Jennifer Maloney

Efficacy and safety of timothy grass allergy immunotherapy tablets in North American children and adolescents

BACKGROUND Allergy immunotherapy tablet (AIT) treatment might be a safe and convenient form of specific immunotherapy but it has not been investigated in North American children and adolescents. OBJECTIVE We sought to investigate the efficacy and safety of timothy grass AIT treatment in North American children/adolescents with grass pollen-induced allergic rhinoconjunctivitis (ARC) with or without asthma. METHODS Three hundred forty-five subjects (5-17 years old) were randomized to once-daily grass AIT treatment (2,800 bioequivalent allergen units, 75,000 standardized quality tablet, approximately 15 μg of Phl p 5) or placebo approximately 16 weeks before the 2009 grass pollen season (GPS). Treatment continued through the GPS. Daily symptoms and allergy rescue medication use were recorded. The primary end point was the total combined score (TCS) of the daily symptom score (DSS) and daily medication score (DMS) for the entire GPS. DSS, DMS, Rhinoconjunctivitis Quality of Life Questionnaire score, and Phl p 5-specific IgG4 and IgE-blocking factor levels were secondary end points. Safety was assessed through adverse events. RESULTS Eighty-nine percent of subjects were multisensitized. TCS, DSS, DMS, and Rhinoconjunctivitis Quality of Life Questionnaire score versus placebo improved 26% (P = .001), 25% (P = .005), 81% (P = .006), and 18% (P = .04). Phl p 5-specific IgG4 and IgE-blocking factor levels were significantly higher at the peak and end of the GPS (P < .001). Treatment was well tolerated. Adverse events were generally mild and transient. Although no investigator-assessed systemic allergic reactions were reported, 1 grass AIT-treated subject experienced an event indicating a systemic reaction (lip angioedema, dysphagia, and cough). CONCLUSIONS Use of once-daily timothy grass AIT treatment effectively treats timothy grass (cross-reactive with Festucoideae grasses) pollen-induced ARC in North American children 5 years and older. Given its convenient administration, lack of dose build-up requirement, safety profile, and efficacy, AIT treatment might become an important addition to the North American ARC treatment armamentarium.

Efficacy and safety of timothy grass allergy immunotherapy tablet treatment in North American adults.

BACKGROUND Immunotherapy for allergic rhinoconjunctivitis (ARC) in North America is generally administered subcutaneously, but alternative formulations might be safer and more convenient. Trials of sublingual formulations in North America are needed to confirm European efficacy and safety data. OBJECTIVE We sought to investigate the efficacy and safety of timothy grass allergy immunotherapy tablet (AIT) treatment in North American subjects with ARC. METHODS Four hundred thirty-nine adults with grass pollen-induced ARC with or without asthma were randomized to once-daily 2,800 bioequivalent allergen units of standardized grass AIT (oral lyophilisate, Phleum pratense, 75,000 standardized quality tablet, containing approximately 15 μg of Phl p 5) or placebo approximately 16 weeks before the 2009 grass pollen season (GPS). The primary end point was the average total combined score of the daily symptom score and the daily medication score during the GPS. Rhinoconjunctivitis Quality of Life Questionnaire with standardized activities (RQLQ[S]) scores, Phl p 5-specific IgG4 levels, and IgE-blocking factor levels were additional end points. Adverse events (AEs) were monitored for safety. RESULTS Relative to placebo, grass AIT treatment improved total combined scores by 20% (P = .005), daily symptom scores by 18% (P = .02), and RQLQ(S) scores by 17% (P = .02). Daily medication scores were improved by 26% and trended toward significance (P = .08). Phl p 5-specific IgG4 and IgE-blocking factor levels were higher after grass AIT treatment compared with those after placebo at the end of the GPS (P < .001). Grass AIT treatment was safe and well tolerated. The majority of AEs were transient mild local reactions with no investigator-diagnosed grass AIT-related serious AEs or reports of anaphylactic shock/respiratory compromise. In the grass AIT group, 1 subject received epinephrine after experiencing a possible grade 1 systemic reaction (local site reactions, chest discomfort, and rash). CONCLUSIONS Timothy grass AIT treatment (cross-reactive with related Pooideae grasses) was demonstrated to be effective, generally safe, and well tolerated in North American adults with grass pollen-induced ARC.

