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 MCT®-associated allergoids did not receive prescriptions for symptomatic asthma medication in the follow up period vs. control group (p = 0.037). Significant differences were also shown for the treatment group of allergoid 2 (15.0%, p < 0.001) and allergoid 3 (11.6%, p < 0.001) and therefore for the entire AIT treatment group (13.8%, p < 0.001, see Figure 3b).
In addition, the prescriptions of symptomatic asthma medication in the MCT®-associated allergoid treatment group were significantly reduced by 33.7% in the follow-up vs. baseline and control group (p = 0.016). These effects could also be demonstrated for the allergoid 2, allergoid 3 and the entire AIT treatment group (22.8%, 25.7%, 24.7%, p < 0.001, see Table 2).
Onset of asthma was analysed for non-asthmatic children and adolescents at baseline. The probability of asthma medication onset during follow-up was significantly reduced for children and adolescents treated within the AIT group compared to controls (OR: 0.74; p = 0.02, see Figure 4a). The probability of not being prescribed symptomatic asthma medication was significantly greater for children and adolescents treated with AIT compared to the control group (see Figure 4c).
Discussion
The TARGET study demonstrates that grass or tree pollen AIT is associated with significantly reduced AR progression, i.e. less symptomatic medication prescriptions in the total AIT group and different allergoid SCIT groups. These results are in line with the results of other RWE studies published by Wahn et al and Vogelberg et al . The beneficial effect was demonstrated for MCT®-associated SCIT allergoid with a higher percentage of patients without AR medication prescription in comparison to the control group. The percentage of patients without AR medication prescription is in line with other RWE studies . In addition, a significant reduction of AR medication prescription in the follow-up vs. baseline and control group was observed for the MCT®-associated allergoid. Beneficial effect was also observed for allergoid 2 and 3.
The TARGET study also showed a significant decrease in the probability of requiring anti-asthmatic medication and amount of anti-asthmatic mediation prescribed during follow up. This beneficial effect was also observed for the different analysed AIT products including a higher percentage of patients without asthma medication in comparison to the control group. 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. Again, this effect was also seen for the AIT subgroup analysis. In terms of the additional reduction in asthma medication during follow-up vs pre-index compared to the control group, the TARGET study revealed a reduction of 29.1% points for the total AIT population. Wahn et al. reported a reduction of 32.0% points 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 five years of follow-up, however, afterwards the probability of asthma free survival is greater for AIT patients compared to control patients. Importantly, the beneficial effect of an AIT on the occurrence of asthma was statistically significant overall as well as for adults and children/adolescents which is in contrast to the study by Wahn et al. This might be due to the higher proportion of children and adolescents in the TARGET study (~45% vs ~20%) as it has been proposed that onset of asthma can be best prevented starting therapy early in childhood and adolescence . The European Academy of Allergy and Clinical Immunology (EAACI) recommend AIT for children and adolescents in order to prevent asthma . Further, another retrospective RWE LRx database study by Devillier et al. point out the consistent long-term benefits of an AIT in patients with AR with or 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 et al., REACT, using claims data of a German health insurance fund database . Fritzsching et al. 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. It must be considered that real-world studies should not be directly compared due to different in- and exclusion criteria, data source, matching of patients and further aspects of differing study design.
The present real‐world findings add to the current body of clinical evidence extending existing RCT evidence for AIT. Becker et al. performed a meta-analysis on RCTs recently showing a significant improvement of allergic symptoms and reduction in medication use in patients treated with MCT®-associated allergoids . Showing a reduction in AR and asthma medication prescription of 24.2% and 35.6% compared to control group after SCIT with MCT®-associated allergoids, the results of the TARGET study are highly valuable data to complement the efficacy data of MCT®-associated SCIT allergoids.
This RWE study had several limitations. Clinical information had to be obtained via proxies like for AR diagnosis by prescription of symptomatic AR medication . Some patients with AR might have not been detected, because a large proportion of AR medication is available over‐the counter. Furthermore, from 2017 onwards some intranasal corticosteroids were not reimbursed. However, for children up to the age of 12 years non-prescription AR drugs can be prescribed at the expense of the statutory health insurance funds which should minimize this effect in this age group. Moreover, all anti-asthmatic medications are prescription-bound. In total, any such bias should affect both the AIT and non-AIT control groups equally, thus not impacting the relative comparisons between the groups.
Importantly, the unmet need for an appraisal of the quality of RWE in AIT has been addressed by Paoletti et al. 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 . RWE will likely prove to be of enormous value to synthesize evidence from the different sources RCTs and RWE studies, a position which is already changing with regard to evolving regulatory opinions, guidance frameworks, and with growing recognition of the value of using RWE that is acceptable for regulatory decision‐making . The FDA and EMA is already developing guidance that defines how regulators consider RWE in their decision-making - both for new and existing approvals .
The main strengths of this study are that it was conducted in a real‐world, large and inclusive patient cohort, with the longest follow up period (after AIT completion) shown in AIT RWE studies (up to 9.5 years, Ø 6.3 years). The current study used a stringent patient‐matching process with at least 58% of eligible patients being matched to appropriate controls. Each AIT group was matched separately to their controls ensuring high data quality and a good comparability of the study cohorts with their controls. This reduced confounding, avoided possible bias from intergroup differences and ensured robustness of findings.
Conclusions
RWE studies are playing an increasingly important role. Health authorities in US 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 and 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 MCT®-associated allergoids on the progression of AR and progression and occurrence of asthma 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 in the individual analyses. 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 MCT®–associated allergoids in AR and asthma under real-world conditions.