SQ sublingual immunotherapy tablets for children with allergic rhinitis: A review of phase three trials.

AIM: To provide paediatricians with a summary of efficacy and safety of SQ sublingual immunotherapy (SLIT) tablets from phase three, randomised, double-blind, placebo-controlled trials in children and adolescents with allergic rhinitis or rhinoconjunctivitis, with and without asthma. METHODS: PubMed searches were conducted and unpublished data were included if necessary. RESULTS: Of the 93 publications, 12 were identified reporting 10 trials. One trial was excluded as paediatric-specific efficacy data were unavailable. The nine eligible trials evaluated grass, house dust mite, ragweed and tree SLIT tablets. Consistent reductions in allergic rhinitis or rhinoconjunctivitis symptoms and medication use were observed with SQ SLIT tablets versus placebo. In a five-year trial, sustained reduction of allergic rhinoconjunctivitis symptoms, asthma symptoms and medication use were observed with SQ grass SLIT tablet versus placebo. The number-needed-to-treat to prevent asthma symptoms and medication use in one additional child during follow-up was lowest in younger children. SQ SLIT tablets were generally well tolerated across trials. CONCLUSION: Evidence supports use of SQ SLIT tablets in children and adolescents with allergic rhinitis or rhinoconjunctivitis, with and without asthma. Long-term data demonstrate disease-modifying effects of SQ grass SLIT tablet and suggest the clinical relevance of initiating allergy immunotherapy earlier in the disease course.

Real-world, long-term effectiveness of allergy immunotherapy in allergic rhinitis: Subgroup analyses of the REACT study.

BACKGROUND: Randomized controlled trials have demonstrated the efficacy of allergy immunotherapy (AIT) in allergic rhinitis (AR) and the disease-modifying effects of the SQ grass sublingual immunotherapy (SLIT) tablet. OBJECTIVE: We sought to assess real-world, long-term effectiveness and safety across AIT subgroups: route of administration, therapeutic allergen, persistence to AIT, and SQ grass SLIT tablet. METHODS: The primary outcome of AR prescriptions from a retrospective cohort study (REAl-world effeCtiveness in allergy immunoTherapy; 2007-2017) was assessed across prespecified AIT subgroups in subjects with AR with and without AIT prescriptions (controls). Safety was assessed as anaphylaxis for 2 days or less of the first AIT prescription. Subgroup follow-up continued until samples were fewer than 200 subjects. RESULTS: Subcutaneous immunotherapy (SCIT) and SLIT tablets showed similarly greater reductions in AR prescriptions than controls (SCIT vs SLIT tablets: year 3, P = .15; year 5, P = .43). Comparably greater reductions in AR prescriptions were observed for grass- and house dust mite-specific AIT than for controls, but significantly smaller reductions were observed for tree-specific AIT (tree vs house dust mite, and vs grass: years 3 and 5, P < .0001). Persistence to AIT was associated with greater reductions in AR prescriptions versus nonpersistence (persistence vs nonpersistence: year 3, P = .09; year 5, P = .006). SQ grass SLIT tablet showed sustained reductions versus controls for up to 7 years (year 3, P = .002; year 5, P = .03). Rates of anaphylactic shock were low (0.000%-0.092%), with no events for SQ SLIT tablets. CONCLUSIONS: These results demonstrate real-world, long-term effectiveness of AIT, complement disease-modifying effects observed in SQ grass SLIT-tablet randomized controlled trials, and highlight the importance of using newer evidence-based AIT products for tree pollen AR.

Kounis syndrome following allergy injection in a paediatric patient.

Kounis syndrome is the concurrence of acute coronary syndrome or coronary vasospasm with conditions associated with the release of inflammatory cytokines through mast cell activation in the setting of allergic or anaphylactic reactions. Many identified triggers have been identified in paediatric patients including exposures, drugs, and immunisations; however, to our knowledge this is the first case report of Kounis syndrome linked to immunotherapy. We present a case of a 9-year-old with seasonal allergies presenting with clinical symptoms of Kounis syndrome following her weekly subcutaneous injection of allergens. Clinicians need a high index of suspicion for Kounis syndrome in patients who develop systemic signs of anaphylaxis with clinical, laboratory, electrocardiographic, and echocardiographic findings of acute coronary syndrome to help direct therapy and improve outcomes.

Allergen Release Profiles of Fast-Dissolving Freeze-Dried Orodispersible Sublingual Allergy Immunotherapy Tablets.

