Long‐term effects of pollen allergoid tyrosine‐adsorbed subcutaneous immunotherapy on allergic rhinitis and asthma

Allergen immunotherapy (AIT) may have a long‐term disease‐modifying effect. The aim of this study was to demonstrate the long‐term effects of pollen allergoid tyrosine‐adsorbed subcutaneous AIT on allergic rhinitis (AR) and asthma (AA) in clinical practice.


| INTRODUC TI ON
Over the last 50 years, the number of patients with allergies may have increased. 1Allergic rhinitis (AR) has a 12-month prevalence in children of 8.8%, increasing to 15.3% in adolescence. 24][5] In Germany, about 1 million children and adolescents are affected by AR, ~0.5 million of adolescents by asthma and among adults the 12-month prevalence of asthma is 6%. 2,6The increasing number of adult patients affected by allergies emphasizes the importance of effective, disease-modifying therapies.
Allergen immunotherapy (AIT) has a long-term disease-modifying effect and may reduce allergic progression or new sensitizations. 1,7,8 the relative risk of developing bronchial asthma within 10 years is 3.5-fold higher for patients with AR and the risk of a change from AR to allergic asthma is greatest for children with hay fever, early AIT initiation for children has been recommended, with a focus on products for which appropriate effects have been shown. 1,7For AIT several standardized products are available, differentiated by the route of application as subcutaneous (SCIT) or sublingual immunotherapy (SLIT).
0][11] SCIT is well investigated in controlled, intermittent and mild persistent asthma. 7The most common adjuvant to strengthen the AIT immune response is aluminium hydroxide. 9,12,13An alternative adjuvant, microcrystalline tyrosine (MCT, 14 ), shows a favourable safety profile inducing even less anaphylactic reactions in mice and induces less TH2 related cytokines which should be suppressed in AIT. 15 SCIT must be administered by a physician and requires regular visits during the 3-year maintenance phase.Thus, patient adherence is essential for efficacy.A low level of compliance and persistence, particularly when using SLIT is observed. 168][19] This may have an influence on the placebo effect.
The efficacy and safety has been proven for various SCIT allergoids preparations including tyrosine-adsorbed allergoids in DBPC studies and meta-analyses under ideal clinical study conditions. 20e efficacy of tyrosine-adsorbed allergoid was demonstrated in a meta-analysis providing evidence for the efficacy of SCIT in pollen allergy-induced allergic rhinoconjunctivitis (ARC), showing significant reduction of allergic symptoms and medication use. 21In addition to DBPC studies, Real-world evidence (RWE) data increase corroboration by allowing insights into the therapeutic effectiveness in more representative populations, especially in children/adolescents, and after AIT completion.RWE studies are playing an increasingly important role.Health authorities in the United States and Europe have recognized the added value of RWE studies and are working on the framework of the 'Real-World Evidence Program'. 22,23e aim of the 'Tyrosine Allergoid-Real World Evidence in Germany-Effectiveness in AIT' (TARGET) study is to demonstrate the long-term effects of tyrosine-adsorbed allergoid pollen SCIT on AR and asthma in adults, children/adolescents (5-65 years) in routine clinical practice.

| Study design
This study was a retrospective data analysis using a German longitudinal prescription database (LRx, IQVIA, Frankfurt am Main, Germany).
The overall analysis period was from January 2008 to June 2020.
The index period was defined from September 2009 to August 2013, including four allergy seasons (September to August).For the AIT group (Figure 1A), eligible patients were initiated on the respective SCIT products at index date during this period.A pre-index period of 12 months before SCIT initiation was determined.Treatment period lasted from index date until expiry of the last prescription of the respective product followed by the follow-up period of at least 2 years until end of the study in June 2020.
For the control group (Figure 1B), index date was defined as the first prescription in the second allergy season during the index period.Treatment period was from index date until expiry of the last prescription of the respective product within a maximum of 5 years followed by the follow-up period of at least 2 years until end of the study in June 2020.
Three authorized allergoids in Germany containing grass or tree pollen were analysed: One tyrosine-adsorbed allergoid and two aluminium hydroxide adjuvanted allergoids (allergoid 2 and 3).For the control group symptomatic AR medications were defined in accordance with the ARIA guideline 2019. 1

| Database
The analyses are conducted with IQVIA™, a German database accessing nationwide pharmacy data collection centres processing anonymized prescription data of all German patients within the statutory health insurance system allowing patient follow-up over time.
The coverage for back data since 2008 is about 35% of all German statutory prescriptions.

