Sandra del Pozo

Background: The mannan‐conjugated birch pollen polymerised allergoid EP‐088_T502 has previously been shown to reduce allergic symptoms and anti‐allergic medication use during the birch pollen season. This confirmatory phase III trial aimed to evaluate the efficacy, safety, tolerability, and immunologic effects of EP‐088_T502 administered as eight subcutaneous injections over six pre‐seasonal treatment visits. Methods: In this double‐blind, placebo‐controlled (DBPC) trial, 278 participants with birch pollen–induced allergic rhinoconjunctivitis (ARC) received either placebo or a cumulative dose of 28,000 mannan therapeutic units (mTU) of EP‐088_T502. The primary efficacy endpoint was the combined symptom and medication score (CSMS) during the peak birch pollen season. Safety, tolerability, health‐related quality of life (QoL), and immunologic parameters were also assessed. Results: In the full analysis set (FAS), EP‐088_T502 significantly reduced the CSMS during the peak birch pollen season compared with placebo (mean absolute difference [MAD] −0.31; 95% confidence interval [CI], −0.56 to −0.05; p = 0.0169). In the per‐protocol (PP) and complete‐case sets, the corresponding MADs were −0.36 ( p = 0.012) and −0.51 ( p = 0.013), respectively. Health‐related QoL improved by 20% in the EP‐088_T502 group compared with placebo during the peak season ( p < 0.005). EP‐088_T502 increased Bet v 1‐specific immunoglobulin G4 (IgG4) levels after treatment compared with placebo (6.4‐fold; p < 0.0001). The Bet v 1‐specific immunoglobulin E (IgE)/IgG4 ratio was reduced by 73% from baseline and by 69% compared with placebo (both p < 0.0001). Thirteen systemic allergic reactions occurred, including one grade III systemic reaction considered related to EP‐088_T502. Conclusions: EP‐088_T502 significantly improved symptom and medication scores in participants with birch pollen–induced ARC and induced a substantial Bet v 1‐specific IgG4 response. The 28,000 mTU regimen induced a substantial immunological response and showed an acceptable safety and tolerability profile.

Background/Objectives: Placebo responses can complicate the interpretation of allergen immunotherapy (AIT) trials because symptom- and medication-based outcomes may be influenced by the trial context in addition to treatment-specific effects. Injection-free comparison cohorts are rarely available in conventional double-blind, placebo-controlled AIT trials. We therefore conducted an exploratory post hoc cross-study comparison of clinical outcomes in two placebo-injection cohorts and an injection-free cohort of birch pollen-allergic participants. Methods: Data from three prospective clinical studies evaluating the mannan-conjugated birch pollen allergoid EP-088-T502—T502-SIT-020, T502-SIT-045, and T502-SIT-068—were assembled for this cross-study comparison. Placebo-injection cohorts from studies T502-SIT-020 and T502-SIT-045 were compared with the injection-free cohort from study T502-SIT-068. Clinical outcomes included the Combined Symptom and Medication Score (CSMS), daily Symptom Score (dSS), and daily Medication Score (dMS). Results: The primary peak-period analysis included 60, 93, and 160 participants from T502-SIT-020, T502-SIT-045, and T502-SIT-068, respectively. During the site-specific 14-day peak birch pollen periods, median CSMS was 2.14 in the injection-free cohort compared with 1.34 and 1.07 in the T502-SIT-020 and T502-SIT-045 placebo-injection cohorts, respectively. These values corresponded descriptively to approximately 37% and 50% lower cohort medians, respectively, relative to the injection-free cohort. Median dSS, which was defined consistently across the three source studies, was 1.22 in the injection-free cohort compared with 0.78 and 0.70 in the two placebo-injection cohorts. Median dMS was 0.93 compared with 0.39 and 0.36, respectively. The same between-cohort pattern was observed in the secondary fixed 1–30 April analysis. Conclusions: Both placebo-injection cohorts showed lower CSMS and dSS values than the injection-free cohort. Because the cohorts were non-concurrent and derived from separate studies, the observed differences do not establish a causal effect of placebo injections.