Background: Sublingual allergy immunotherapy tablets (SLIT-tablets) provide a well-tolerated and clinically efficacious treatment for allergic disease such as allergic rhinitis and allergic asthma. In SLIT, uptake of allergen by immune-competent cells in the oral mucosa activates the immune system and leads to tolerance toward the sensitizing allergen. The ability to deliver the full allergen content into solution within the recommended sublingual holding time is therefore an essential quality of SLIT-tablets that must be supported by the tablet formulation for all relevant allergen sources. SLIT-tablets based on a fast-dissolving orodispersible freeze-dried formulation (Zydis) are currently available for 5 of the most prevalent allergens: tree (birch and related species from the birch-homologous group), grass, ragweed, Japanese cedar, and house dust mite. Objectives: The purpose of this study was to examine the allergen release properties of three freeze-dried SLIT-tablets containing tree, ragweed, and Japanese cedar extracts, respectively. The correlation between SLIT-tablet allergen release and the level of allergen-specific T-cell activation was examined for the tree SLIT-tablet. Methods: Allergen release kinetics and tablet disintegration times for the 3 freeze-dried SLIT-tablets were examined. For all 3 tablets, the magnitude of solubilized major allergen relative to time in solution was compared to external controls to achieve a measure of the total allergen release. Additional assessments of allergen release occurring after the initial timepoint (15 or 30 seconds in solution) were done independently of external controls by linear regression analyses. For the tree SLIT-tablet, the immunological potency of the released major allergen was assessed at each experimental timepoint by a Bet v-specific T-cell activation assay. Results: All 3 SLIT-tablets disintegrated within 1 second after contact with assay buffer without any detectible residue. Complete release of major allergens (Bet v 1, Amb a 1, and Cry j 1, respectively) was seen at the earliest experimental time points (15 or 30 seconds). For the tree SLIT-tablet, full T-cell activation was achieved at 30 seconds (earliest experimental time point). Conclusions: The freeze-dried SLIT-tablet formulation consistently provides rapid and complete release of allergen from a wide range of species in a standardized in vitro assay. Full release of the SLIT-tablet allergen content within the sublingual holding time is a prerequisite for maximal exposure of allergens to the sublingual mucosa immune system. The freeze-dried SLIT-tablet formulation examined here supports short sublingual holding times and furthermore offers a convenient administration form of allergy immunotherapy.

Simplified AIT for allergy to several tree pollens-Arguments from the immune outcome analyses following treatment with SQ tree SLIT-tablet.

BACKGROUND: The SQ tree SLIT-tablet (containing birch extract) proved clinically significant effects during the pollen season for birch as well as alder/hazel. Immune outcomes of this treatment for allergens from multiple birch homologous trees need further investigation. We hypothesize that birch pollen extract AIT modulates a highly cross-reactive immune response and that this may be the basis for the observed clinical cross-protection. METHODS: Blood samples were collected from 397 birch allergic patients during SQ tree SLIT-tablet or placebo treatment (1:1) for up to 40 weeks. Serum IgE and IgG4 specific to birch, and birch homologous tree pollens from alder, hazel, hornbeam, beech and chestnut were measured by ImmunoCAP. IgE-Blocking Factor (IgE-BF) for alder, birch and hazel during treatment was measured by Advia Centaur and blocking effects for birch and all these birch homologous tree pollens were further investigated by basophil activation (BAT). Antibody readouts were investigated in patient subsets. T-cell responses (proliferation) to allergen extracts and peptide pools (group 1 allergens) were investigated in T-cell lines from 29 untreated birch pollen-allergic individuals. RESULTS: Significant Pearson correlations between serum IgE towards birch, alder, hazel, hornbeam and beech were observed (r-values > .86). T-cell reactivity was observed throughout the birch homologous group. Almost identical kinetics for changes in IgE towards birch, alder and hazel were observed during treatment and similar species-specific changes were seen for serum-IgG4 . IgG4 reactivity towards birch and alder, hazel, hornbeam and beech correlated significantly at end-of-treatment (r-values > .72). Treatment resulted in similar IgE-BF kinetics for alder, birch, and hazel and blocking of BAT for multiple trees in most actively treated patients investigated. CONCLUSIONS: Systematic analyses of T-cell and antibody cross-reactivities before and during birch pollen extract AIT provide the immunological basis for the observed clinical effect of SQ tree SLIT-tablet treatment of tree pollen allergy induced by multiple trees in the birch homologous group.