Randomized controlled trial of a ragweed allergy immunotherapy tablet in North American and European adults

BACKGROUND In North America and Europe, millions of patients experience symptoms of allergic rhinitis with or without conjunctivitis (AR/C) on exposure to ragweed pollen. The disease burden can be significant, with most patients relying on symptomatic medications without disease-modifying potential. However, novel sublingual immunomodulatory treatment options may potentially play an important role if efficacy and side effect profiles allow the convenience of self-administration. OBJECTIVES This study evaluated an allergy immunotherapy tablet (AIT; SCH 39641/MK-3641) for treatment of ragweed-induced AR/C in the first large randomized, double-blind multinational trial of this therapeutic modality for ragweed allergy. METHODS Adults (n = 784) with short ragweed-induced AR/C were randomly assigned to approximately 52 weeks of daily self-administered ragweed AIT of 1.5, 6, or 12 units of Ambrosia artemisiifolia major allergen 1 (Amb a 1-U) or placebo. Subjects could use as-needed allergy rescue medication. Symptoms and medications were recorded daily. The primary efficacy end point was total combined daily symptom/medication score (TCS) during peak ragweed season. Safety was monitored through adverse event diaries maintained through study duration. RESULTS During peak ragweed season, ragweed AIT of 1.5, 6, and 12 Amb a 1-U reduced TCS by 9% (-0.76; P = .22), 19% (-1.58; P = .01), and 24% (-2.04; P = .002) compared with placebo. During the entire season, ragweed AIT of 1.5, 6, and 12 Amb a 1-U reduced TCS by 12% (-0.88; P = .09), 18% (-1.28; P = .01), and 27% (-1.92; P < .001) compared with placebo. Treatment was well tolerated; no systemic allergic reactions occurred. CONCLUSIONS In this trial, ragweed AIT of 12 Amb a 1-U was effective and tolerable with a safety profile that permitted daily self-administration of ragweed allergen immunotherapy.

Randomized controlled trial of ragweed allergy immunotherapy tablet efficacy and safety in North American adults.

BACKGROUND Ragweed is an important cause of allergic rhinitis with or without conjunctivitis (AR/C) in North America and elsewhere. Allergen immunotherapy enabling safe patient self-administration is considered an unmet clinical need. Allergy immunotherapy tablet (AIT) treatment has shown promising efficacy and safety for grass allergy but has not been assessed for ragweed allergy. OBJECTIVE To evaluate efficacy and safety of 2 short ragweed AIT doses in patients with AR/C. METHODS Adults with ragweed pollen-induced AR/C were randomized 1:1:1 to daily ragweed AIT (6 or 12 Amb a 1 units) or placebo before, throughout, and after ragweed season (approximately 52 weeks). Patients could use predefined allergy rescue medications in season. Efficacy end points included peak and entire season total combined score (TCS) and its components daily symptom score (DSS), and daily medication score (DMS). Safety assessments included adverse events. RESULTS A total of 565 patients were randomized. During peak season, the 6- and 12-Amb a 1 unit ragweed AIT doses showed 21% (-1.76 score) and 27% (-2.24 score) improvement in TCS vs placebo (P < .05). The 6- and 12-Amb a 1 unit AIT doses significantly improved DSS and DMS vs placebo (P < .05). Peak and entire season efficacy were comparable. The 12-Amb a 1 unit AIT dose reduced peak-season TCS vs placebo by 21% and 25% in subgroups with and without local application-site reactions, respectively. Most treatment-related adverse events were mild, oral reactions; no systemic allergic reactions were reported. One patient in the 6-Amb a 1 unit group received epinephrine at an emergency facility for sensation of localized pharyngeal edema. CONCLUSION In this trial, ragweed AIT was effective and well tolerated in ragweed-allergic North American adults. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00783198.

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.

Safety of house dust mite sublingual immunotherapy standardized quality tablet in children allergic to house dust mites

BACKGROUND Sublingual immunotherapy (SLIT) tablets could be an important alternative to subcutaneous immunotherapy for house dust mite (HDM) allergy in children. OBJECTIVE To characterize the safety, tolerability, and duration of local adverse events (AEs) of an HDM SLIT tablet (MK-8237; Merck, ALK Abellò, and Torii) in North American children 12 to 17 years old with HDM allergic rhinitis with and without conjunctivitis and with or without asthma. METHODS In this phase 1, multicenter, double-blinded, randomized trial (NCT01678807), children received placebo, HDM SLIT tablet 6 standardized quality (SQ) HDM, or 12 SQ-HDM once daily for 28 days. The primary end point was the proportion of subjects with treatment-emergent AEs receiving active treatment vs placebo. The secondary end point was the proportion of subjects who discontinued owing to AEs. RESULTS In total 195 subjects were randomized. The 2 HDM SLIT tablet doses were well tolerated. No anaphylactic reactions, systemic allergic reactions, AEs requiring epinephrine, serious AEs, or local swellings in the mouth or throat assessed as severe were reported. The proportion of subjects with treatment-emergent AEs was 54% with 6 SQ-HDM and 57% with 12 SQ-HDM (nonsignificant vs 43% with placebo). Local AEs were the most commonly reported treatment-emergent AEs. On day 1, the median duration of individual local AEs ranged from 1 to 43 minutes. The proportion of subjects who discontinued owing to AEs was 0%, 6.2%, and 6.2%, and who experienced treatment-related AEs was 25%, 45%, and 52% for the placebo, 6 SQ-HDM, and 12 SQ-HDM groups, respectively. CONCLUSION The 6 and 12 SQ-HDM doses of the HDM SLIT tablet MK-8237 were well tolerated, and local AEs were of short duration. TRIAL REGISTRATION ClinicalTrials.gov, identifier NCT01678807.

