Consistent efficacy and safety of sublingual immunotherapy tablets across allergens and geographic regions.

Background: The clinical development program of the SQ grass, ragweed, tree, and house dust mite (HDM) sublingual immunotherapy (SLIT)-tablets for allergic rhinitis/conjunctivitis (AR/C) included clinical trials conducted in North America, Europe, and Japan. Objective: Data from these trials were analyzed to assess efficacy, immunologic mechanisms, and safety outcomes across allergens and geographic regions. Methods: Thirteen phase III, double-blind, placebo controlled trials in the subjects with AR/C were conducted in North America, Europe (including Russia), and Japan (N = 7763 analyzed). Trials were generally similar with respect to medical practice, target population, eligibility criteria, and efficacy and safety monitoring. Data were analyzed for the approved doses in North America and Europe. Four statistical models were used to enhance comparison of the efficacy end points among the trials. Results: The SLIT-tablets demonstrated consistent efficacy across allergens and regions, regardless of the statistical analysis used. Relative improvement in the primary efficacy end point compared with placebo by using the predefined protocol analysis ranged from 17.9% to 32.8%, 17.5% to 19.3%, 20.6% to 38.3%, and 39.6% with the grass, HDM, ragweed, and tree SLIT-tablets, respectively. The kinetics of specific immunoglobulin E (IgE) and IgG4 responses were similar among the allergens and regions. Local application-site reactions were the most common adverse events for all allergens and in all regions. Most treatment-related adverse events for all allergens and in all regions were mild in severity. The rate of systemic allergic reactions was similar across regions (0%-0.54%). Conclusion: Confirmatory phase III trials for SLIT-tablets in the treatment of AR/C showed consistent efficacy, immunologic, and safety outcomes across allergens and geographic regions.

Efficacy of Japanese cedar pollen sublingual immunotherapy tablets for Japanese cypress pollinosis.

Background: We previously demonstrated the efficacy of Japanese cedar (JC) pollen sublingual immunotherapy (SLIT) tablets for treating seasonal allergic rhinitis in a clinical trial (trial no. 206-2-1) that covered 5 pollen dispersal seasons from 2015 to 2019. Objective: Our aim was to perform post hoc analysis of the 206-2-1 trial data to evaluate the efficacy of JC pollen SLIT tablets for patients with rhinitis induced by pollen from Japanese cypress (JCY), a related Cupressaceae species that has a pollen dispersal season overlapping with that of JC. Methods: Data were analyzed for 240 patients who received placebo during the first pollen dispersal season in 2015, were then rerandomized to receive JC SLIT tablets (the PA group) or placebo (the PP group) for 18 months (the 2016 and 2017 dispersal seasons), and were observed untreated for 2 years (the 2018 and 2019 dispersal seasons). The PA and PP groups were assigned to "high" and "low" subgroups if their rhinitis symptoms were exacerbated/did not change or decreased, respectively, during the peak JCY pollen dispersal period in 2015. The mean total nasal symptom and medication scores and other outcomes were compared for the high-PP, high-PA, low-PP, and low-PA groups during the 2016 to 2019 peak JCY pollen dispersal periods. Results: The mean total nasal symptom and medication scores were significantly lower for the high-PA and low-PA groups than for the corresponding PP groups over the 4 years of treatment and observation. JCY pollen-specific IgE levels increased in both PA groups. Conclusion: JC pollen SLIT tablets effectively suppressed JCY pollinosis symptoms, supporting the clinical relevance of immunologic cross-reactivity between JC and JCY allergens.

[Pharmacological and clinical study results of Berotralstat Hydrochloride for long-term prophylactic treatment of hereditary angioedema].

Hereditary angioedema (HAE) is a rare disease that causes serious health problem and affects on quality of life for patient due to recurrent episodes of angioedema in various body such as the skin, larynx, digestive tract, and limbs. Many HAE patients have deficiency or dysfunction of C1 inhibitor, impaired regulation of plasma kallikrein activity and overproduction of bradykinin, resulting in leading to episodes of increased capillary hyper permeability and angioedema. Therapy of HAE consists of on-demand treatment for acute attack and prophylactic treatment by suppressing the onset of acute attack in the short and long term. However, no drug has been approved for long-term prophylaxis in Japan. Berotralstat hydrochloride (ORLADEYO Capsules 150 mg) is an oral, selective plasma kallikrein inhibitor approved for the suppression of the onset of acute attacks in HAE in Japan in January 2021. Preclinical studies demonstrated that Berotralstat is a potent and highly specific inhibitor of human plasma kallikrein activity. Berotralstat suppressed bradykinin production in the HUVEC system. Clinical studies demonstrated that oral administration of Berotralstat to HAE type I or type II patients at a dose of 150 mg once daily showed a reduction of HAE attack rate and clinically significant change in angioedema quality of life score. The most common side effect was gastrointestinal symptoms. In conclusion, preclinical and clinical data indicated that Berotralstat is an effective treatment for long-term prophylactic treatment by suppressing the onset of acute attack in HAE patient and is considered to be a useful treatment option for patients.

