Lebrikizumab in Uncontrolled Asthma: Reanalysis in a Well-Defined Type 2 Population.

BACKGROUND: LAVOLTA (L)I, LII, and ACOUSTICS were randomized, placebo-controlled, Phase 3 trials of lebrikizumab, a monoclonal antibody targeting IL-13 in patients with uncontrolled asthma. Failure to demonstrate efficacy may have been related to patient selection in those trials. OBJECTIVE: To assess the efficacy in a well-defined subpopulation of patients with elevated blood eosinophil counts and a minimum number of prior asthma exacerbations. We performed an additional analysis in a subpopulation of patients with elevated FeNO and prior exacerbations. METHODS: Adult (LI and LII) and adolescent patients (aged 12-17 years weighing ≥40 kg, ACOUSTICS) with uncontrolled asthma received lebrikizumab (125 mg, n = 832; or 37.5 mg, n = 829) or placebo (n = 833) subcutaneously every 4 weeks. Post hoc analysis of the annualized adjusted exacerbation rate (AER) was performed in a subpopulation of patients with baseline blood eosinophils of 300 cells/µL or greater and history of one or more exacerbations. In this subpopulation, there were 227 patients in the placebo group, 222 in the lebrikizumab 37.5-mg group, and 217 in the lebrikizumab 125-mg group. We summarized safety in patients who received at least one dose of lebrikizumab using adverse events. RESULTS: Lebrikizumab significantly reduced AER compared with placebo in adults (AER reduction: 125 mg [38%]; and 37.5 mg [41%]) and adolescents (AER reduction:125 mg [59%]; 37.5 mg [64%]) with baseline blood eosinophils of 300 cells/µL or greater and one or more exacerbations. Most adverse events were mild or moderate in severity and did not lead to treatment discontinuation. CONCLUSION: Lebrikizumab significantly reduced asthma exacerbations in a subpopulation of patients with elevated blood eosinophils, elevated FeNO, and a history of asthma exacerbation.

Current and emerging therapies for eosinophilic esophagitis.

Background: Eosinophilic esophagitis (EoE) is a Type-2 chronic inflammatory food antigen-driven disease of the esophagus, characterized by eosinophilic predominant inflammation and a constellation of symptoms. The incidence and prevalence of EoE has increased over the past 2 decades. There is an unmet need for approved less burdensome treatment options. Objective: To describe the underlying pathophysiology and diagnosis of EoE and discuss the currently available treatment options. We also aim to review the new and emerging therapies for EoE. Methods: A search of a medical literature data base was performed for articles that discuss treatment for EoE. Results: A comparison of current therapies showed that dietary elimination, swallowed topical corticosteroids, and proton-pump inhibitor therapy are all effective for different populations. Emerging therapies that were reviewed include new topical corticosteroids and biologics directed against Type 2 inflammation. Conclusion: EoE is a chronic inflammatory disorder that can be debilitating, with long-term sequelae. There are no current approved therapies in the United States. Numerous new treatments are on the horizon. Increasing amounts of data are helping to tailor treatment for each patient. Ultimately, shared decision-making is the best approach to guide treatment choices with patients to manage the ever-increasing burden of this disease.

Continuous and Daily Oral Immunotherapy for Peanut Allergy: Results from a 2-Year Open-Label Follow-On Study.

BACKGROUND: The randomized, controlled PALISADE trial demonstrated the benefit of daily oral immunotherapy with Peanut (Arachis Hypogaea) allergen powder-dnfp (PTAH, formerly AR101) in peanut-allergic children and adolescents. OBJECTIVE: ARC004, the open-label follow-on study to PALISADE, used 5 dosing cohorts to explore PTAH treatment beyond 1 year and alternative dosing regimens in peanut-allergic individuals. METHODS: Active arm (PTAH-continuing) PALISADE participants who tolerated 300-mg peanut protein at the exit double-blind placebo-controlled food challenge and placebo arm (PTAH-naive) participants could enter ARC004. PTAH-continuing participants were assigned to receive daily (cohorts 1 and 3A) or non-daily (cohorts 2, 3B, and 3C) dosing regimens; PTAH-naive participants were built up to 300 mg/d PTAH, followed by maintenance dosing. At study completion, participants underwent an exit double-blind placebo-controlled food challenge with doses up to 2000 mg peanut protein. Data were assessed using descriptive statistics. RESULTS: Overall, 358 (87.5%) eligible participants (4-17 years) entered ARC004 (PTAH-continuing, n = 256; PTAH-naive, n = 102). Among PTAH-continuing participants, exposure-adjusted adverse event rates were 12.94 to 17.54/participant-year and 25.95 to 42.49/participant-year in daily and non-daily dosing cohorts, respectively; most participants (83%) experienced mild or moderate adverse events. Daily dosing cohorts appeared to have higher desensitization rates than non-daily dosing cohorts. Of all PTAH-continuing cohorts, cohort 3A had the longest daily dosing duration and the highest desensitization rates. Changes in immune markers with PTAH continuation demonstrated ongoing immunomodulation. Outcomes in PTAH-naive participants mirrored those of the PALISADE active arm. CONCLUSIONS: Continued daily PTAH treatment beyond 1 year showed sustained safety and efficacy. Ongoing immunomodulation was observed during the second year of treatment.