Background/Objectives: Allergic rhinoconjunctivitis (AR) induced by house dust mites (HDMs) is a common condition that impairs quality of life, and allergen immunotherapy is the only treatment accepted to modify its natural course. However, real-world evidence on polymerized HDM subcutaneous immunotherapy (SCIT) remains limited. We evaluated the up to 24-month effectiveness of polymerized HDM SCIT and examined how baseline symptom burden affects the measured response. Methods: In a retrospective, single-arm, real-world cohort, 353 patients (mean age 15.9 (12.3) years) with HDM-induced AR with/without asthma (asthma subpopulation, n = 112) initiated polymerized SCIT (ALXOID^®, Inmunotek S.L., Spain) with an extract of house dust mites (Dermatophagoides pteronyssinus, D. farinae, Blomia tropicalis). Patients were followed for up to 24 months; 139 contributed an observation at month 12 and 67 at month 24. The primary outcome was the Rhinoconjunctivitis Combined Symptom–Medication Score (RCSMS); secondary outcomes were a visual analog scale (VAS) and the ESPRINT-15 quality-of-life questionnaire. Effectiveness was estimated using mixed models for repeated measures. The pre-specified primary-analysis population was restricted to a baseline RCSMS ≥ 2 to avoid floor effects and regression to the mean at low baseline scores. Results: At month 24, the RCSMS decreased by 0.938 points (−35.3%) in the full cohort and by 48.3% in the baseline RCSMS ≥ 2 population; in the full cohort, the VAS and ESPRINT-15 improved by 50.6% and 69.7%, respectively (all p < 0.001; within-subject effect sizes were small for the full-cohort RCSMS and medium for all other outcomes). The shape of the improvement trajectory did not differ by age group, and all age groups exceeded the minimal clinically important difference; the age analysis was exploratory. Patients with baseline RCSMS < 2 showed continued improvement in VAS and ESPRINT-15 scores. In contrast, the RCSMS increased, a pattern consistent with a statistical floor effect, suggesting limited responsiveness of the score at low baseline values. Conclusions: Up to 24 months, polymerized HDM SCIT was associated with clinically meaningful improvements in symptoms, medication use, and quality of life, most clearly in patients with a baseline RCSMS ≥ 2. Baseline symptom severity should be considered when interpreting combined symptom–medication outcomes in allergen immunotherapy. The single-arm design precludes causal inference.

Background/Objectives: Placebo responses can substantially influence patient-reported outcomes in clinical trials and are particularly relevant in allergen immunotherapy (AIT), where treatment efficacy is commonly assessed using symptom- and medication-based endpoints. We conducted an exploratory post hoc cross-study comparison of birch pollen-allergic participants who received pre-seasonal placebo injections in two randomised, double-blind, placebo-controlled AIT trials with participants from a third trial in whom the planned study injections were not administered before the corresponding birch pollen season. Methods: Data were pooled from three prospective clinical studies evaluating the mannan-conjugated birch pollen allergoid EP-088-T502: T502-SIT-020, T502-SIT-045, and T502-SIT-068. Placebo-injection cohorts from studies T502-SIT-020 and T502-SIT-045 were compared with the injection-free cohort from study T502-SIT-068. Clinical outcomes included the Combined Symptom and Medication Score (CSMS), daily Symptom Score (dSS), and daily Medication Score (dMS). Results: The three comparison cohorts comprised 321 participants: 161 in the injection-free cohort and 160 in the placebo-injection cohorts. Participants in the injection-free cohort had significantly higher symptom and medication scores during the secondary fixed 1–30 April analysis period than participants in the placebo-injection cohorts. Median CSMS was 1.97 in the injection-free cohort compared with 1.32 and 0.86 in the placebo-injection cohorts. Likewise, median dSS (1.08 vs. 0.79 and 0.59) and dMS (0.87 vs. 0.33 and 0.25) were higher in the injection-free cohort. Pairwise comparisons indicated statistically significant between-cohort differences. Conclusions: In this non-randomised, non-concurrent cross-study comparison, symptom and rescue-medication scores were lower in the placebo-injection cohorts than in the injection-free cohort. Because the cohorts were derived from separate studies conducted in different years, these findings are hypothesis-generating and do not establish a causal effect of placebo injections. Trial-related contextual factors and other cross-study differences should be considered when interpreting the results.

