ALK-Abelló (Denmark)

Long-lived immunoglobulin E (IgE) responses against innocuous environmental and dietary antigens (Ags) are maintained by an IgG1-dominant memory B cell (MBC) compartment primed for interleukin-4 (IL-4) responsiveness. The plasticity of the MBC compartment destined for IgE class switch recombination remains poorly understood. In this work, we report critical IL-4 and IL-13 dependency for the pathogenic IgE fate of type 2-polarized MBCs in allergy. Initiation of a recall response in the absence of IL-4 and IL-13 signaling diminished the type 2 MBC phenotype in mice and humans. This permitted the emergence of long-lived Ag-specific IgG2c+ MBCs in mice. The divergence to a type 1-like response was dependent on interferon-γ signaling and arose from both unswitched and class-switched Ag-specific B cells in vivo. This reprogrammed fate was sustained even beyond therapeutic intervention, revealing fundamental insights into the plasticity of the allergen-specific recall response.

Tablet formulations of allergen extracts are widely recommended over other formulations for the sublingual immunotherapy (SLIT) of respiratory allergies. However, with adequate clinical trial evidence, SLIT (liquid) drop formulations may be a relevant allergy treatment option. The RHAPSODY multinational, Phase III, parallel-group, double-blind, placebo-controlled, randomised clinical study of adults with moderate-to-severe, grass-pollen-induced allergic rhinoconjunctivitis (ARC) with or without asthma was conducted at 45 investigating centres in six European countries. Participants received 26 months of continuous treatment with active 5-grass-pollen SLIT drops or placebo. The primary efficacy endpoint was the average daily total combined score (TCS, comprising a symptom score and a rescue medication score) during the second peak grass pollen season (PGPS). Of the 445 randomised patients (mean ± standard deviation (range) age: 32.6 ± 9.9 (18-63); males: 55.1%), 389 completed the trial. The primary efficacy endpoint showed a statistically significant difference in favour of active treatment versus placebo (average difference in the daily TCS: 1.88 (95% CI: 0.60-3.17); relative difference 26.51% (95% CI: 9.42-40.55); p = 0.0036). The difference (0.17 points) in the average weekly Rhinitis Quality of Life Questionnaire score during the second PGPS in favour of the active treatment was clinically relevant but not statistically significant. The differences in efficacy were generally driven by the medication score, rather than the symptom score. Most adverse events were mild and local. RHAPSODY was the first well-powered clinical trial to show the positive risk-benefit ratio of 5-grass-pollen SLIT drops in adult participants with moderate-to-severe grass-pollen-induced ARC.

ABSTRACTBackgroundIn children, house dust mite (HDM) sensitisation is a contributing factor for developing allergic asthma. HDM allergen immunotherapy has demonstrated efficacy and safety in adults with allergic asthma; however, evidence for its use in children is limited. MT‐11 evaluated the efficacy and safety of the SQ HDM sublingual immunotherapy (SLIT) tablet in children (5–17 years) with HDM allergic asthma.MethodsThis phase III, randomised, double‐blind, placebo‐controlled trial randomised 533 children with a recent history of asthma exacerbations, despite treatment with inhaled corticosteroids and/or long‐acting beta‐agonists, to daily treatment with SQ HDM SLIT‐tablet or placebo for 24–30 months. The primary endpoint was the annualised rate of clinically relevant asthma exacerbations. Adverse events (AEs) were reported throughout the trial.ResultsThe rate ratio for the annualised rate of clinically relevant asthma exacerbations was 0.89 (95% CI: 0.60, 1.31), in favour of the SQ HDM‐SLIT tablet; superiority over placebo was not established. Most treatment‐related AEs (TRAEs) were of mild or moderate severity, and few subjects discontinued due to TRAEs (< 2%). The most common TRAEs were local application site reactions (oral pruritus, throat irritation, ear pruritus, and upper abdominal pain). There was no increased incidence of asthma‐related events, and no anaphylaxis or adrenaline use in the SQ HDM SLIT‐tablet group.ConclusionAs a result of the coronavirus disease 2019 pandemic, asthma exacerbation rates were much lower than expected, contributing to the primary endpoint not being met. The SQ HDM SLIT‐tablet was well tolerated in a paediatric population with inadequately controlled HDM allergic asthma.Trial RegistrationClinicaltrials.gov identifier: NCT03654976; EudraCT number: 2016‐004363‐39

BackgroundAllergic rhinitis (AR) affects up to 40% of children in the United States and Europe. AR is often associated with asthma and has a negative impact on quality of life for the children and their families.ObjectiveWe investigated the AR burden in children with moderate to severe perennial AR in Canada, Denmark, and the United Kingdom, focusing on the role of concomitant asthma. We assessed the health impact on the children, their receipt of allergy medication and health care services, and the impact on their families.MethodsAn online survey was distributed to caregivers of children aged 5 to 17 with moderate to severe perennial AR (both with and without asthma) and to a control group of caregivers of children without allergies.ResultsIn total, 877 and 855 caregivers of children with perennial AR and without allergies, respectively, completed the survey. Children with AR and asthma, compared with those without asthma, experienced more sleep disturbances (69% vs 58%), schoolwork limitations (33% vs 22%), daily activities restrictions (55% vs 41%), and missed school hours (7.2 vs 4.6 hours per month). Children with AR and asthma had a higher receipt of allergy medication compared with those without asthma, and they also visited their general practitioner more often (4.6 vs 3.5 times a year). Overall, 32% of all caregivers of children with AR expressed dissatisfaction with allergy medication.ConclusionPerennial AR, especially with concomitant asthma, imposes a substantial disease burden in children and their families, highlighting the need for long-term disease control.