AR101 Oral Immunotherapy for Peanut Allergy.

BACKGROUND: Peanut allergy, for which there are no approved treatment options, affects patients who are at risk for unpredictable and occasionally life-threatening allergic reactions. METHODS: In a phase 3 trial, we screened participants 4 to 55 years of age with peanut allergy for allergic dose-limiting symptoms at a challenge dose of 100 mg or less of peanut protein (approximately one third of a peanut kernel) in a double-blind, placebo-controlled food challenge. Participants with an allergic response were randomly assigned, in a 3:1 ratio, to receive AR101 (a peanut-derived investigational biologic oral immunotherapy drug) or placebo in an escalating-dose program. Participants who completed the regimen (i.e., received 300 mg per day of the maintenance regimen for approximately 24 weeks) underwent a double-blind, placebo-controlled food challenge at trial exit. The primary efficacy end point was the proportion of participants 4 to 17 years of age who could ingest a challenge dose of 600 mg or more, without dose-limiting symptoms. RESULTS: Of the 551 participants who received AR101 or placebo, 496 were 4 to 17 years of age; of these, 250 of 372 participants (67.2%) who received active treatment, as compared with 5 of 124 participants (4.0%) who received placebo, were able to ingest a dose of 600 mg or more of peanut protein, without dose-limiting symptoms, at the exit food challenge (difference, 63.2 percentage points; 95% confidence interval, 53.0 to 73.3; P<0.001). During the exit food challenge, the maximum severity of symptoms was moderate in 25% of the participants in the active-drug group and 59% of those in the placebo group and severe in 5% and 11%, respectively. Adverse events during the intervention period affected more than 95% of the participants 4 to 17 years of age. A total of 34.7% of the participants in the active-drug group had mild events, as compared with 50.0% of those in the placebo group; 59.7% and 44.4% of the participants, respectively, had events that were graded as moderate, and 4.3% and 0.8%, respectively, had events that were graded as severe. Efficacy was not shown in the participants 18 years of age or older. CONCLUSIONS: In this phase 3 trial of oral immunotherapy in children and adolescents who were highly allergic to peanut, treatment with AR101 resulted in higher doses of peanut protein that could be ingested without dose-limiting symptoms and in lower symptom severity during peanut exposure at the exit food challenge than placebo. (Funded by Aimmune Therapeutics; PALISADE ClinicalTrials.gov number, NCT02635776 .).

Safety of a novel intranasal formulation of azelastine hydrochloride and fluticasone propionate in children: A randomized clinical trial.

BACKGROUND: The safety of a novel intranasal formulation of azelastine hydrochloride (AZE) and fluticasone propionate (FP) has been established in adults and adolescents with allergic rhinitis but not in children <12 years old. OBJECTIVE: To evaluate the safety and tolerability of an intranasal formulation of AZE and FP in children ages 4-11 years with allergic rhinitis. METHODS: The study was a randomized, 3-month, parallel-group, open-label design. Qualified patients were randomized in a 3:1 ratio to AZE/FP (n = 304) or fluticasone propionate (FP) (n = 101), one spray per nostril twice daily, and to one of three age groups: ≥4 to <6 years, ≥6 to <9 years, and ≥9 to <12 years. Safety was assessed by child- or caregiver-reported adverse events, nasal examinations, vital signs, and laboratory assessments. RESULTS: The incidence of treatment-related adverse events (TRAEs) was low in both the AZE/FP (16%) and FP-only (12%) groups after 90 days' continuous use. Epistaxis was the most frequently reported TRAE in both groups (AZE/FP, 9%; FP, 9%), followed by headache (AZE/FP, 3%; FP, 1%). All other TRAEs in the AZE/FP group were reported by ≤1% of the children. The majority of TRAEs were of mild intensity and resolved spontaneously. Results of nasal examinations showed an improvement over time in both groups, with no cases of mucosal ulceration or nasal septal perforation. There were no unusual or unexpected changes in laboratory parameters or vital signs. CONCLUSION: The intranasal formulation of AZE and FP was safe and well tolerated after 3 months' continuous use in children with allergic rhinitis.The study was registered on ClinicalTrials.gov (NCT01794741).

Real-world use of omalizumab in patients with chronic idiopathic/spontaneous urticaria in the United States.