Aqueous intradermal low-dose house dust mite immunotherapy in tropical settings: a valid cost-effective approach for developing nations?

INTRODUCTION: Aqueous allergen injections, an effective and century-old technique, is considered a second-line approach in daily clinical practice. Inconveniences still surround conventional subcutaneous immunotherapy (SCIT) administration, such as a need for frequent injections, prolonged up-dosing schedules, elevated costs, and the unlikely possibility of a systemic reaction. The intradermal immunotherapy route (IDR) might favorably impact many of the aforementioned issues (Table 1). House dust mite (HDM) allergens are the main perennial sensitizers in the tropics, and as such, are solely employed in immunotherapy treatments. METHODS: We carried out a year-long real-life study in 25 perennial allergic rhinitis children, symptomatic on exposure to house dust, employing an intradermal low-dose allergen mix consisting of 50 ng of Dermatophagoides pteronyssinus/Dermatophagoides farinae and 120 ng of Blomia tropicalis, under a unique cost-wise protocol. Basal symptoms/signs and face Visual Analog Scale (fVAS) scores were recorded for 2 weeks and later compared with those registered throughout the 1-year treatment. Serum-specific IgG4 and IL-10 levels were employed in the assessment of the immune responses. RESULTS: Symptoms/signs and fVAS scores were significantly reduced from days 42 and 49, respectively, and remained so until treatment completion. Increases in specific IgG4's and IL-10 levels reflected significant immune responses. Injections were well tolerated and families reported improved health status (quality of life, QoL). CONCLUSIONS: A unique cost-effective immunotherapy alternative for deprived allergic communities in tropical settings is depicted; further research is needed.

The moderating role of allergy immunotherapy in asthma progression: Results of a population-based cohort study.

BACKGROUND: Allergic asthma causes substantial morbidity and constitutes a public health burden, which increases with asthma severity. There is evidence that allergy immunotherapy (AIT) prevents the progression of allergic rhinitis (AR) to asthma. However, evidence is missing on the potential of AIT to prevent progression from milder to more severe asthma. METHODS: This population-based cohort study utilized healthcare data (2005 to 2014) from a statutory health insurance in Germany. The severity of asthma was classified according to the treatment steps recommended by the global initiative for asthma (GINA). The effect of AIT on the transition between the GINA steps was analyzed using multivariable Cox regression models adjusted for age and sex. RESULTS: From the total cohort of 1,739,440 patients, 39,167 individuals aged 14 years or older were classified as having incident asthma during the observation period and were included in the study. From these, 4111 patients (10.5%) received AIT. AIT exposure was associated with a significantly decreased likelihood of asthma progression from GINA step 1 to GINA step 3 (HR 0.87; 95% CI 0.80-0.95) and GINA step 3 to GINA step 4 (HR 0.66; 95% CI 0.60-0.74). GINA medication for step 2 and step 5 was rarely prescribed. CONCLUSIONS: This observational study in a real-world setting indicates that patients with allergic asthma who receive AIT are less likely to experience progression of asthma severity than asthma patients not receiving AIT.

Is allergy immunotherapy with birch sufficient to treat patients allergic to pollen of tree species of the birch homologous group?

Pollen from various Fagales tree species prolongs the season and makes tree pollen allergy a major health problem. Despite involving the same causative allergens, allergy immunotherapy (AIT) treatment habits differ significantly across different geographical regions. Diagnosis and treatment with AIT in patients allergic to tree pollen were discussed by a group of German medical experts who give practical recommendations based on the available data. Regulatory perspective: According to current guidelines on allergen products, birch pollen are the representative allergen source of the birch homologous group including several Fagales trees based on sequence and structural similarity of their allergen proteins. Immunological perspective: A high level of IgE cross-reactivity towards allergens from the birch homologous group has been observed in basic research and clinical trials. Clinical perspective: Clinical trial data show that the efficacy of birch pollen AIT is not only related to birch pollen allergy but extends to pollen from other trees, especially alder, hazel and oak. In order to optimize diagnosis and treatment of tree pollen allergy, the experts recommend to focus diagnosis and respective treatment with AIT primarily to birch as the representative allergen of the Fagales tree homologous group, but further diagnostics may be needed for some patients to determine adequate treatment.

State of the Art: Development of a Sublingual Allergy Immunotherapy Tablet for Allergic Rhinitis in Japan.

