Allergen Immunotherapy: The Evidence Supporting the Efficacy and Safety of Subcutaneous Immunotherapy and Sublingual Forms of Immunotherapy for Allergic Rhinitis/Conjunctivitis and Asthma.

Allergen immunotherapy (AIT) is a recognized key therapeutic modality for the treatment of allergic respiratory disease. Definitive studies have provided evidence-based data to demonstrate its effectiveness in allergic rhinitis and asthma due to the inhalation of proteinaceous allergic substances from specific seasonal pollens, dust mites, animal allergens, and certain mold spores. Over the ensuing decades, laboratory investigations have provided objective evidence to demonstrate immunologic changes, including production of protective IgG antibody, suppression of IgE antibody, upregulation of regulatory T cells, and induction of a state of immune tolerance to the offending allergen(s). Tangential to this work were carefully designed clinical studies that defined allergen dose and duration of treatment, established the importance of preparing extracts with standardized allergens (or well-defined extracts) based on major protein moieties, and used allergen provocation models to demonstrate efficacy superior to placebo. In the United States, the use of subcutaneous immunotherapy extracts for AIT was grandfathered in by the Food and Drug Administration based on expert literature review. In contrast, sublingual tablet immunotherapy underwent formal clinical development programs (phase I-III clinical trials) that provided the necessary clinical evidence for safety and efficacy that led to regulatory agency approvals for the treatment of allergic rhinitis in properly characterized patients with allergy. The allergy specialist's treatment options currently include traditional subcutaneous AIT and specific sublingual tablets approved for grass, ragweed, house dust mites, trees belonging to the birch-homologous group, and Japanese cedar. Tangential to this are sublingual drops that are increasingly being used off-label (albeit not approved by the Food and Drug Administration) in the United States. This article will review the evidence-based literature supporting the use of these forms of AIT, as well as focus on several current controversies and gaps in our knowledge base that have relevance for the appropriate selection of patients for treatment with specific AIT.

Dose Adjustment After Gaps in Administration of Subcutaneous Immunotherapy From a Past Survey: Work Group Report of the AAAAI Allergen Standardization and Allergy Diagnostics Committee.

The allergen immunotherapy practice parameters third update recommendations on dose adjustment after a gap in administration during the build-up are based solely on expert opinion, and no recommendations for gaps during maintenance are given. In a previous survey among American Academy of Allergy, Asthma & Immunology (AAAAI) members on subcutaneous allergen immunotherapy, this was addressed, but details were never published. Members of the Immunotherapy, Allergen Standardization, and Allergy Diagnostics Committee of the AAAAI convened a workgroup to address this issue and reanalyze results on the particular survey section. Build-up: many practitioners start dose-adjusting if a patient comes in 14.1/14 days (mean/median) after the last dose and restart immunotherapy after an interruption of 85/90 days. Dosing frequency during maintenance is generally every 3 (12%) to 4 weeks (73%). Maintenance: allergists start dose-adjusting if a patient comes in 5.1/5 weeks (mean/median) after the last dose and completely restart after an interruption of 16/12 weeks (some replied in days [90.4/90 days] or months [4.43/4 months]). Subgroups: physicians with ≥11 years in practice in nonacademic centers or rural/suburban settings tolerate longer gaps before restarting subcutaneous immunotherapy (SCIT). There is no uniform dose-adjustment protocol after gaps in SCIT administration. Prospective studies shall have to help find the best trade-off between safety (dose reduction) without giving in on efficacy (too much dose reduction).

Subcutaneous allergen immunotherapy in the treatment of allergic respiratory disease.

Subcutaneous immunotherapy is recognized as a cornerstone in the management of allergic respiratory disease in patients who are properly characterized with allergy and with allergic rhinoconjunctivis and/or well-controlled asthma, and who are willing to adhere to the rigorous treatment program. A key tenet is that it affords the opportunity to effect long-term clinical remission through its disease-modifying properties. Furthermore, it has the potential to prevent the progression of allergic rhinitis to asthma, prevent new allergen sensitivities, and improve a patient's quality of life.

New insights in mite immunotherapy - sublingual tablets.