Disease-Modifying Effect of Japanese Cedar Pollen Sublingual Immunotherapy Tablets.

BACKGROUND: Japanese cedar (JC) pollinosis is a common allergic rhinitis in Japan. JC pollen sublingual immunotherapy (SLIT) tablets are licensed for the treatment of JC pollinosis. OBJECTIVE: To assess the disease-modifying effects of JC pollen SLIT tablets over 5 years (2014-2019), comprising a 3-year treatment period and 2-year follow-up. METHODS: A total of 1042 patients with JC pollinosis (aged 5-64 years) were included in the study. An optimal dose-finding study was performed in the first 15 months, after which 240 patients in the placebo (P) group and 236 patients in the optimal active dose (A) group (5000 Japanese allergy units) were re-randomized to receive P or A for an additional 18 months (designated AA, AP, PA, and PP groups). Clinical efficacy was evaluated by the total nasal symptom and medication score (TNSMS) during the peak symptom period of each JC pollen season over 3 years of treatment and 2 years of observation after treatment cessation. RESULTS: The AA, AP, and PA groups exhibited significantly reduced TNSMS; however, the largest relative reduction was seen in the AA group both during the treatment period (third season, 46.3% vs PP, P < .001) and during the 2-year follow-up period (fourth and fifth seasons, 45.3% and 34.0% vs PP, respectively; P < .001). The most common adverse drug reactions were mild reactions at the administration site. CONCLUSIONS: JC pollen SLIT tablets show sustained clinical efficacy during 3 years of treatment and sustained disease-modifying effects for at least 2 years after treatment cessation.

[Developmental history of sublingual immunotherapy].

Allergen immunotherapy is the only curative treatment for IgE-mediated allergic diseases in contrast to symptomatic treatment such as anti-histamine agents. Subcutaneous immunotherapy (SCIT) has been introduced in Japan for treatment of allergic rhinitis and/or asthma caused by pollens and/or house dust mites (HDM) in early 1960s, and the clinical efficacy has been well-known. However, the major drawbacks of SCIT are necessity of repeated painful injections as well as the risk of severe systemic adverse reactions. Sublingual immunotherapy (SLIT) was developed to resolve these issues. In Japan, Japanese cedar (JC) pollen SLIT-drop was developed initially for treatment of JC pollinosis, and approved for patients of 12 years of age and older in 2014. For adolescent and adult patients with HDM-allergic rhinitis, HDM SLIT-tablet was launched in 2015 and subsequently approved to be also available for pediatric patients (<12 years of age) in 2018. Moreover, JC pollen SLIT-tablet for JC pollinosis was approved in 2018 for all patients with no age limit. Here, we also describe that the formulation technologies of SLIT tablets and distribution of allergens after sublingual administration as well as the development of SLIT drop/tablets.

Safety profile of the SQ house dust mite sublingual immunotherapy-tablet in Japanese adult patients with house dust mite-induced allergic asthma: a randomized, double-blind, placebo-controlled phase I study.

Objective: The SQ house dust mite (HDM) sublingual immunotherapy (SLIT)-tablet has demonstrated effective treatment of HDM-induced allergic asthma in patients 18 years or older in European trials. This study investigated its safety and immunology profile in Japanese adult patients with mild-to-moderate HDM-induced allergic asthma. Methods: In this randomized, double-blind, placebo-controlled study, 48 Japanese patients were randomly assigned to a daily treatment of SQ HDM SLIT-tablet or placebo (3:1) for 14 d with or without an up-dosing regimen. Active groups comprised 5000, 10,000 or 20,000 Japanese Allergy Unit (JAU) for 14 d, and the up-dosing group comprised 5,000 JAU in day 1-3, 10,000 JAU in day 4-7 and 20,000 JAU in day 8-14. Results: No marked differences were observed in the incidence rate of adverse events (AEs) and their severity among active groups. The five most common investigational medicinal product (IMP)-related AEs were local events at the application site observed within 30 min after the intake of the SQ HDM SLIT-tablet. Although most events recovered within 1 h, mouth edema indicated a different profile of duration with more than 25% of the events lasting for more than 1 h. Conclusions: The SQ HDM SLIT-tablet of up to 20,000 JAU was well tolerated, and safety profile was acceptable for Japanese subjects with HDM-induced allergic asthma.