Background/Objectives: Previous studies have demonstrated the safety of pre-seasonal treatment with the mannan-conjugated birch pollen allergoid EP-088-T502. However, the safety of a combined pre- and co-seasonal treatment regimen has not yet been investigated. As climate change is associated with earlier and less predictable onset of birch pollen seasons, planned pre-seasonal allergen immunotherapy may unintentionally overlap with natural pollen exposure. Therefore, evaluation of the safety of treatment administered during the pollen season is of increasing clinical relevance. This study aimed to compare, in a purely descriptive manner, the safety and tolerability of pre-seasonal versus pre- and co-seasonal treatment with EP-088-T502. Methods: In this prospective, open-label, phase III trial (T502-SIT-059) (EudraCT No.: 2022-004082-20), patients (N = 109) who had participated in a preceding pivotal phase III study were offered continuation treatment with active EP-088-T502 (10,000 mTU/mL) across five treatment visits. For the subgroup analysis, all patients who completed their last treatment visit before 9 April 2023 (and, thus, before the start of the birch pollen season in Germany) were assigned to the pre-seasonal group (N = 20). Those who performed the last treatment visit thereafter were assigned to the pre-/co-seasonal group (N = 83). Due to post hoc subgroup allocation and unequal subgroup sizes, all subgroup analyses were purely descriptive. Results: No deaths nor serious adverse events (SAEs) were reported during the study. No epinephrine administration was required. Systemic adverse drug reactions (SADRs, N = 3) occurred in two patients who had previously received placebo. No grade III or IV systemic reactions, according to the German AWMF classification, were observed. Patients receiving pre- and co-seasonal treatment developed smaller wheals (mean diameter) compared with the pre-seasonal group (immediate reactions: 0.6 vs. 0.7 cm; late-phase reactions: 0.3 vs. 0.4 cm at the last treatment visit). This was also reflected in the medians (immediate reactions: 0.2 cm vs. 0.4 cm; late-phase reactions: 0.2 vs. 0 cm at the last treatment visit). Of all AEs that were (possibly) related to EP-088-T502 (N = 89), 74 (83%) occurred at the first three treatment visits (before the birch pollen season). The frequency of AEs appeared descriptively similar between groups for the last two treatment visits. Patients who had received placebo in the previous trial experienced more treatment-related side effects compared to patients who had already received EP-088-T502 in the previous year. Conclusions: These data suggest that EP-088-T502 is safe and well-tolerated, even when administered during the birch pollen season, regardless of prior exposure to EP-088-T502.

Background: The mannan-conjugated birch pollen polymerised allergoid EP-088_T502 has previously been shown to reduce allergic symptoms and anti-allergic medication use during the birch pollen season. This confirmatory phase III trial aimed to evaluate the efficacy, safety, tolerability, and immunologic effects of six pre-seasonal subcutaneous injections.Methods: In this DBPC trial, 278 participants with birch pollen–induced allergic rhinoconjunctivitis (ARC) received either placebo or a cumulative dose of 28,000 mTU EP-088_T502. The primary efficacy endpoint was the combined symptom and medication score (CSMS) during the peak birch pollen season. Safety, tolerability, health-related quality of life (QoL), and immunologic parameters were also assessed.Results: EP-088_T502 significantly reduced the CSMS during the peak birch pollen season compared with placebo (mean absolute difference [MAD] −0.31; p=0.016, FAS). In the PP and Complete Cases sets, MAD were -0.36 (p=0.012) and -0.51 (p=0.013), respectively. Health-related QoL improved by 20% in the EP-088_T502 group compared with placebo during the peak season (p<0.005). EP-088_T502 increased Bet v1-specific IgG4 levels after treatment compared with placebo (6.4-fold; p<0.0001). The Bet v1-specific IgE/IgG4 ratio was reduced by 73% from baseline and by 69% compared with placebo (both p<0.0001). Thirteen systemic allergic reactions occurred, including one grade III systemic reaction considered related to EP-088_T502.Conclusions: EP-088_T502 significantly improved symptom and medication scores in participants with birch pollen–induced ARC and induced a substantial Bet v1-specific IgG4 response. The higher cumulative dose was associated with enhanced immunologic effects and an acceptable safety and tolerability profile.

