Matthias F. Kramer

Purpose of Review: This review examines whether allergen immunotherapy (AIT) for grass pollen allergy should expand beyond the recent trend towards a mono-species approach based on Phleum pratense . It explores whether multi-species formulations better reflect natural exposure and could improve clinical outcomes. Recent Findings: Research from aerobiology and immunology shows that grass pollen exposure involves diverse species with distinct flowering periods, influenced by climate and geography. Molecular analyses reveal species-specific allergen profiles, including unique peptides and variations in major allergens such as Group 1 and 5. Patient data confirm symptom variability across the season. In-vitro studies have observed limits to the cross-reactivity of T-cell epitopes, and comparative clinical studies suggest benefits for multi-species treatment options. Summary: Evidence indicates that mono-species extracts alone do not represent the full allergenic spectrum of grass pollen. Broad-spectrum AIT formulations incorporating multiple grass species provide a more comprehensive repertoire of allergens and epitopes, potentially enhancing immunogenicity and therapeutic benefit. This supports the hypothesis that diversity does not equate to dilution in broad-spectrum formulations. The approach aligns with patient symptom patterns and may improve efficacy and asthma prevention. Future research could further refine species selection and leverage molecular diversity to optimize treatment strategies.

Background: Regulatory authorities recommend a combination of symptom and medication scores during the grass pollen season as a primary endpoint for Phase III allergen immunotherapy (AIT) trials targeting allergic rhinoconjunctivitis. However, many composite primary endpoint scales exist; none are validated, nor do they have a well‐justified minimal clinically important difference (MCID). Methods: Direct patient feedback from 1071 grass‐allergic patients was obtained to determine the minimally relevant improvement in allergic symptoms and translated into an MCID for the EAACI recommended CSMS _0–6 . Additionally, a clinically relevant threshold for the validated Rhinitis Quality of Life Questionnaire (RQLQ(S)) was determined from studies of registered SLIT products and subsequently used as an anchor to derive the MCID for CSMS _0–6 using the data of a Phase III clinical trial with PQ Grass 27,600 SU (RESONATE). Results: 69% of grass‐allergic patients were satisfied with a 1‐point‐improvement (e.g., from “severe” to “moderate”) in their most severe symptom. This translated into an MCID range for CSMS _0–6 of −0.23 to −0.21 points or −17% to −16%. Furthermore, a −0.34 point difference in RQLQ(S) compared to placebo was justified as clinically meaningful based on Phase III data from 2 registered SLIT grass tablets. Using this RQLQ(S) threshold as an anchor, an MCID of CSMS _0–6 of −0.21 points (−16%) was derived using RESONATE. Conclusions: Both patient feedback and RESONATE results support an average MCID of −0.22 points on the CSMS _0–6 scale and −16% on a composite primary endpoint scale, providing minimal thresholds to be achieved after AIT compared to placebo to conclude a positive Phase III trial outcome.

Background: A short‐course pre‐seasonal subcutaneous injection of PQ Grass is clinically effective for the treatment of allergic rhinitis, though its mechanism remains unclear. The aim of the study was to interrogate immunological mechanisms induced by PQ Grass conventional and extended regimens. Methods: A RDBPC exploratory field study involving participants that either received injections of PQ Grass with a cumulative dose of 27,600 SU conventional (six once weekly injections) or extended regimen (three once weekly injections followed by three once monthly injections) or placebo containing microcrystalline tyrosine (MCT) (placebo + MCT) or saline (placebo) was performed. Humoral, cellular, and molecular responses were assessed at baseline (V1), end of treatment, prior to grass pollen season (V12) and end of pollen season (V15). Immunoglobulin analyses and cellular/gene microarray analyses were performed in the sub‐study cohort consisting of PQ Grass Conventional ( n = 25 and n = 10, respectively), PQ Grass Extended ( n = 26 and n = 10, respectively), Placebo with MCT ( n = 13 and n = 5, respectively), and Placebo (saline; n = 12 and n = 5, respectively). Results: Both PQ Grass regimens, conventional and extended, were associated with improvement in total combined scores (TCS) with a relative difference of −35.0% ( p = 0.03) and −40.8% ( p = 0.01) against placebo with MCT, respectively. Both PQ Grass treatment regimens were associated with increases in the sIgG ₄ /sIgE ratio (all, p < 0.05) and induction of IgA ₁ (all, p < 0.05) and IgA ₂ (all, p < 0.01) compared to placebo groups. Nasal fluid ( p < 0.01) and serum ( p < 0.05) blocking antibodies are functional and have the capacity to inhibit allergen‐IgE complex formation and binding to B cells in the PQ Grass groups. In vitro cellular and microarray gene analyses demonstrated that the extended PQ Grass regimen was more proficient in modulating the immune response towards a tolerogenic milieu by dampening pro‐inflammatory type 2 immune response and the associated cytokines ( p < 0.05), immune deviation towards a Th1 response ( p < 0.05), and induction of FOXP3 ⁺ Treg cells ( p < 0.05). Conclusions: For the first time, we highlight differential mechanisms of tolerance induction by PQ Grass, with the extended regimen being superior in modulating T cell compartments. Trail Registration: Trial number: PQGrass309, EudraCT number: 2020‐000408‐13, Clinicaltrials.gov identifier: NCT04687059, and NCT05540717