BACKGROUND: Omalizumab was approved for the treatment of chronic idiopathic urticaria (CIU)/chronic spontaneous urticaria (CSU) in the United States in March 2014. OBJECTIVE: This study sought to describe real-world omalizumab use, in the United States, in a large cohort of patients with CIU/CSU. METHODS: Patients with CIU/CSU (ages ≥12 years) initiated on omalizumab (index date) with ≥12 months of pre- and postindex data were identified in the an insurance claims data base (January 1, 2013, to July 31, 2016). Treatment patterns, including the dosing regimen and continuous use of omalizumab (no gaps for ≥60 days), were described during the 12-month postindex follow-up period. RESULTS: A total of 1546 patients (mean ± standard deviation [SD] ages, 44 ± 14.5 years; 73.1% women) were identified. Most of the patients (84.5%) were initiated on omalizumab 300-mg dose; 90% maintained the initial dose, 7.5% had a dose increase, and 4.6% had a dose decrease. The mean ± SD omalizumab treatment duration was 9.1 ± 3.8 months, the mean ± SD number of omalizumab administrations was 8.3 ± 4.8, and the mean ± SD administration frequency was 44 ± 29 days. A proportion of the patients continuously treated with omalizumab for 6, 9, and 12 months was 67.3, 54.8, and 47.4%, respectively. Among the patients who discontinued omalizumab for ≥3 months (39.8%), 21% restarted the treatment after a mean ± SD of 4.4 ± 1.3 months. The proportion of patients who used other CIU/CSU-related medications decreased pre- to postindex (94.8 to 81.1%), with the highest decrease observed in oral corticosteroids (75.7 to 49.9%). CONCLUSION: In this large real-world study, the majority of the patients with CIU/CSU were initiated on a 300-mg omalizumab dose and treated without titration up or down for 9 months on average. Most of the patients were continuously treated with omalizumab for ≥6 months, and one-fourth of the patients who discontinued treatment resumed it. Moreover, compared with baseline levels, the use of other CIU/CSU-related medications was lower after omalizumab initiation, with the most prominent decrease observed in oral corticosteroids.

Medical therapy versus dietary avoidance in eosinophilic esophagitis: Which approach is better?

BACKGROUND: Eosinophilic esophagitis (EoE) is a chronic immune-mediated esophageal disease characterized by esophageal symptoms and esophageal eosinophilia. It is induced by food triggers and by environmental allergens in some patients. No U.S. Food and Drug Administration approved therapies exist for patients with EoE. Common therapies include topical corticosteroids (TCS) and dietary restriction. METHODS: This article reviewed the pros and cons of a medical versus dietary approach in treating EoE in children and adults. Available data on short- and long-term efficacy, ease of implementation, cost, adverse effects, and quality of life (QoL) were summarized. RESULTS: Although no comparative studies of TCS versus dietary restrictions exist, they seemed to be equivalent from an efficacy standpoint. However, each therapy offers different advantages and disadvantages. TCS allow ingestion of multiple food triggers and improve QoL of patients with EoE. However, TCS have the potential for topical and/or systemic adverse effects and can be costly in the long run. Dietary restriction therapies allow identification of food triggers and are less costly in the long run. However, they are more challenging to implement because they require a team approach with a dietitian and an allergist. In addition, they decrease the QoL of some children with EoE, often require extensive allergy testing and multiple endoscopies, and are not effective when environmental allergens trigger EoE. Therefore, the choice of medical versus dietary therapy needs to be individualized based on a thorough medical evaluation and discussion with patients with EoE and their families. CONCLUSION: Research is needed to establish the lowest most effective and safe dose of TCS and the extent of adherence needed when eliminating foods for EoE, and to find less-invasive ways to monitor histologic disease activity. Potential results from this research may allow more tailored therapies or specific combination therapies that would take advantage of each treatment modality to maximize benefits to the patient while maintaining disease remission.

Intranasal corticosteroids: the role of patient preference and satisfaction.

Allergic rhinitis (AR) is a disease with a significant global burden, associated with many comorbidities and quality-of-life issues. Overwhelming evidence shows that intranasal corticosteroids are the most effective treatment for AR to control the disease, decrease comorbidities, and decrease costs. Poor adherence is a major barrier to achieving control of AR. This article addresses patient preferences and satisfaction regarding intranasal corticosteroids and factors leading to better adherence. We review and summarize the published literature. Factors affecting patient preference and, ultimately, adherence include a variety of sensory components such as odor, taste, comfort of delivery, delivery devices (aerosol versus aqueous) and patient cost. The intensity of adverse sensory attributes is negatively correlated with patient preference and the likelihood of adherence. Selection of an intranasal steroid (INS) with patient preference and satisfaction in mind can influence patient outcomes and cost. Providers need to assess each patient to determine which inhaled INS will lead to the best adherence, thereby improving outcomes in our patients and ultimately reducing the overall global burden of this disease.