Background/Objectives: Previous studies have demonstrated the safety of pre-seasonal treatment with the mannan-conjugated birch pollen allergoid EP-088-T502. However, the safety of a combined pre- and co-seasonal treatment regi-men has not yet been investigated. This study aimed to compare the safety and tolera-bility of pre-seasonal versus pre- and co-seasonal treatment with EP-088-T502. Meth-ods: In this prospective, open-label, phase III trial (T502-SIT-059) (EudraCT No.:2022-004082-20), patients (N=109) who had participated in a preceding pivotal phase III study were offered continuation treatment with active EP-088-T502 (10.000 mTU/mL) across five treatment visits. For the subgroup analysis, all patients who completed their last treatment visit before 9 April 2023 (and thus before the start of the birch pollen season in Germany) were assigned to the pre-seasonal group (N=20). Those who performed the last treatment visit thereafter were assigned to the pre/co-seasonal group (N=83). Both groups were compared in terms of local and sys-temic immediate and late phase reactions and other EP-088-T502-related adverse events (AEs). Results: No deaths nor serious adverse events (SAEs) were reported during the study. No epinephrine administration was required. Systemic adverse drug reactions (SADRs, N=3) occurred in two patients who had previously received placebo. No grade III or IV systemic reactions according to the German AWMF classification were observed. Patients receiving pre- and co-seasonal treatment developed smaller wheals (mean diameter) compared with the pre-seasonal group (immediate reactions: 0.6 vs. 0.7 cm, late phase reactions: 0.3 vs. 0.4 cm at the last treatment visit). This was also reflected in the medians (immediate reactions: 0.2 cm vs. 0.4 cm, late-phase reac-tions: 0.2 vs. 0 cm at the last treatment visit). Of all AEs that were (possibly) related to EP-088-T502 (N=89), 74 (83%) occurred at the first three treatment visits (before the birch pollen season). The frequency of AEs was comparable between groups for the last two treatment visits. Patients who had received placebo in the previous trial experienced more treatment related side effects compared to patients who had already received EP-088-T502 in the previous year. Conclusions: These data suggest that EP-088-T502 is safe and well tolerated even when administered during the birch pollen season, regardless of prior exposure to EP-088-T502.

Background: Mannan‐conjugated allergoids represent an effective option for treating allergic diseases. This study evaluated the clinical impact of the mannan‐conjugated, polymerised birch pollen allergoid EP‐088_T502 in patients with birch pollen‐induced allergic rhinoconjunctivitis over 3 years. Methods: Following up to a double‐blind, placebo‐controlled dose‐finding study, in this open, long‐term extension study, 154 birch pollen‐allergic patients were enrolled in Germany. Patients were treated with a cumulative dose of 48,000 mTU EP‐088_T502 administered subcutaneously over five pre‐seasonal visits in each of the two treatment years (2021, 2022) with a subsequent follow‐up year in 2023. The primary efficacy endpoint was the combined symptom and medication score (CSMS) during the peak birch pollen season, which was compared with the CSMS of the placebo group during the peak pollen season of 2020. Safety, tolerability, and immunogenicity were also analysed. Results: Compared to the placebo group of the preceding study, median CSMS during the peak birch pollen seasons showed reductions of 47.5% in 2021 ( p < 0.001), 51.8% in 2022 ( p < 0.001), and 36.5% in 2023 ( p < 0.001). Median daily symptom scores were reduced by 40.7% in 2021 ( p < 0.001), 40.7% in 2022 ( p < 0.001), and 25.6% in 2023 ( p < 0.010). Median daily medication scores reached 0.07 in 2021 and 0.04 in 2022 ( p < 0.001) and were reduced by 65.9% in 2023 ( p < 0.003). Immunological responses showed a 4.82‐fold increase in Bet v1 sIgG4 ( p = 0.001) and a marked decrease (−65.5%, p = 0.001) in the sIgE/sIgG4 ratio after the first treatment phase. EP‐088_T502 demonstrated good safety and tolerability, with only six mild to moderate systemic allergic reactions (Grade I/II). No epinephrine was used. Conclusion: In this open‐label study, two consecutive years of pre‐seasonal short‐course allergen immunotherapy (AIT) with EP‐088_T502 markedly reduced symptoms and medication need in patients with birch pollen‐induced rhinoconjunctivitis. Persistent therapeutic effects observed during the follow‐up year, although limited by attrition of the study population, suggest sustained clinical improvement and indicate the potential disease‐modifying impact of this treatment regimen.