Objective The symptom burden associated with allergic rhinitis (AR) negatively impacts the life of people living with the condition. Although the impact of AR on educational outcomes and the effect of AR-relieving medication have been investigated, the availability of up-to-date, population-based, real-world evidence is limited. Therefore, the aim was to investigate the impact of AR and AR-relieving medication on educational outcomes. Methods A register-based study was conducted using Danish registers. Educational outcomes were defined as the average 9th-grade final grade. Individuals diagnosed with AR before the age of 13, born between 1986 and 2006, and with observed final examination grades were included as cases. To investigate the impact of AR-relieving medication, cases were stratified by medication use. The impact of AR was estimated through a comparison of individuals with AR to their sibling with no history of AR. Results 52,808 cases were included (33,035 with siblings). Cases with no filled prescriptions of AR-relieving medication in their final examination year had an average grade of 7.09. Cases with a minimum of one collection had a higher average. Cases initiated on AIT had an average test score that was 0.60 points higher than cases with no filled prescriptions of aH or INCs in the final examination year. The average grade among cases with paired siblings was 7.29 whilst their siblings had an average grade that was −0.04 lower. Conclusion In the Danish context, AR does not affect educational outcomes; however, more frequent use of AR-relieving medications is associated with better educational outcomes.

Allergen-specific immunotherapy (IT) is emerging as a viable option for treatment of peanut allergy. Yet, prophylactic IT remains unexplored despite early introduction of peanut in infancy was shown to prevent allergy. There is a need to understand how allergens interact with the immune system depending on the route of administration, and how different dosages of allergen may protect from sensitisation and a clinical active allergy. Here we compared peanut allergen delivery via the oral, sublingual (SL), intragastric (IG) and subcutaneous (SC) routes for the prevention of peanut allergy in Brown Norway (BN) rats. BN rats were administered PBS or three different doses of peanut protein extract (PPE) via either oral IT (OIT), SLIT, IGIT or SCIT followed by intraperitoneal (IP) injections of PPE to assess the protection from peanut sensitisation. The development of IgE and IgG1 responses to PPE and the major peanut allergens were evaluated by ELISAs. The clinical response to PPE was assessed by an ear swelling test (EST) and proliferation was assessed by stimulating splenocytes with PPE. Low and medium dose OIT (1 and 10 mg) and all doses of SCIT (1, 10, 100 µg) induced sensitisation to PPE, whereas high dose OIT (100 mg), SLIT (10, 100 or 1000 µg) or IGIT (1, 10 and 100 mg) did not. High dose OIT and SLIT as well as high and medium dose IGIT prevented sensitisation from the following IP injections of PPE and suppressed PPE-specific IgE levels in a dose-dependent manner. Hence, administration of peanut protein via different routes confers different risks for sensitisation and protection from peanut allergy development. Overall, the IgE levels toward the individual major peanut allergens followed the PPE-specific IgE levels. Collectively, this study showed that the preventive effect of allergen-specific IT is determined by the interplay between the specific site of PPE delivery for presentation to the immune system, and the allergen quantity, and that targeting and modulating tolerance mechanisms at specific mucosal sites may be a prophylactic strategy for prevention of peanut allergy.

Background and aimsAllergic rhinitis (AR) is an inflammatory disorder triggered by an allergic immune response to inhaled allergens. Birch pollen is the major allergenic tree pollen in parts of Europe. ITULAZAX® is a sublingual immunotherapy tablet for the treatment of adults with moderate‐to‐severe AR and/or conjunctivitis induced by pollen from the birch homologous group. The aim was to compare the costs of treating AR with ITULAZAX® versus subcutaneous ALUTARD SQ® Betula verrucosa (ALUTARD SQ®) from a Danish societal perspective.MethodsA cost‐minimization model was developed to capture costs of allergy immunotherapy (AIT), interactions with healthcare professionals (HCPs) in three different care settings (general practice, allergy specialist, and hospital), and indirect costs arising from absenteeism and presenteeism. The cost‐minimization analysis was conducted over a 3‐year time horizon with costs reported in 2021 Danish Kroner (DKK) and Euros (EUR) based on the European Central Bank 365‐day average exchange rate. One‐way sensitivity analyses were performed.ResultsThe base case analysis showed that the total cost of treatment over 3 years was estimated to be DKK 49,117 (EUR 6598) per patient with ALUTARD SQ®, compared with DKK 30,996 (EUR 4164) with ITULAZAX®, reflecting a cost saving of DKK 18,121 (EUR 2434) per patient with ITULAZAX® over 3 years. Over the 3‐year time horizon, costs of AIT were predicted to increase by DKK 17,928 (EUR 2408) with ITULAZAX®, while costs of interactions with HCPs were predicted to decrease by DKK 22,528 (EUR 3027) versus ALUTARD SQ®, more than offsetting the increased cost of ITULAZAX®.ConclusionsGiven the equivalent effectiveness of the two AIT products, and the cost savings with ITULAZAX® versus ALUTARD SQ® from a Danish societal perspective, ITULAZAX® should be considered as a cost‐saving alternative to ALUTARD SQ® for the treatment of birch pollen‐induced moderate‐to‐severe AR in adults.