PURPOSE OF REVIEW: Sublingual tablet immunotherapy has been demonstrated to be effective for allergies induced by exposure to grass, ragweed, specific trees (Japanese Cedar; birch homologous tree mix), and house dust mites (HDM). This review provides both an overview of the evidence-based clinical studies that address the use of the HDM SLIT-tablet for the treatment of HDM-induced allergic rhinitis/conjunctivitis and its appropriate use in carefully selected asthmatic patients and provides the clinician with practical management considerations. RECENT FINDINGS: Solid evidence-based clinical studies have shown that the HDM SLIT-tablet is both well tolerated in patients with mild-to-moderate asthma and has demonstrated a meaningful improvement in exacerbations, need for rescue medication, quality of life, and asthma control. SUMMARY: The HDM SLIT-tablet provides the allergy specialist with a well-tolerated treatment that has established superior safety to subcutaneous injection therapy, which can be administered easily as a sublingual dissolvable tablet, and which provides the opportunity to address one of the more difficult aspects in the management of an inducer of perennial allergic disease - that of persistent airway inflammation and allergic asthma.

One Hundred Ten Years of Allergen Immunotherapy: A Broad Look Into the Future.

Allergen immunotherapy (AIT) is the only disease-modifying treatment option for patients with type 1-mediated allergic diseases such as allergic rhinitis/rhinoconjunctivitis with/without allergic asthma. Although many innovations have been developed since the first clinical report of Noon et al in 1911, the improvement of clinical efficacy and tolerability of this treatment is still an important unmet need. Hence, much progress has been made in the characterization of the cell types, cytokines, and intracellular signaling events involved in the development, maintenance, and regulation of allergic reactions, and also in the understanding of the mechanisms of tolerance induction in AIT. This comprehensive review aims to summarize the current innovative approaches in AIT, but also gives an outlook on promising candidates of the future. On the basis of an extensive literature review, integrating a clinical point of view, this article focuses on recent and future innovations regarding biologicals, allergen-derived peptides, recombinant allergens, "Toll"-like receptor agonists and other adjuvants, and novel application routes being developed for future AIT.

A 300 IR sublingual tablet is an effective, safe treatment for house dust mite-induced allergic rhinitis: An international, double-blind, placebo-controlled, randomized phase III clinical trial.

BACKGROUND: Allergic rhinitis induced by house dust mites (HDMs) is a highly prevalent but often underdiagnosed and undertreated/untreated chronic disease. It often has a negative impact on sleep, work, leisure activities, and health-related quality of life. Allergen immunotherapy is a proven, safe treatment for respiratory allergies. OBJECTIVE: We sought to assess the efficacy and safety of a 300 index of reactivity (IR) sublingual tablet formulation of Dermatophagoides pteronyssinus:Dermatophagoides farinae 1:1 extract in adolescents (aged ≥12) and adults with moderate to severe HDM-induced allergic rhinitis. METHODS: In a phase III, international, double-blind, placebo-controlled, randomized clinical trial, participants received approximately 12 months of treatment with placebo or the 300 IR tablet. The primary end point was the average total combined score during 4 weeks at the end of the treatment period. RESULTS: A total of 1607 participants were randomized, and 1476 (including 555 [37.6%] with concomitant mild controlled asthma at inclusion) comprised the full analysis set. Over the primary evaluation period, the least squares mean average total combined score in the 300 IR group (3.62) was significantly lower (P < .0001) than in the placebo group (4.35), with a relative least squares mean difference of -16.9% (95% CI, -24.0% to -9.2%). All prespecified secondary end points were consistently improved in the 300 IR group, relative to placebo. The 300 IR tablet was generally well tolerated. Treatment-related adverse events (mainly mild or moderate local reactions) were reported for 51.0% of the patients in the 300 IR group and 14.9% in the placebo group. CONCLUSIONS: The 300 IR sublingual HDM tablet is an effective, safe treatment for HDM-induced allergic rhinitis.

Placebo effects in allergen immunotherapy-An EAACI Task Force Position Paper.

The placebo (Latin "I will please") effect commonly occurs in clinical trials. The psychological and physiological factors associated with patients' expectations about a treatment's positive and negative effects have yet to be well characterized, although a functional prefrontal cortex and intense bidirectional communication between the central nervous system and the immune system appear to be prerequisites for a placebo effect. The use of placebo raises certain ethical issues, especially if patients in a placebo group are denied an effective treatment for a long period of time. The placebo effect appears to be relatively large (up to 77%, relative to pretreatment scores) in controlled clinical trials of allergen immunotherapy (AIT), such as the pivotal, double-blind, placebo-controlled (DBPC) randomized clinical trials currently required by regulatory authorities worldwide. The European Academy of Allergy and Clinical Immunology (EAACI) therefore initiated a Task Force, in order to better understand the placebo effect in AIT and its specific role in comorbidities, blinding issues, adherence, measurement time points, variability and the natural course of the disease. In this Position Paper, the EAACI Task Force highlights several important topics regarding the placebo effect in AIT such as a) regulatory aspects, b) neuroimmunological and psychological mechanisms, c) placebo effect sizes in AIT trials, d) methodological limitations in AIT trial design and e) potential solutions in future AIT trial design. In conclusion, this Position Paper aims to examine the methodological problem of placebo in AIT from different aspects and also to highlight unmet needs and possible solutions for future trials.