Safety of ragweed sublingual allergy immunotherapy tablets in adults with allergic rhinoconjunctivitis.

A sublingually administered allergy immunotherapy tablet (AIT) is under development to treat ragweed (Ambrosia artemisiifolia)-induced allergic rhinoconjunctivitis (ARC). This study investigates the optimal tolerable dose of once daily ragweed pollen AIT.Subjects 18-50 years old with ragweed-induced ARC were enrolled at two U.S. centers in a double-blind, placebo-controlled,dose-escalation study outside ragweed season. Groups (12 subjects each) were to be randomized 3:1 to 28 days of active treatment (groups assigned in sequence to 3, 6, 12, 24, 50, or 100 units of Ambrosia artemislifolia major allergen 1 [Amb a 1 U],without dose buildup at any level) or matching placebo. Recruitment to 50 Amb a 1-U was discontinued because of adverse events (AEs) after four AIT subjects were enrolled; 100 Amb a 1-U was not initiated. Fifty-three subjects were randomized (AIT,n = 40; placebo, n = 13); four discontinued, all because of AEs (AIT, n = 3; placebo, n = 1). Treatment-related AEs (TRAEs) were more frequent with AIT (73%) than placebo (31%), increasing with dose level. AIT TRAEs were mostly mild (94%) or moderate(5%). No serious TRAEs or anaphylactic shock occurred. The most common TRAEs with AIT were localized pruritus, nasal irritation, and throat irritation. Median onset for common AIT application site reactions was 24 ≤ hours after first treatment (median duration, 15-50 minutes). AIT increased immunoglobulin (Ig) significantly more than placebo (ragweed-specific IgE [6, 12, and 24 Amb a 1-U]; IgG4 [all doses]; p < 0.05). Three subjects in dose groups ≥ 24 Amb a 1-U experienced symptoms suggestive of systemic reaction. Of tested doses, ragweed AIT 24 <Amb a 1-U once-daily was well tolerated in subjects with ragweed-induced ARC. Clinical trial registration URL and registration number: www.clinicaltrials.gov/ct2/show/NCT01134705 [corrected].

Sequential Treatment Initiation with Timothy Grass and Ragweed Sublingual Immunotherapy Tablets Followed by Simultaneous Treatment Is Well Tolerated.

BACKGROUND Dual treatment with grass and ragweed sublingual immunotherapy (SLIT) tablets has not been studied. OBJECTIVE To characterize the safety and tolerability of dual grass and ragweed SLIT-tablet administration. METHODS This open-label, multicenter trial (NCT02256553) enrolled North American adults (N = 102) allergic to grass and ragweed. The trial had 3 periods, each of 2 weeks duration. In period 1, subjects received once-daily timothy grass SLIT tablet (2800 bioequivalent allergen unit; Merck, Inc, Kenilworth, NJ/ALK, Hørsholm, Denmark). In period 2, subjects received a short ragweed SLIT tablet (12 Ambrosia artemisiifolia 1-U; Merck/ALK) every morning and a grass SLIT tablet every evening. In period 3, subjects received once-daily grass and ragweed SLIT tablets within 5 minutes (simultaneous intake). The primary end point was the proportion of subjects with 1 or more local swelling events in each period. Secondary end points were the proportion of subjects with 1 or more local adverse events (AEs), that discontinued the treatment because of AEs, and subjects with 1 or more local AEs requiring treatment. RESULTS No severe swellings, systemic allergic reactions, asthma attacks, or reactions requiring epinephrine were reported. Most (99%) AEs were graded mild to moderate. The proportions of subjects with 1 or more local swelling events were 14%, 22%, and 15% for periods 1, 2, and 3, respectively. For periods 1, 2, and 3, the proportions of subjects with 1 or more local AEs were 71%, 69%, and 56%, respectively; the proportions discontinuing the treatment because of treatment-related AEs were 5%, 1%, and 2%, and the proportions with 1 or more local AEs requiring treatment were 4%, 4%, and 1%. CONCLUSIONS In this trial, a 4-week sequential SLIT-tablet dosing schedule followed by simultaneous intake of timothy grass and ragweed tablets was well tolerated.