Background/Objectives: The guideline on allergen-specific immunotherapy of the European Academy of Allergy and Clinical Immunology recommends subcutaneous allergen-specific immunotherapy for the treatment of allergic rhinitis in children and adults with moderate to severe symptoms. The five years cohort study described below was designed in 2020 to demonstrate non-inferiority in terms of safety, tolerability and efficacy in a paediatric population compared with adult patients treated with microcrystalline tyrosine-adsorbed allergoids for their tree and grass pollen allergy in a perennial setting. Here, we present the preliminary findings from the first year. Methods: The Combined Symptom and Medication Score was chosen as the primary endpoint of this therapy. Secondary endpoints include the Rhinoconjunctivitis Quality of Life Questionnaire, the retrospective Rhinoconjunctivitis score, the Asthma Control Test and the Rhinitis Control Test, as well as an analysis of adverse drug reactions. Results: A total number of 320 patients were enrolled into this study, with 129 of these patients in the age group between 5 and 17 years and 191 patients in the adult age group. Mean Combined Symptom and Medication Score values did not differ significantly between minors and adults in the first pollen season after treatment induction. The retrospective score showed a strong and significant reduction in rhinoconjunctivitis and asthma symptoms. Treatment was well tolerated, with more than 80% of patients reporting no adverse drug reactions. Conclusions: The validity of this study approach of a cohort study has been confirmed by this first interim analysis for the initial course of therapy in the first year.

Background: PQ Grass 27600 SU (PQ Grass) cumulative dose is a pre‐seasonal, six‐injection, aluminium‐free, modified subcutaneous immunotherapy product under development for the treatment of allergic rhinitis (AR). A pivotal Phase III randomised double‐blind, placebo‐controlled clinical trial was performed to evaluate the efficacy and safety of PQ Grass in subjects with seasonal AR. Methods: An adaptive group sequential trial PQGrass306 (G306) with one pre‐defined interim analysis was designed, using 2 parallel groups applying a 1:1 active versus placebo randomisation of patients aged 18–65. The primary efficacy endpoint was the EAACI (European Academy of Allergy and Clinical Immunology) Combined Symptom and Medication Score (EAACI‐CSMS _0–6 ) averaged over the peak grass pollen season (GPS). Results: 858 subjects were screened and 555 subjects were randomised. Based on the results of the pre‐defined interim analysis, the trial was stopped for success showing superiority in favour of PQ Grass. The primary endpoint EAACI‐CSMS _0–6 (peak GPS) demonstrated a highly significant and clinically meaningful point difference of PQ Grass over placebo of −0.27 points (95% CI: −0.42 to −0.12), corresponding to a relative difference of −20.3% ( p = 0.0005). Highly consistent and beneficial results were obtained for PQ Grass for all key secondary endpoints. Significant induction of blocking IgG4 and IgA antibody subclasses occurred. PQ Grass was well tolerated, and no unexpected safety signals occurred. Conclusions: This pivotal Phase III trial demonstrated a significant and clinically meaningful effect on the primary endpoint as well as highly consistent secondary endpoint results and a supportive safety profile.

The transitioning of named patient products (NPPs) of therapy allergens is regulated under the German therapy allergen ordinance (TAO) since 2008. The establishment of a sound dose–response relationship constitutes a pivotal aspect in clinical development programs of drugs in general. Up to now, there are only few comprehensive studies dedicated to the determination of a dose–response relationship in allergen immunotherapy (AIT) because of various challenges. Among these aggravating factors are high placebo effects, variability of trial endpoints and especially for native allergens a narrow therapeutic window and safety profile. The phase II trials of the modified allergen tyrosine associated—monophosphoryl lipid A (MATA MPL) platform for birch and grasses established convincing and significant dose–response relationships decisive for AIT product optimization. The significant dose–response relationship for birch and grass allergoids reached an efficacy plateau and allowed the definition of critical milestones in drug development such as the median effective dose (ED50) for the MATA MPL platform combining modified allergens (allergoids) with microcrystalline tyrosine (MCT) and MPL in an adjuvant system. This marked a pivotal milestone in AIT drug development allowing the definition of the “optimal dose” (optimal risk–benefit ratio) to be taken forward to phase III trial. The MATA MPL platform is characterized by a scientifically sound dose–response relationship across allergens which underlines the pivotal role of a well-defined optimal dose as a success factor for phase III.