Allergic rhinitis (AR) caused by house dust mite (HDM) and Japanese cedar pollen (JCP) represents a significant, expanding health problem in Japan. Allergic symptoms often have a severe impact on the QOL such as sleep disturbance and reduced school and work performance. In addition to the classical symptoms, AR is known to be a risk factor for the development of allergic asthma, a potentially life-threatening condition. Allergy immunotherapy (AIT) is a well-documented, safe, effective treatment option for respiratory allergic disease. It has been demonstrated that AIT can provide relief from clinical symptoms and that AIT has the potential to provide long-term post-treatment effect. Although the mechanism of AIT is not fully understood, it can actively modulate protective allergen-reactive pathways of the immune system and alter the natural course of disease. Unlike pharmacotherapy, AIT addresses the basic immunological mechanisms that are responsible for the development and persistence of allergic conditions. Currently two main routes of AIT administration are commonly available, subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT). Both SCIT and SLIT are clinically effective, and SLIT is particularly well tolerated, with a lower risk of systemic allergic reactions compared with SCIT. To date, SLIT tablets have been developed for a range of different allergies including HDM and JCP and are the best-documented AIT treatment form. Here we introduce the current status of development of a SLIT tablet in Japan for AR, examine the clinical aspects and mechanism of action of AIT, and discuss the future directions of SLIT.

The SQ tree SLIT-tablet is highly effective and well tolerated: Results from a randomized, double-blind, placebo-controlled phase III trial.

BACKGROUND: The SQ tree sublingual immunotherapy (SLIT)-tablet (ALK-Abelló, Hørsholm, Denmark) is developed for treatment of tree pollen-induced allergic rhinoconjunctivitis (ARC). OBJECTIVE: The aim of this pivotal phase III trial was to demonstrate the efficacy and safety of the SQ tree SLIT-tablet. METHODS: This was a randomized, double-blind, placebo-controlled trial with 634 subjects (12-65 years) with moderate-to-severe ARC despite use of symptom-relieving medication. Eligible subjects were randomized 1:1 to active or placebo treatment. The primary end point was the average daily ARC total combined score (TCS) during the birch pollen season (BPS) analyzed for subjects with diary data during the BPS. Secondary end points included average daily symptom scores (DSS) during the BPS, average TCS and DSS during the tree pollen season (TPS), and average daily medication scores (DMS) in the BPS and TPS. RESULTS: The primary and key secondary end points demonstrated statistically significant and clinically relevant effects of the SQ tree SLIT-tablet compared with placebo. For the BPS, absolute (relative) differences from placebo were 3.02 (40%) for TCS, 1.32 (37%) for DSS, and 1.58 (49%) for DMS (all P < .0001). For the TPS, absolute (relative) differences from placebo were 2.27 (37%) for TCS, 0.99 (33%) for DSS, and 1.20 (47%) for DMS (all P < .0001). Treatment was well tolerated. The most frequently reported treatment-related adverse events were mild or moderate local reactions related to sublingual administration. CONCLUSION: The trial demonstrated the efficacy and safety of the SQ tree SLIT-tablet compared with placebo during the BPS and TPS in adolescents and adults with birch pollen-induced ARC (EudraCT 2015-004821-15).

Allergen Immunotherapy and Atopic Dermatitis: the Good, the Bad, and the Unknown.

PURPOSE OF REVIEW: In light of the recent advancements in atopic dermatitis treatment, this review aims to summarize the utility and efficacy of allergy immunotherapy in atopic dermatitis patients. We examine its mechanism, pathophysiology, cost-efficacy, and current guidelines for clinical practice. RECENT FINDINGS: The literature supports the use of allergy immunotherapy in atopic conditions such as allergic rhinitis and asthma but insufficient evidence exists to suggest its efficacy in atopic dermatitis. The use of allergy immunotherapy has been shown to provide long-term cost savings in both the USA and the European Union in certain populations but differences in prescribing patterns and manufacturing make it difficult to study its impact on a larger, generalizable scale. Conflicting meta-analyses data and conclusions highlight the need for better, higher quality research to better understand allergy immunotherapy utility in atopic dermatitis.

Establishment of enzyme-linked immunosorbent facilitated antigen binding as a biomarker assay for Japanese cedar pollen allergy immunotherapy.