| Patients
Patients meeting the following criteria were included in the overall AIT group: age ≥5 and ≤ 65 years; received at least one prescription F I G U R E 1 Study periods for patients in the AIT group (A) and the control group (B) including pre-index period, treatment period and follow-up period.
of a symptomatic AR medication (intranasal corticosteroids (INCS), oral and intranasal H1-antihistamines (AH)) during the pre-index period (Figure 1A); received treatment with one of the selected AIT products with at least four prescriptions in ≥3 consecutive pollen seasons between index date and end of year 5; initiated treatment with one of these products between September 2009 and August 2013, and ≥2 years of follow-up after treatment.
Each AIT group has a matched control group with patients between the age ≥5 and ≤65 years with AR and/or asthma with at least three prescriptions of symptomatic AR medication in three successive allergy seasons (September to August) and with at least 2 years of follow-up (Figure 1B).
Patients were excluded if they had received any specific immunotherapy in the entire database history (January 2008 to June 2020); had severe asthma (defined as having prescriptions of biologics for asthma) or perennial asthma defined as ≥3 prescriptions of inhaled corticosteroids (ICS), long-acting ß2-agonists (LABA) in combination with inhaled corticosteroids, theophylline or leukotriene receptor antagonists (LTRA), distributed over any three successive 4-month periods before the index date]; if they had COPD-specific maintenance medication in the entire database history; if they had extreme (0.25% of largest) values in terms of number of AR, allergic conjunctivitis (AC) or anti-asthmatic prescriptions during pre-index or follow-up period or if they had prescriptions of allergens of the focus product of both grass and tree pollen (Table S1).
Patients in the different control groups (Table S2) underwent exact matching with those in each AIT group.More than 58% of the patients were matched based on all defined covariates.Subsequently, in separate matching steps, covariates were removed to match the remaining patients.Details can be found in Table S3.

| Outcomes
The impact on AR progression was measured by symptomatic AR medication prescription after expiry of AIT treatment considering the probability of requiring symptomatic AR medication in the follow-up period and the number and reduction of AR prescriptions in the follow-up period standardized by year compared to the preindex period.
For asthmatic patients, defined as patients treated with two prescriptions of anti-asthmatic medication (short-acting-ß2-agonists (SABA), inhaled corticosteroids (ICS), leukotriene receptor antagonists (LTRA), fix combination of ICS and long-acting-ß2-agonists (LABA)) in the same or two sub-sequent allergy seasons, the impact of the study products on the progression of asthma was measured analogously.The other patients were classified as non-asthmatic at baseline.After expiry of AIT treatment the impact of the study products on asthma progression was measured by the probability of requiring anti-asthmatic medication and number and reduction of anti-asthmatic prescriptions in the follow-up period standardized by year after AIT compared to the pre-index period.
For non-asthmatic patients at index date, the impact on asthma incidence was measured analogously by the occurrence and by time to prescription of anti-asthmatic medication in the follow-up period.

| Statistical analysis
Descriptive statistics were presented for all outcome variables and covariates.Analyses of AR progression, progression or occurrence of asthma were carried out using a general linear regression model, with the ratio of annual number of prescriptions in the follow-up period versus the pre-index period used as the outcome variable.
Analysis of AR and asthma medication intake was achieved by logistic regression with a stepwise selection of significant covariates.The individual length of the analytical time span was included as a covariate.Time to asthma medication intake was investigated using survival analysis.The proportion of patients with any level of treatment between the AIT and non-AIT control groups was also analysed by logistic regression.Statistical analyses were based on two-way testing without exception.For all statistical tests, significance level was set to 5% (p < .05).Analyses were performed using SAS 9.4 software SAS Institute, Inc., Cary, NC, USA.