Mind the gaps: Clinical trial concepts to address unanswered questions in aeroallergen immunotherapy-An NIAID/AHRQ Workshop.

The Agency for Healthcare Research and Quality and the National Institute of Allergy and Infectious Diseases organized a workshop to develop trial concepts that could improve the use and effectiveness of aeroallergen immunotherapy (AAIT). Expert groups were formed to accomplish the following tasks: (1) propose a study design to compare the effectiveness and safety of subcutaneous versus sublingual AAIT; (2) propose a study design to compare the effectiveness and safety of AAIT by using 1 or a few allergens versus all or most allergens to which a patient is sensitized; (3) propose a study design to determine whether AAIT can alter the progression of childhood allergic airways disease; and (4) propose a study design to determine the optimal dose and duration of AAIT to achieve maximal effectiveness with acceptable safety. Study designs were presented by the workgroups, extensively discussed at the workshop, and revised for this report. The proposed trials would be of long duration and require large highly characterized patient populations. Scientific caveats and feasibility matters are discussed. These concepts are intended to help the development of clinical trials that can address some of the major questions related to the practice of AAIT for the management and prevention of allergic airways disease.

Ragweed sublingual tablet immunotherapy: part II - practical considerations and pertinent issues.

Sublingual allergen immunotherapy (SLIT) has been demonstrated to be both efficacious and safe for the treatment of respiratory allergies such as allergic rhinoconjunctivitis or allergic asthma. Based on the clinical documentation of SLIT ragweed tablets, they have gained marketing authorization in the USA by the US FDA in 2014 for adult patients. Following clinical data from (pivotal) multicenter Phase II and III trials as performed in the USA and Canada and real life experience after registration in 2014, SLIT ragweed tablets can be recommended as efficacious and safe treatment option with disease modifying potential when adequately indicated and performed. Therefore, several practical issues should be considered for treating ragweed allergic patients with these tablets. This second part of a thorough review on ragweed SLIT tablets addresses important clinical questions which should be taken into account by the subscribing practitioner before initiation and during the treatment.

Ragweed sublingual tablet immunotherapy: part I - evidence-based clinical efficacy and safety.

Sublingual tablet immunotherapy provides an attractive alternative approach to allergen immunotherapy, as the allergen is administered as a rapidly dissolving sublingual tablet. Part I of this two-part series on the ragweed sublingual tablet describes the dose-ranging clinical work, the safety studies and the clinical outcomes from the pivotal trials which provide clear evidence for statistically significant and clinically meaningful benefit in the treatment of patients suffering from ragweed-induced seasonal allergic rhinitis-conjunctivitis with or without milder asthma. The robust results observed in the clinical trials performed with the ragweed sublingual tablet are defined by the quality of their study design, their use of a standardized allergen extract, their consistent reproducibility in demonstrating therapeutic efficacy and their properly quantified and graded safety data.

International Consensus Statement on Allergy and Rhinology: Allergic Rhinitis.

BACKGROUND: Critical examination of the quality and validity of available allergic rhinitis (AR) literature is necessary to improve understanding and to appropriately translate this knowledge to clinical care of the AR patient. To evaluate the existing AR literature, international multidisciplinary experts with an interest in AR have produced the International Consensus statement on Allergy and Rhinology: Allergic Rhinitis (ICAR:AR). METHODS: Using previously described methodology, specific topics were developed relating to AR. Each topic was assigned a literature review, evidence-based review (EBR), or evidence-based review with recommendations (EBRR) format as dictated by available evidence and purpose within the ICAR:AR document. Following iterative reviews of each topic, the ICAR:AR document was synthesized and reviewed by all authors for consensus. RESULTS: The ICAR:AR document addresses over 100 individual topics related to AR, including diagnosis, pathophysiology, epidemiology, disease burden, risk factors for the development of AR, allergy testing modalities, treatment, and other conditions/comorbidities associated with AR. CONCLUSION: This critical review of the AR literature has identified several strengths; providers can be confident that treatment decisions are supported by rigorous studies. However, there are also substantial gaps in the AR literature. These knowledge gaps should be viewed as opportunities for improvement, as often the things that we teach and the medicine that we practice are not based on the best quality evidence. This document aims to highlight the strengths and weaknesses of the AR literature to identify areas for future AR research and improved understanding.

