumab continued another 12m in the active group. DBPCFC at 28 months. Repeated at 32 months after 8 weeks discontinuation of OIT J Allergy Clin Immunol 2016; 136:

24 Outcomes Active group reached maintenance faster (198 vs 225 doses, 26 vs 30 weeks) Success (desens) at m28: 89% omalizumab, 71% placebo (non significant) Sustained unresponsiveness (m32): 48% omalizumab, 36% placebo (ns) Adverse events: Total: 16% vs 2% of doses (p<0.0005) Treatment used: 3.8% vs 0% (P<0.0008) J Allergy Clin Immunol 2016; 136:

25 Egg

26 Regular feeding with baked egg in children with egg allergy 6 months daily intake. Tolerance 95% (expected 60%-70%) Konstantinou et al. JACI 2008

27 55 children, 5-11yrs, sige ku/l 40 received OIT, 15 placebo 3-phase: Initial-day dose escalation, build-up, maintenance (up to 2g of egg-white powder) DBPCFC at 10m with 5g, at 22m with 10g and at 24m for active group after discontinuing OIT

28 Efficacy and safety of egg OIT More children withdrew in active (5 vs 2, 4 vs 1 because of reactions) Total reactions: Placebo 4% of doses, active 25%, Children with any reaction: Placebo 20%, active 78% No serious adverse events Burks W et al NEJM 2012;367:233

29 Follow-up of the Burks study OIT continued open label Outcome: Sustained Desensitisation increased to 77.5% (31/40) SU increased to 50% (20/40) J Allergy Clin Immunol 2016; 137:

30 Sustained unresponsiveness is associated with better long-term outcome

31 DBPC randomised pilot study with 29 children, 1-5.5yrs old, allergic to egg - Hydrolysed egg with low allergenicity All patients tolerated it at day 1 Daily use for 6 months Outcome: Negative challenge with boiled egg: 36% in active vs 21% control (not significant) Minimal adverse events (n=7 in 6 patients, all mild, 4 probably related) Significant increase in IgG4, decrease in basophil activation in the active group Giavi S. et al Allergy 2016; DOI: /all.12905

32 Peanut

33 23 children (3-14yrs) sensitised (median 95kU/L) + DBPCFC Initial rush protocol (7d) achieved in only 1/23 Long-term build up achieved (0.5g peanut with 20% increases every 2 weeks) in 14/23 after 7 months Maintenance 2 months, then outcome DBPCFC J Allergy Clin Immunol 2010; 126: 83-91

34 Significant increase in tolerated dose with not too many adverse reactions J Allergy Clin Immunol 2010; 126: 83-91

35 28 children (1-16y), sige 106kU/L, 3 phase protocol: rush (1d), build-up (44wks), maintenance (4wks) Partially defatted peanut flour, up to 4g (~16 peanut equivalent) 3 drop-out, 16 active, 9 placebo Varshney P et al. J Allergy Clin Immunol 2011; 127:

36 Efficacy Varshney P et al. J Allergy Clin Immunol 2011; 127:

37 Safety Initial day: 9/19 of active required treatment (2 adrenaline) Build-up: symptoms in 1.2% of 407 doses Varshney P et al. J Allergy Clin Immunol 2011; 127:

38 85 children, 7-16 yrs, sige 26 wks of OIT vs avoidance (open label) 2phase with 2wk increments Maintenance of 800mg peanut flour Subsequent OIT for the avoidance group

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40 INTERACTIVE QUESTION 2: Value of OIT How close to the bedside do you think OIT should currently be? A. Still experimental only B. Can be used clinically in specific settings C. Use should be widespread

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42 Meglio P et al. Curr Opin Allergy Immunol 2013; 13:

43 OIT : Research or Clinical procedure? Can be performed as a clinical procedure only in highly specialised centres* * EAACI Food Allergy Guidelines

44 SLIT vs OIT: safer but less effective

45 Milk SLIT vs. Milk OIT Keet CA et al. J Allergy Clin Immunol 2012; 129:

46 Other

47 Fish - SC

48 EU FP7 project, intending to bring hypoallergen-based immunotherapies against fish and peach to the clinical trial stage

49 mcyp c1 (parvalbumin w point mutations at calcium-binding sites) I. Swoboda et al. J. Immunol. 2007;178:

50 Douladiris N et al. J. Allergy Clin Immunol. 2015

51 mcyp c1 is immunogenic, stable and not toxic Phase I/IIa successful (minor AE, induction of IgG Phase IIb underway L. Zuidmeer et al. CEA 2013

52 Epicutaneous Immunotherapy Very little data (one letter, 2 abstracts) In a small study in milk, trend of improvement of the tolerated dose Local and some distant reactions no anaphylaxis Dupont et al. J Allergy Clin Immunol 2010; 125: 1165

53 Promising (but still not there )

54 INTERACTIVE QUESTION 3: Alternative approaches Which of the following approaches do you find convincing? A. Hypoallergens B. SLIT C. EPIT Note: Each option should be voted separately

55 Conclusions Food allergy immunotherapy is advancing fast Oral immunotherapy is currently the main option Efficacy is high, still there are frequent side effects Current clinical value debated Exchange of random with expected reactions Reduced risk for reactions to traces Alternative approaches under investigation

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57 Thank you