| Patient population
Within the index period, 181,496 patients received prescriptions within the AIT group.5959 patients fulfilled the inclusion criteria with a median AIT treatment duration of 1092 days.Eligible patients had at least 2 follow-up years with the median follow-up duration of 6.3 years (Table 1).Of these 44.8% received grass and 55.2% tree pollen allergoids.504 of these patients received the tyrosineadsorbed allergoid, 3329 patients allergoid 2 and 2126 patients allergoid 3. The same number of matched control patients were included for each group (Table 1).For each study product about half of the patients were classified at index as adults (3256 patients >18-65 years), followed by a high number of children (1958 patients 5-12 years) and adolescents (745 patients 13-18 years).Baseline characteristics are summarized in Table 1.AIT therapy was mainly prescribed by Specialists (ENT specialist, dermatologist, pulmonologist, 58.9%), followed by Paediatricians (26.5%) and Generalists (14.5%).Slightly more than half of the children/adolescents received AIT therapy through Paediatricians (56.1%), 59.0% of those treated with the tyrosine-adsorbed allergoid, 52.9% with allergoid 2 and 59.6% with allergoid 3. The second most frequent prescribers of AIT therapy in this age group were Specialists (Table 1).Before AIT initiation 26.6% of the patients already had received asthma medication.The proportion of asthma was higher for patients initiated on the tyrosine-adsorbed allergoid (31.9%) than for patients initiated on allergoid 2 or 3 (25.5% and 27.1%).The percentage of juvenile asthma patients was higher (30.6%) than in adults (23.3%, age > 18 years).

TA B L E 1 (Continued)
This proportion was highest in children/adolescents treated with tyrosine-adsorbed allergoid, at 36.8%.The percentage of asthma patients was lower for allergoid 2 (29.2%) and allergoid 3 (30.8%)(Table 1).Descriptive statistics of number of AR and asthma medication prescriptions for the pre-index period, follow-up period and pre-index/follow-up ratio are depicted in Tables S4 and S5.  2).

| AIT effectiveness on AR progression
The average number of prescriptions at baseline versus follow-up was 1.4 versus 0.2 (allergoid 2), 1.5 versus 0.2 (allergoid 3) and 1.5 versus 0.2 (entire AIT group).All endpoints were significant for children/adolescents and adults in the individual analyses (Table 2).

| AIT effectiveness on asthma progression
Asthma progression was analysed for asthmatic patients at baseline (Figure 3A).With 17.8%, significantly more patients treated with tyrosine-adsorbed allergoids did not receive prescriptions for symptomatic asthma medication in the follow-up period versus  3A).

| AIT effectiveness on onset of asthma
Asthma onset was analysed for non-asthmatic patients at baseline.The probability of asthma medication onset during follow-up was significantly reduced for patients treated within the AIT group compared to controls (OR: 0.77; 95% CI 0.66, 0.90; p = .001(all patients, 5-65 years); OR: 0.78; 95% CI 0.64, 0.96, p = .017(adults, <18-65 years), Figure 4A).The probability of not being prescribed symptomatic asthma medication was significantly greater for patients treated with AIT compared to the control group Figure 4B).

| AIT effectiveness on asthma progression and onset of asthma in children and adolescents
The progression of asthma was analysed for asthmatic children and adolescents at baseline.With 16.3%, significantly more patients treated with tyrosine-adsorbed allergoids did not receive prescriptions for symptomatic asthma medication in the follow-up period versus controls (OR: 0.51; 95% CI 0.27, 0.96; p = .037,Figure 3B).

F I G U R E 2 Proportion of all patients
(5-65 years) not receiving AR medication prescription during follow-up period.
Asthma onset was analysed for non-asthmatic children/adolescents at baseline.The probability of asthma medication onset during follow-up was significantly reduced for children/adolescents treated within the AIT group compared to controls (OR: 0.74; 95% CI 0.58, 0.95, p = .020,Figure 4A).The probability of not being prescribed symptomatic asthma medication was significantly greater for children/adolescents treated with AIT compared to controls (Figure 4C).