Treatment effect of sublingual immunotherapy tablets and pharmacotherapies for seasonal and perennial allergic rhinitis: Pooled analyses.

BACKGROUND: Data comparing the treatment effect of allergy immunotherapy and pharmacotherapy are lacking. OBJECTIVE: We sought to indirectly compare the treatment effect of sublingual immunotherapy (SLIT)-tablets with pharmacotherapy for seasonal allergic rhinitis (SAR) and perennial allergic rhinitis (PAR). METHODS: Pooled data from randomized, double-blind, placebo-controlled trials for the clinical development programs of selected allergic rhinitis treatments were evaluated. Total nasal symptom scores (TNSSs) relative to placebo were compared. Subjects scored symptoms daily during entire pollen seasons in 6 timothy grass SLIT-tablet trials (n = 3094) and 2 ragweed SLIT-tablet trials (n = 658) and during the last 8 weeks of treatment in 2 house dust mite (HDM) SLIT-tablet trials (n = 1768). Subjects scored symptoms daily in 7 montelukast (10 mg, n = 6799), 9 desloratadine (5 mg, n = 4455), and 8 mometasone furoate nasal spray (MFNS; 200 µg daily, n = 2140) SAR or PAR trials. SLIT-tablet trials allowed rescue medication use, whereas most pharmacotherapy trials did not. A fixed-effect meta-analysis method estimated differences in on-treatment average TNSSs. RESULTS: In grass and ragweed SLIT-tablet trials, overall improvement in TNSSs relative to placebo was 16.3% and 17.1%, respectively. In HDM SLIT-tablet trials, TNSS overall improvement relative to placebo was 16.1%. In the montelukast, desloratadine, and MFNS trials, TNSS overall improvement relative to placebo was 5.4%, 8.5%, and 22.2%, respectively, for SAR trials, and 3.7%, 4.8%, and 11.2%, respectively, for PAR trials. CONCLUSIONS: Although comparisons were limited by study design heterogeneity and use of rescue medications in SLIT-tablet trials, effects on nasal symptoms with timothy grass and ragweed SLIT-tablets were nearly as great as with MFNS and numerically greater than with montelukast and desloratadine for SAR. HDM SLIT-tablet effects were numerically greater than all pharmacotherapies for PAR. SLIT-tablets offer the additional benefit of long-term efficacy.

Coseasonal Initiation of Allergen Immunotherapy: A Systematic Review.

BACKGROUND: It is unclear whether allergen immunotherapy (AIT) can be safely initiated during the pollen season (coseasonal initiation [CSI]) because of a potential increased risk of systemic allergic reactions. OBJECTIVE: To systematically review publications reporting the safety of subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT) CSI to validate or invalidate the perception of increased safety risk. METHODS: PubMed, EMBASE, Ovid, Literatura Latino Americana em Ciências da Saúde (LILACS), and Cochrane Library databases were searched without limits for studies of any design reporting SCIT or SLIT CSI for pollen allergen. Congress abstracts were included. RESULTS: Nineteen eligible studies were identified: 8 SCIT (n = 947 subjects total; n = 340 double-blind placebo-controlled [DBPC]) and 11 SLIT (n = 2668 subjects total; n = 565 DBPC). Study characteristics and safety reporting were heterogeneous. No epinephrine administrations were reported. Discontinuation frequencies were 6% or less and 10% or less with SCIT and SLIT CSI, respectively. In SCIT studies, systemic allergic reaction frequency was 0% to 7% with "up to peak season" or CSI, 0% to 6% with "after peak season" or out-of-season initiation, and 0% to 7% with placebo. In SCIT studies, serious treatment-related adverse event (AE) frequency with CSI ranged from 0% to 2%; few severe AEs were reported. In SLIT studies, systemic allergic reaction frequency ranged from 0% to 4% with CSI, 0% with out-of-season initiation, and 0% to 2% with placebo. Overall, 2 serious treatment-related AEs with SLIT CSI were reported. Severe AE frequency in SLIT studies ranged from 0% to 8% with CSI, 0% to 12% with out-of-season initiation, and 0% to 8% with placebo. CONCLUSIONS: No increase in AEs of concern was observed with SCIT or SLIT CSI; however, additional data with standardized regimens and doses are needed.

Allergen Immunotherapy: Vaccine Modification.

There is a need for newer therapeutic agents that improve the safety of allergen immunotherapy, provide ease of delivery to patients that fosters compliance and allows access to a greater proportion of the allergic population who could benefit from this disease-modifying treatment, and achieve an acceptable therapeutic benefit for patients committing to the treatment. The advances in sublingual allergen immunotherapy are encouraging, as this offers patients a noninjectable form of treatment of inhalant allergies. The continued research and development of the novel therapeutic constructs discussed in this article holds the promise of accomplishing the aforementioned goals in the future.