Background/Objectives: Allergen immunotherapy (AIT) with chemically modified allergoids represents a promising approach for the treatment of allergic rhinoconjunctivitis. This post hoc analysis investigated the clinical efficacy of a mannan-conjugated birch pollen allergoid (T502) by comparing outcomes in patients who received placebo in one pollen season and active treatment in the following year. Methods: Data were derived from four randomized clinical trials (EudraCT Numbers: 2018-002522-23, 2020-004126-32, 2021-002252-36, and 2022-004082-20) conducted over four consecutive years. Two independent patient groups were analyzed, with each group receiving placebo in the first year and subcutaneous T502 (10,000 mTU/mL) in the subsequent year. Daily symptom score (dSS), daily medication score (dMS), and combined symptom and medication score (CSMS) were assessed during the birch pollen season in April of each year. Results: In the first comparison between placebo in 2020 and an early treatment start in January 2021, treatment with T502 led to a 43.79% reduction in dSS (p ≤ 0.0001), a 71.43% reduction in dMS (p ≤ 0.001), and a 42.1% reduction in CSMS (p ≤ 0.001), all statistically significant. In the second comparison between placebo in 2022 and a late treatment start in March 2023, the reduction in dMS was 74.47% (p ≤ 0.001), whereas reductions in dSS (1.47%, p = 0.898) and CSMS (20.3%, p = 0.057) were not statistically significant. Conclusions: Subcutaneous immunotherapy (SCIT) with T502 significantly reduces allergic symptoms and medication use, particularly when all injections are completed before the onset of the birch pollen season in April. These findings highlight both the clinical value of T502 and the importance of optimized treatment timing.

Background/Objectives: Allergen immunotherapy (AIT) with chemically modified allergoids represents a promising approach for the treatment of allergic rhinoconjunctivitis. This post-hoc analysis investigated the clinical efficacy of a mannan-conjugated birch pollen allergoid (T502) by comparing outcomes in patients who received placebo in one pollen season and active treatment in the following year. Methods: Data were derived from four randomized clinical trials (EudraCT Numbers. 2018-002522-23, 2020-004126-32, 2021-002252-36, 2022-004082-20) conducted over four consecutive years. Two independent patient groups were analyzed, each receiving placebo in the first year and subcutaneous T502 (10,000 mTU/mL) in the subsequent year. Daily symptom score (dSS), daily medication score (dMS), and combined symptom and medication score (CSMS) were assessed during the birch pollen season each April. Results: In the first comparison between 2020 and the early start in January 2021, treatment with T502 led to a 43.79% reduction in dSS (p = 0.000), a 71.43% reduction in dMS (p = 0.001), and a 42.1% reduction in CSMS (p = 0.001), all statistically significant. In the second comparison between 2022 and a late start in March 2023, the reduction in dMS was 74.47% (p = 0.001), whereas reductions in dSS (1.47%, p = 0.898) and CSMS (20.3%, p = 0.057) were not statistically significant. Conclusions: Subcutaneous immunotherapy (SCIT) with T502 significantly reduces allergic symptoms and medication use, particularly when all injections are completed before the onset of the birch pollen season in April. These findings highlight both the clinical value of T502 and the importance of optimized treatment timing.