BACKGROUND: Clinical efficacy of allergen-specific Immunotherapy (AIT) towards Japanese cedar (JC) pollen allergy is firmly established but JC pollen-specific biomarker assays are lacking. Treatment-related increase of allergen-specific antibodies is a robust biomarker of successful AIT. Allergen-specific non-IgE antibodies are believed to reduce the effects of allergen exposure by competing with IgE for allergen binding, and in-vitro assays quantifying the effects of AIT-induced IgE-blocking antibodies are advantageous. A cell-free enzyme-linked immunosorbent facilitated antigen binding (ELIFAB) assay of JC pollen was established. METHODS: Serum IgE-allergen complexes were captured by immobilized recombinant CD23, and allergen-IgE-CD23 complexes were detected by a biotin-conjugated anti-human IgE antibody. Sera from JC pollen-allergic subjects without or with subcutaneous immunotherapy (SCIT) with JC pollen extract were used (n = 11/group). RESULTS: Optimal assay conditions were established at 20 µg/mL CD23 and 0.3 µg/mL JC pollen extract, and the dependency on CD23 and IgE was verified. The data show that the JC pollen ELIFAB assay is fit for purpose and demonstrates that the IgE-blocking activity is significantly increased in the JC pollen SCIT group compared with the non-treated group. CONCLUSION: The JC pollen ELIFAB assay represents a simple, cell-free biomarker assay for monitoring the development of IgE-blocking antibody activity during JC pollen AIT.

Safety profile of the SQ house dust mite sublingual immunotherapy-tablet in Japanese adult patients with house dust mite-induced allergic asthma: a randomized, double-blind, placebo-controlled phase I study.

Objective: The SQ house dust mite (HDM) sublingual immunotherapy (SLIT)-tablet has demonstrated effective treatment of HDM-induced allergic asthma in patients 18 years or older in European trials. This study investigated its safety and immunology profile in Japanese adult patients with mild-to-moderate HDM-induced allergic asthma. Methods: In this randomized, double-blind, placebo-controlled study, 48 Japanese patients were randomly assigned to a daily treatment of SQ HDM SLIT-tablet or placebo (3:1) for 14 d with or without an up-dosing regimen. Active groups comprised 5000, 10,000 or 20,000 Japanese Allergy Unit (JAU) for 14 d, and the up-dosing group comprised 5,000 JAU in day 1-3, 10,000 JAU in day 4-7 and 20,000 JAU in day 8-14. Results: No marked differences were observed in the incidence rate of adverse events (AEs) and their severity among active groups. The five most common investigational medicinal product (IMP)-related AEs were local events at the application site observed within 30 min after the intake of the SQ HDM SLIT-tablet. Although most events recovered within 1 h, mouth edema indicated a different profile of duration with more than 25% of the events lasting for more than 1 h. Conclusions: The SQ HDM SLIT-tablet of up to 20,000 JAU was well tolerated, and safety profile was acceptable for Japanese subjects with HDM-induced allergic asthma.

Allergy immunotherapies for allergic rhinitis: systematic review and assessment of evolving quality.

Summary: Background. Heterogeneity in the design and quality of trials evaluating allergy immunotherapies (AITs) limits their comparability, making it difficult for physicians, patients, and payers to select the best treatment option. Methods. This systematic review evaluated the quality of randomised controlled trials (RCTs) of registered grass AITs using the National Institute of Health and Care Excellence checklist. Results. 17 of 44 unique RCTs (38.6%) (sample size range: 18-1,501 subjects) were subcutaneous grass immunotherapy trials and 27 (61.4%) were sublingual grass immunotherapy trials (Allergovit, 5 trials; Alutard, 8; Grazax, 13; Oralair, 6; Staloral, 8; Pollinex, 2; Phostal and Purethal, 1 each). Three trials (6.8%; all Grazax) fulfilled every quality criterion. Quality assessments revealed inconsistencies in study quality and reporting. Study quality trended towards improvement over time, particularly after 2009. Conclusions. When as-sessing grass AIT, it is important to focus not only on endpoints but also on the quality of evidence.

Cost-effectiveness of the SQ HDM SLIT-tablet for the treatment of allergic asthma in three Eastern European Countries.