| DISCUSS ION
The TARGET study demonstrates that grass or tree pollen AIT is associated with significantly reduced AR progression, which is in line with other RWE studies. 24,25The beneficial effect was demonstrated for tyrosine-adsorbed SCIT allergoid with a higher percentage of patients without AR medication prescription in comparison to the control group (Figure 2) like in a previous RWE study. 24Significant reduction of AR medication prescription in the follow-up versus baseline and control group was observed for the tyrosine-adsorbed allergoid (Table 2).
The study shows a significant decrease in the probability of requiring anti-asthmatic medication (Figure 3A) and amount of antiasthmatic medication prescribed during follow-up (Table 2).As for AR medication, the control group also requires less anti-asthmatic medication.The proportion of asthmatic children/adolescents not requiring anti-asthmatic medication during follow-up is even greater compared to adults (Figure 3B).This effect is also seen for the AIT subgroup analysis.The study revealed an asthma medication reduction of 29.1% for the total AIT population (Table 2).Wahn et al. reported a reduction of 32.0% overseeing a shorter follow-up period of up to 6 years.
The Kaplan-Meier curves for AIT patients and patients without AIT are very close in the first 5years of follow-up, afterwards, the probability of asthma-free survival is greater for AIT patients (Figure 4B,C).Importantly, the beneficial effect of an AIT on the occurrence of asthma was statistically significant overall as well as for adults and children/adolescents (Figure 4A) which is in contrast to the study by Wahn, Bachert. 24This might be due to the higher proportion of children/adolescents in our study (~45% vs. ~20%) as it has been proposed that asthma onset can be best prevented starting therapy early in childhood. 1,7,26The European Academy of Allergy and Clinical Immunology recommends AIT for children/adolescents in order to prevent asthma. 27Further, another retrospective RWE study by Devillier, Demoly 28 point out the consistent long-term benefits of an AIT in patients with AR with/without associated asthma in terms of slower progression of AR and asthma medication intake, and reduced risk of new-onset asthma medication use, mirroring the efficacy findings in RCTs in the real-world setting.The findings of the TARGET study are supported by a recent retrospective cohort study by Fritzsching, Contoli, 29 which also found AIT patients to be associated with greater reductions in AR and asthma prescriptions and a reduction in asthma treatment compared to control subjects.
In addition, Zielen et al. 2018 30  a reduction of asthma medication and a positive effect on AR and asthma progression.It must be considered that real-world studies should not be directly compared due to different in-and exclusion criteria, data source, patient matching and further aspects of differing study design.
These real-world findings add to the current body of clinical evidence extending existing RCT evidence for AIT 31  is available over the counter.However, for children up to 12 years these can be prescribed at the expense of the statutory health insurance funds (SHI).Since October 2016, there are also restrictions in the SHI reimbursement of INCS 1 ; however, 90% of INCS packs delivered in Germany remain prescribes. 30Further, the percentage of INCS in symptomatic AR prescriptions in this study is around 42% in both, total AIT and control group.In summary, any such bias should affect the matched AIT and non-AIT control groups equally, thus not impacting the relative comparisons between both groups and conclusions. 24portantly, the unmet need for an appraisal of the quality of RWE in AIT has been addressed by Paoletti, Di Bona 32 who recently initiated a systematic review of observational studies of AIT to provide an essential source of real-world data and improve quality in clinical decision-making.4][35] FDA and EMA is already developing guidance that defines how regulators consider RWE in their decisionmaking-both for new and existing approvals. 23e main strengths of this study are that it was conducted in a real-world, large patient cohort, with the longest follow-up period shown in AIT RWE studies (up to 9.5 years, Ø 6.4 years).A stringent patient-matching process with at least 58% of eligible patients being matched to appropriate controls was used.Each AIT group was matched separately to their controls ensuring high data quality and good comparability of the study cohorts with their controls.This reduced confounding, avoided possible bias from intergroup differences and ensured robustness of findings.

F I G U R E 3 F I G U R E 4
Proportion of asthmatic adult patients (A) and asthmatic children and adolescents (B) not receiving antiasthmatic medication during follow-up period.Probability of developing asthma (A) and time to asthma onset for all patients (age 5-65 years (B) and for children and adolescents (C).
RWE studies are playing an increasingly important role.Health authorities in the United States and Europe have recognized the added value of RWE studies.In addition to DBPC studies, RWE data increase corroboration by allowing insights into the therapeutic effectiveness after AIT completion, especially in children/adolescents.The TARGET study has the longest follow-up period (after AIT completion) shown in AIT RWE studies so far and demonstrates the long-term benefit of pollen (grasses or trees) allergoid SCIT including tyrosine-adsorbed allergoids on AR progression and Asthma progression and occurrence up to 9.5 years of follow-up in clinical practice.Importantly, also the prevention of asthma was demonstrated.Results were significant for all patients (5-65 years) but also for children/adolescents and adults.The results of the TARGET study substantiate the findings of other RWE studies in patients with pollen-induced allergies and demonstrate the effectiveness of authorized SCIT allergoids including tyrosine-adsorbed allergoids in AR and asthma under real-world conditions.AUTH O R CO NTR I B UTI O N S Christian Vogelberg, Ludger Klimek and Sven Becker contributed to design, concept and interpretation of data, writing and approval of the version to be published.Silvia Kruppert contributed to design and concept, data analysis and interpretation, writing and approval of the version to be published.