Short ragweeds is highly cross-reactive with other ragweeds

BACKGROUND The most widespread ragweed (Ambrosia) species in North America are short ragweed (Ambrosia artemisiifolia; Amb a), giant ragweed (Ambrosia trifida; Amb t), and western ragweed (Ambrosia psilostachya; Amb p). Varied geographic distributions of ragweed species raise questions regarding the need for ragweed species-specific allergen immunotherapy. OBJECTIVE To determine allergenic cross-reactivity among ragweed species by immunologic analyses of sera from subjects allergic to ragweed from North America and Europe. METHODS Sera were collected from 452 subjects allergic to ragweed who participated in Amb a sublingual immunotherapy tablet clinical trials. All subjects had positive skin prick test and serum IgE against Amb a. Ragweed-specific IgE (pre treatment) and IgG4 (post treatment) were measured by ImmunoCAP. IgE inhibition studies among Amb a, Amb t, and Amb p were conducted. Using pooled sera from another ragweed-allergic population, IgE inhibition studies of 7 less widespread Ambrosia species also were conducted. RESULTS A strong correlation between Amb a vs Amb p and Amb t serum IgE levels was observed. In the vast majority of pretreatment sera, Amb a inhibited Amb a, Amb p, and Amb t IgE reactivity by more than 90%. Strong correlations were observed between Amb a vs Amb p and Amb t post-treatment IgG4 levels. In pooled sera, Amb a extract inhibited the binding of serum IgE to all 10 ragweed species by 98%-100%. CONCLUSION In a population of subjects allergic to Amb a, substantial allergenic cross-reactivity among Amb a, Amb p, and Amb t was demonstrated. These in vitro data suggest that an Amb a-based single-species ragweed allergen immunotherapy may be therapeutically active in patients exposed to diverse ragweed pollens. TRIAL REGISTRY Clinicaltrials.gov, NCT00770315, NCT00783198, and NCT00330083.

The efficacy and safety of the Timothy grass allergy sublingual immunotherapy tablet in Canadian adults and children

BackgroundThe effect of sublingual Timothy grass immunotherapy tablet 2800 BAU (grass SLIT-T) has been evaluated in three North American trials in adults and children who have allergic rhinitis with or without conjunctivitis (AR/C). This paper examines the effects of grass SLIT-T in Canadians.MethodsData for grass-allergic Canadians in three randomized, placebo-controlled, double-blind trials were analyzed post hoc: 1) adults ≥18 y, grass-pollen season [GPS] 2009; 2) children 5– <18 y, 2009; and 3) adults 18–65 y and children 5– <18 y, GPS 2012. Data from the GPS 2009 trials were pooled to provide a more precise estimate of treatment effects than the individual studies would provide. In every trial, participants received once-daily grass SLIT-T or placebo approximately 12 weeks before and continuing throughout the GPS. Participants used daily electronic diaries to record AR/C symptoms and medication use for treatment of symptoms. The therapeutic effect of grass SLIT-T was measured as a total combined score (TCS = daily symptom score + daily medication score) averaged over the entire GPS. Safety was assessed by monitoring adverse events (AEs).ResultsIn the three trials, 386 Canadian participants were randomized; the overall population had 2284 participants. Canadian participants treated with grass SLIT-T in the pooled adult-pediatric 2009 trials showed a 38% mean TCS reduction relative to placebo (-2.06 difference [95% CI: -3.72, -0.39]; 3.32 vs. 5.37). Participants treated with grass SLIT-T in the adult-pediatric 2012 trial showed a 37% median TCS reduction relative to placebo (-1.53 difference [95% CI: -2.1, -0.3]; 2.58 vs. 4.11). Similar efficacy findings were observed over the peak GPS. Approximately 90% of treatment-related AEs were mild or moderate in severity. Two Canadian participants had moderate systemic allergic reactions (skin, respiratory, abdominal symptoms) to grass SLIT-T; symptoms resolved within 1 hour without medical intervention or treatment. No serious or life-threatening treatment-related AEs occurred.ConclusionThe 2800 BAU Timothy grass SLIT-T significantly improved AR/C induced by Timothy grass pollen in adults and children ≥5 y in Canadians, which was consistent with the robust efficacy observed in the overall trial population. The treatment was generally well tolerated.Trial registrationClinicaltrials.gov identifiers NCT00562159, NCT00550550, NCT01385371.