Summary: Background.The SQ® house dust mite (HDM) sublingual immunotherapy (SLIT)-tablet (ACARIZAX®, ALK-Abelló A/S, Hørsholm, Denmark) is an allergy immunotherapy tablet for people with allergic respiratory disease. This analysis aims to assess the cost-effectiveness of the SQ HDM SLIT-tablet from the perspective of three Eastern European countries: Czech Republic, Poland and Slovakia. Methods.A cost-utility model per country was developed, which compared the SQ HDM SLIT-tablet as add-on to pharmacotherapy with pharmacotherapy alone in patients with HDM allergic asthma (AA) over a five year time horizon. The effectiveness of the two interventions was based on the results from a large-scale randomised controlled trial. In the models, annual costs and quality-adjusted life year (QALY) scores from the trial were extrapolated over a five year period, and the incremental cost-effectiveness ratios (ICERs) were estimated. One-way deterministic sensitivity and scenario analyses were undertaken. Results.The SQ HDM SLIT-tablet is cost-effective in all three markets over the five year time horizon (ICERs of less than € 10,000 per additional QALY). Treatment with the SQ HDM SLIT-tablet improves patient outcomes, with QALY gains of 0.35, versus pharmacotherapy only. In all three countries, the SQ HDM SLIT-tablet also incurs increased costs compared to pharma-cotherapy treatment only. The sensitivity analysis identified utility values from the clinical trial as the main driver of the model results. Conclusion.The SQ HDM SLIT-tablet is a cost-effective treatment option for people with HDM AA in three different health care settings in Eastern Europe.

Results from the 5-year SQ grass sublingual immunotherapy tablet asthma prevention (GAP) trial in children with grass pollen allergy.

BACKGROUND: Allergy immunotherapy targets the immunological cause of allergic rhinoconjunctivitis and allergic asthma and has the potential to alter the natural course of allergic disease. OBJECTIVE: The primary objective was to investigate the effect of the SQ grass sublingual immunotherapy tablet compared with placebo on the risk of developing asthma. METHODS: A total of 812 children (5-12 years), with a clinically relevant history of grass pollen allergic rhinoconjunctivitis and no medical history or signs of asthma, were included in the randomized, double-blind, placebo-controlled trial, comprising 3 years of treatment and 2 years of follow-up. RESULTS: There was no difference in time to onset of asthma, defined by prespecified asthma criteria relying on documented reversible impairment of lung function (primary endpoint). Treatment with the SQ grass sublingual immunotherapy tablet significantly reduced the risk of experiencing asthma symptoms or using asthma medication at the end of trial (odds ratio = 0.66, P < .036), during the 2-year posttreatment follow-up, and during the entire 5-year trial period. Also, grass allergic rhinoconjunctivitis symptoms were 22% to 30% reduced (P < .005 for all 5 years). At the end of the trial, the use of allergic rhinoconjunctivitis pharmacotherapy was significantly less (27% relative difference to placebo, P < .001). Total IgE, grass pollen-specific IgE, and skin prick test reactivity to grass pollen were all reduced compared to placebo. CONCLUSIONS: Treatment with the SQ grass sublingual immunotherapy tablet reduced the risk of experiencing asthma symptoms and using asthma medication, and had a positive, long-term clinical effect on rhinoconjunctivitis symptoms and medication use but did not show an effect on the time to onset of asthma.

Efficacy and safety of SQ house dust mite sublingual immunotherapy-tablet in Japanese children.

BACKGROUND: The SQ house dust mite (HDM) sublingual immunotherapy (SLIT)-tablet (TO-203, Torii, Japan/ALK, Denmark) treatment has been effective against respiratory allergic diseases in patients aged ≥12 years during European, Japanese, and North American trials. This trial was conducted to investigate the efficacy and safety of this treatment in Japanese children (5-17 years) with moderate-to-severe HDM allergic rhinitis (AR). METHODS: In this randomized, double-blind, placebo-controlled trial, 458 Japanese children were randomly assigned to a daily SQ HDM SLIT-tablet [10 000 Japanese Allergy Unit (JAU), equivalent to 6 SQ-HDM in Europe and the US] or placebo (1:1) treatment for 1 year. Inclusion required an AR symptom score of ≥7 on at least 7 days during a 14-day run-in period while symptomatic treatment was withdrawn. The primary endpoint was the total combined rhinitis score (TCRS) comprising AR symptom and medication scores during the last 8 weeks of the treatment period. RESULTS: The analysis of primary endpoint demonstrated statistically significant absolute reduction in TCRS of 1.22 with a relative difference of 23% (95% confidence interval, 14% to 31%) in the 10 000 JAU compared with placebo. Predefined stratified analyses revealed the same degree of efficacy of 1.11 (P = 0.002), 21% (8% to 32%) and 1.36 (P = 0.001), 26% (11% to 38%), respectively, in pediatric (5-11 years) and adolescent subjects (12-17 years). The treatment was well tolerated by both pediatric and adolescent subjects. CONCLUSION: This trial, for the first time, demonstrated the efficacy and safety of the HDM SLIT-tablet in pediatric patients with moderate-to-severe HDM AR (JapicCTI-152953).