Advances in synthetic peptide immuno-regulatory epitopes.

Synthetic peptide immuno-regulatory epitopes (SPIRE) represent a new class of therapeutics for allergen immunotherapy that offer the potential to suppress the IgE-mediated allergic disease process through induction of T-cell tolerance. These synthetic T-cell-tolerizing peptides have been designed to induce immunologic tolerance via binding to MHC class II molecules on antigen presenting cells, with subsequent upregulation of regulatory T-cells.

Safety and tolerability of a short ragweed sublingual immunotherapy tablet.

BACKGROUND: MK-3641 is a short ragweed sublingual tablet under investigation for immunotherapy of ragweed pollen-induced allergic rhinitis. OBJECTIVE: To characterize the safety and tolerability of a ragweed sublingual tablet (Merck/ALK-Abelló) in ragweed-allergic adults with or without conjunctivitis. METHODS: Data from 4 randomized, double-blinded, placebo-controlled trials of MK-3641 (2 28-day and 2 52-week trials) were evaluated. Pooled analyses examined short-term safety over 28 days from all 4 trials and long-term safety from the 52-week trials. RESULTS: Across all studies, 757, 198, 454, and 1,058 subjects were randomized to placebo or 1.5, 6, or 12 Amb a 1-U of MK-3641, respectively. Treatment-related adverse events were more frequent in the 6- and 12-Amb a 1-U MK-3641 groups than in the placebo group and were primarily local application-site reactions occurring in the first few days of treatment. There was no treatment-associated loss of asthma control or worsening of asthma associated with treatment. No swellings led to airway obstruction or respiratory compromise. No treatment-related anaphylactic shock, life-threatening, or serious treatment-related adverse events were reported for any MK-3641 dose. Of the 1,707 MK-3641-treated subjects, 1 systemic (anaphylactic) reaction was reported (0.06%). The 52-week long-term assessment was generally similar to the safety profile based on the 28-day assessment. CONCLUSION: MK-3641 doses up to and including 12 Amb a 1-U were well tolerated, with no unexpected safety findings. Sublingual immunotherapy risks such as worsening asthma or airway swellings that could cause airway obstruction were not observed. Systemic reactions and use of epinephrine were uncommon. In these studies, after the first dose was administered in a health care setting, self-administration was well tolerated. TRIAL REGISTRATION: clinicaltrials.gov Identifiers: NCT01469182, NCT00783198, NCT00770315, and NCT00978029.

Efficacy and safety of grass sublingual immunotherapy tablet, MK-7243: a large randomized controlled trial.

BACKGROUND: In North America, few studies have evaluated sublingual immunotherapy for allergic rhinitis with or without conjunctivitis (AR/C); pediatric data are sparse. The authors report findings from the largest published immunotherapy trial yet conducted in adults and children. OBJECTIVE: To evaluate grass sublingual immunotherapy tablet (MK-7243) treatment in subjects with AR/C. METHODS: North American subjects (5-65 years old) with grass allergy were randomized 1:1 to once-daily MK-7243 (2,800 BAU Phleum pratense) or placebo. The first dose was given at the investigator's office; subsequent doses were self-administered at home. The primary end point was total combined score (TCS; rhinoconjunctivitis daily symptom score [DSS] plus daily medication score [DMS]) over the entire grass pollen season (GPS). Key secondary end points included entire-season DSS, DMS, peak-season TCS, and rhinoconjunctivitis quality-of-life questionnaire scores. Safety outcomes included adverse events (AEs). RESULTS: One thousand five hundred one subjects were randomized (85% polysensitized, 25% had asthma). MK-7243 yielded improvements vs placebo of 23% in entire-season TCS (median difference -0.98, P < .001), 29% in peak-season TCS (median difference -1.33, P < .001), 20% in entire-season DSS (median difference -0.64, P = .001), 35% in entire-season DMS (mean difference -0.48, P < .001), and 12% in peak-season rhinoconjunctivitis quality-of-life questionnaire (median difference -0.13, P = .027). Efficacy between children and adults was similar. Most AEs were transient local application-site reactions, with no serious treatment-related AEs or anaphylactic shock. Three subjects (1 placebo, 2 MK-7243) had moderate systemic allergic reactions. CONCLUSION: MK-7243 was effective in polysensitized grass-allergic North American children and adults with AR/C in this large trial, confirming previous research.