Secondary prevention of allergic disease. Dr Adam Fox United Kingdom

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1 Secondary prevention of allergic disease Dr Adam Fox United Kingdom

2 Disclosures Lecture fees: Danone, Mead Johnson, ALK-Abello, Stallergenes, Allergy Therapeutics Industry-sponsored grant: Danone, ALK-Abello Consultancy: NICE, Danone, Mead Johnson, Arla, Thermofisher Scientific

3 St Thomas Hospital, London, UK

4 Contents of Today s Presentation How do we define prevention? Evidence for secondary prevention of allergic disease Grazax Asthma Prevention trial (GAP) Implications of a positive outcome

5 Patient s side Illness Prevention definitions: general Prevention levels absent Doctor s side Disease present absent Primary prevention (illness absent, disease absent) Secondary prevention (illness absent, disease present) present Tertiary prevention (illness present, disease present)

6 Prevention and the allergic march According to ARIA Level Definition with respect to allergy Primary prevention Primary prevention is employed where there is no evidence of allergic sensitisation, focused on populations at high risk of becoming sensitised Secondary prevention Secondary prevention is employed in individuals who show evidence of sensitisation but not evidence of allergic symptoms Tertiary prevention Tertiary prevention are preventive strategies for the management of established allergic rhinitis or asthma Bousquet et al. Allergy 2008;63 (Suppl 86):8-160

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8 Secondary Prevention

9 Preventive effect Randomised, controlled prospective trials Subcutaneous Immunotherapy Authors/study Population Study design/type Endpoint: preventive effects of SIT Polosa et al Adults, yrs (n=30) AR (Parietaria) Randomised, double-blind, placebo-controlled, 3-year trial Alutard SQ, ALK-Abelló At 3 years: Asthma developed in 14% vs 47% of controls (p=0.056) No asthma PAT Trial (Preventive Allergy Treatment) Möller et al Niggeman et al Children, 6-14 yrs (n=205) AR (grass/birch) Randomised, open, controlled, 10-year follow-up trial Alutard SQ, ALK-Abelló At 3, 5, 10 years: Significant reduction in development of asthma Jacobsen et al No asthma

10 Preventive Allergy Treatment (PAT) Alutard SQ Open, randomised, controlled trial, (Den, Swe, Fin, Nor, Ger) 205 children (6 to 14 years), with clinical history of rhinoconjunctivitis to grass pollen (60%), birch pollen (21%), or both (19%) Despite negative histories of asthma at screening, 42 children (20%) were identified as having mild asthma in the baseline season Subjects randomized to receive either: Alutard SQ (Phl p and/or Bet v) 100,000 SQ Open control group usual therapy Subjects received 3 years treatment and were followed for total of 10 years! Möller et al. JACI 2002;109:251-6 Jacobsen et al. Allergy 2007:62:943-8

11 Subjects developing asthma (%) SCIT preventive effect Reduced risk of developing asthma Subject developing asthma at 3, 5, and 10 years (percent of subjects; n=151) * * * OR=2.5 OR=3.1 OR=2.5 Control Alutard SQ 45% 20 0 ** p< years Treatment Follow-up Möller et al. JACI 2002;109:251-6 Jacobsen et al. Allergy 2007:62:943-8

12 Preventive effect Randomised, controlled prospective trials Sublingual Immunotherapy Authors/study Population Study design/type Preventive effects of SIT Novembre et al Children, 5-14 yrs (n=113) AR (grass) No asthma Randomised, open, controlled, 3-year trial SLIT drops, ALK-Abelló At 3 year: Asthma development: 18% vs 41% of controls (p=0.04, OR 3.8) Marogna et al Children, 5-17 yrs (n=216) AR (multiple species) ± intermittent asthma Randomised, open, controlled, 3-year trial SLIT drops, Anallergo At 3 year: Development of mild persistent asthma: 1.5% vs 28.8% of control (p<0.001)

13 Novembre et al ALK-SLIT drops Open, randomised, controlled trial Italy 113 children (5 to 14 years), with clinical history of rhinoconjunctivitis to grass pollen, no asthma Subjects randomised to receive either: ALK-SLIT drops (biologically standardised 5-grass mixture), pre-seasonally and co-seasonally regimen Open control group usual therapy Subjects received 3 years treatment Novembre E et al. JACI 2004;114:851-7

14 Percent of subjects (%) SLIT drop asthma preventive effect Percentages of children with and without asthma* after 3 years (age and centre adj. odds-ratio = 3.8) 82% Asthma No asthma % ALK-SLIT drops 41% 59% Control group * 3 episodes of wheezing-breathing difficulty and/or cough, separated by 1 week, and requiring bronchodilator Novembre E et al. JACI 2004;114:851-7

15 GRAZAX Asthma Prevention Trial GT-21 (GAP) 16

16 GRAZAX Summary Grazax demonstrated to be both efficacious and well tolerated in children with grass pollen induced rhinoconjunctivitis Grazax proven to result in a disease-modifying effect in adults Grazax induces similar immunological response in children as in adults; supporting hypothesis that disease-modifying effect will also occur in children Extrapolation from adult studies is not acceptable and paediatric studies are required* Hence there is a rationale that Grazax can stop the allergic march and prevent the development of asthma in children with allergic rhinoconjunctivitis The GAP trial we hope will provide a conclusive answer to this question! *Calderon et al. EAACI Position statement, 2012

17 GAP study principles Randomised, parallel group, double-blind, placebo-controlled, multicentre trial Recruit children with proven grass pollen related rhinoconjunctivitis who do not have asthma or overlapping symptomatic allergies Randomised to 3 years of Grazax or Placebo Regularly screen for asthma through treatment and 2 year follow-up period Primary outcome is time to onset of asthma

18 Key entry criteria Children 5-12 years of age at time of randomisation A clinical relevant history of grass pollen induced allergic rhinoconjunctivitis having received symptomatic treatment during GPS 2009 and GPS 2010 Positive SPT response and positive specific IgE against Phleum pratense Without medical history of asthma and/or wheezing within last 2 years or since 5th birthday

19 Screening 1 GAP Trial Design Screening 2 Randomisation Status Grazax n= SQ-T AIT daily Placebo AIT n=310 Year monthly visits Screening (1st season) Treatment period (3 years) Post-treatment period (2 years)

20 Trial Recruitment Enrolment of 620 subjects was planned Total of 812 children randomised, distributed 100 centres 37% girls, 96% Caucasian, mean age at randomisation was 9.4 years 71% of subjects had at least one first degree relative with a history of allergy and 35% had at least one first degree relative with a history of asthma 26

21 27 Sensitisation pattern at screening

22 Clinical Implications of Preventive Trials if Positive?

23 Clinical Implications Significant change in health economics of SIT if disease prevention proven Long-term view required by health providers Enhanced importance of early recognition of allergic disease Requirement for capacity to desensitise significantly larger numbers of children

24 Summary SIT offers potential to halt the allergic march Current studies underway should provide robust answers about disease prevention Disease preventative effects may significantly alter the place of SIT in clinical practice

25 Acknowledgements GAP team St Thomas Hospital Prof Gideon Lack (joint site PI) Dr George DuToit Dr Kate Swan Roisin Fitzsimons Victoria Timms Graham Roberts (CI) Sue Driver (ALK)