Efficacy and safety of the SQ house dust mite sublingual immunotherapy tablet in Japanese adults and adolescents with house dust mite-induced allergic rhinitis.

BACKGROUND: The SQ house dust mite (HDM) sublingual immunotherapy (SLIT) tablet has been approved in 11 European countries and Japan for patients with HDM-induced respiratory allergic disease. OBJECTIVE: This trial was conducted to confirm the efficacy and safety of the SQ HDM SLIT tablet in Japanese patients with moderate-to-severe HDM-induced allergic rhinitis (AR). METHODS: The trial was a randomized, double-blind, placebo-controlled trial including 946 Japanese adults and adolescents (12-64 years). Subjects were randomly assigned to daily treatment with the SQ HDM SLIT tablet at a dose of 10,000 Japanese allergy units (JAU) or 20,000 JAU or to placebo (1:1:1). The primary end point was the total combined rhinitis score (TCRS), which is composed of AR symptom and medication scores during the efficacy evaluation period. Symptom and medication scores of AR and conjunctivitis, rhinitis quality of life, and symptom-free and symptom-severe days were evaluated as secondary end points. RESULTS: Analysis of the primary end point demonstrated statistically significant reductions in TCRSs of 1.15 (22%, P < .001) in the 10,000-JAU group and 0.99 (19%, P < .001) in the 20,000-JAU group compared with the placebo group. The statistically significant treatment effect was evident from 12 weeks of treatment onward. All secondary end points, except AR medication score, were statistically significant in favor of active treatment compared with placebo. Post hoc analysis of TCRSs in adolescents showed the same efficacy as in adults (P < .05). The treatment was well tolerated by both adults and adolescents. CONCLUSION: The trial confirmed the efficacy and safety profile of the SQ HDM SLIT tablet in Japanese adult and adolescent patients with moderate-to-severe HDM-induced AR. These data support the robust efficacy and safety profile of previously reported European data.

Intradermal grass pollen immunotherapy increases TH2 and IgE responses and worsens respiratory allergic symptoms.

BACKGROUND: Repeated low-dose grass pollen intradermal allergen injection suppresses allergen-induced cutaneous late-phase responses comparably with conventional subcutaneous and sublingual immunotherapy. OBJECTIVE: We sought to evaluate the efficacy and safety of grass pollen intradermal immunotherapy in the treatment of allergic rhinitis. METHODS: We randomly assigned 93 adults with grass pollen-induced allergic rhinitis to receive 7 preseasonal intradermal allergen injections (containing 7 ng of Phl p 5 major allergen) or a histamine control. The primary end point was daily combined symptom-medication scores during the 2013 pollen season (area under the curve). Analysis was by intention to treat. Skin biopsy specimens were collected after intradermal allergen challenges, and late-phase responses were measured 4 and 7, 10, or 13 months after treatment. RESULTS: There was no significant difference in the primary end point between treatment arms (active, n = 46; control, n = 47; median difference, 14; 95% CI, -172.5 to 215.1; P = .80). Among secondary end points, nasal symptoms were worse in the intradermal treatment group, as measured based on daily (median difference, 35; 95% CI, 4.0-67.5; P = .03) and visual analog scale (median difference, 53; 95% CI, -11.6 to 125.2; P = .05) scores. In a per-protocol analysis intradermal immunotherapy was further associated with worse asthma symptoms and fewer symptom-free days. Intradermal immunotherapy increased serum Phleum pratense-specific IgE levels (P = .001) compared with those in the control arm. T cells cultured from biopsy specimens of subjects undergoing intradermal immunotherapy had higher expression of the TH2 surface marker CRTH2 (P = .04) and lower expression of the TH1 marker CXCR3 (P = .01), respectively. Late-phase responses remained inhibited 7 months after treatment (P = .03). CONCLUSION: Intradermal allergen immunotherapy suppressed skin late-phase responses but was not clinically effective and resulted in worsening of respiratory allergic symptoms.