Anne Marie Salapatek

Pollinex® Quattro: a novel and well–tolerated, ultra short–course allergy vaccine

Pollinex® Quattro is a novel, ultra short-course vaccine for treatment of seasonal allergic rhinitis from grass, tree or ragweed pollen allergy. Its unique formulation combines chemically modified allergens adsorbed onto a L-tyrosine depot to enhance tolerability with the novel adjuvant, monophosphoryl lipid A, to improve efficacy. Controlled clinical studies indicate that four preseasonal injections with grass or tree formulations significantly reduce rhinoconjunctivitis symptoms and medication use, as well as elevate allergen-specific immunoglobulin G and blunt elevation of immunoglobulin E upon allergen exposure. Postmarketing surveillance studies indicate similar clinical outcomes. In all cases, the allergy vaccine was well tolerated with minimal local reactions, while systemic reactions were rare and mild. Results from recent investigational trials with grass and ragweed formulations are consistent with previous efficacy and safety outcomes, and will be used toward product registration in North America.

Mometasone furoate nasal spray provides early, continuing relief of nasal congestion and improves nasal patency in allergic patients.

Background Patients report nasal congestion as the most bothersome seasonal allergic rhinitis (SAR) symptom. Measurement of this symptom in previous research has largely been based on subjective patient ratings. This study was designed to measure efficacy, onset, and duration of action of the corticosteroid mometasone furoate nasal spray (MFNS) on nasal congestion using an environmental exposure chamber (EEC) and the objective assessment acoustic rhinometry (AcR). Methods In a randomized, double-blind, placebo-controlled study, ragweed-sensitive subjects were exposed to ragweed pollen (3500 ± 500 pollen grains/m3) in an EEC (day 1). Subjects rated instantaneous total nasal symptom score (TNSS), including NSS for congestion (NSS-C). Qualifying subjects received MFNS, 200 micrograms, or placebo and rated postdosing symptoms; a subset received MFNS, 200 micrograms, or placebo q.d. for 6 subsequent days, returning to EEC on day 8. Days 1 and 8 assessments included AcR, TNSS, and the Rhinoconjunctivitis Quality of Life Questionnaire developed for use in the EEC (RQOLQ-EEC). Results At day 1, hour 6, patients receiving MFNS (n = 155) reported significantly reduced congestion versus placebo (n = 155) per AcR and NSS-C after one dose, showing numerically superior TNSS change from baseline (p = NS). Among the subset who received 6 additional days of treatment, MFNS (n = 78) yielded significantly lower TNSS versus placebo (n = 77) before day 8 EEC entry and throughout 4-hour exposure (p < 0.05), except at 3.5 hours. AcR showed lower congestion with MFNS versus placebo before day 8 EEC exposure and at 24 and 26 hours after final dose (p < 0.05 for all). AcR and NSS-C correlated at multiple time points. Day 8 RQOLQ-EEC between-group scores were significantly different (p = 0.02) for practical problems. Conclusion MFNS, 200 micrograms, showed onset of nasal congestion relief at 6 hours and duration of action beyond 24 hours postdosing. Objective and subjective assessments were correlated in subjects with maximal (placebo) or minimal (MFNS treatment) congestion symptoms; both assessments were correlated with improved QOL.

Onset of action of the fixed combination intranasal azelastine-fluticasone propionate in an allergen exposure chamber

BACKGROUNDnA fixed-dose combination of intranasal azelastine hydrochloride and fluticasone propionate (MP-AzeFlu) is the most effective treatment of allergic rhinitis, but its onset of action requires further investigation.nnnOBJECTIVEnTo compare the onset of action of MP-AzeFlu with the free combination of oral loratadine (LORA) and intranasal fluticasone propionate (INFP).nnnMETHODSnIn this single-center, randomized, placebo-controlled, double-blind, double-dummy, 3-period crossover trial, allergic rhinitis symptoms were induced in asymptomatic patients by ragweed pollen challenge in an allergen environmental exposure chamber. Patients received single-dose MP-AzeFlu, LORA/INFP, or placebo and were monitored for 4 hours. The primary outcome was onset of action measured by total nasal symptom score (TNSS). Secondary measures were total ocular symptom score (TOSS), total score of the 7 nasal and ocular symptoms (T7SS), and the global visual analog scale (VAS).nnnRESULTSnThe full analysis set included 82 patients, of which 78 completed all treatments. TNSS was significantly reduced versus placebo from 5 minutes for MP-AzeFlu and 150 minutes for LORA/INFP onward (both P < .05) till the end of assessment (0-4 hours). MP-AzeFlu reduced TNSS to a greater extent at each time point from 5 to 90 minutes (P < .05) and over the entire assessment interval (P ≤ .005) versus LORA/INFP or placebo. No statistically significant difference between LORA/INFP and placebo was observed over the assessment interval (Pxa0= .182). The onset of action of MP-AzeFlu assessed by TOSS, T7SS, and VAS was 10 minutes, 2 hours earlier than with LORA/INFP.nnnCONCLUSIONnMP-AzeFlu had a more rapid onset of action (5 minutes) and was more effective than LORA/INFP.

A Pilot Study Investigating Clinical Responses and Biological Pathways of Azelastine/Fluticasone in Nonallergic Vasomotor Rhinitis before and after Cold Dry Air Provocation

Background: Nonallergic vasomotor rhinitis (NAVMR) has been considered a diagnosis by exclusion due to unknown mechanisms or lack of diagnostic biomarkers. Methods: To determine clinical responses and biological pathways in NAVMR subjects challenged to cold dry air (CDA) in an environmental exposure chamber (EEC) pre- and posttreatment with azelastine/fluticasone (AzeFlu), 30 NAVMR subjects, prescreened for CDA-induced symptoms (approx. 14°C, <15% relative humidity, ×1 h) were randomized to treatment with AzeFlu (n = 20) or placebo (n = 10) for 2 weeks. Total nasal symptoms scores, minimum cross-sectional area, cough, and conjunctival redness were recorded at visit 1 (pretreatment) and visit 2 (posttreatment) before, during, and after CDA challenge. At both visits, nasal lavage fluid (NLF) and nasal scrapings (NS) were collected pre- and post-CDA challenge. Substance P, neurokinin-A, and calcitonin gene-related peptide concentrations in NLF were analyzed pre- and postchallenge at each visit. Their relationship with CDA-induced symptoms was determined by statistical analysis. MicroRNA sequencing from NS determined differentially expressed miRNA between the treatment groups post-CDA challenge at each visit. Results: The minimum cross-sectional area (p < 0.05), cough count (p < 0.05), and substance P (p < 0.01) improved posttreatment with AzeFlu versus placebo. Gene targets for differentially expressed miRNAs at visit 1 were enriched for biological pathways regulating epithelial ciliogenesis and cell integrity that were modified in the AzeFlu-treated group versus placebo posttreatment. Conclusions: This study demonstrated the feasibility of an EEC model to investigate CDA-induced clinical responses and pathobiology in NAVMR subjects pre- and posttreatment with AzeFlu. NAVMR disease mechanisms for other nonallergic triggers can be investigated similarly.

Olopatadine/Mometasone Combination Nasal Spray Improves Seasonal Allergic Rhinitis Symptoms in an Environmental Exposure Chamber Study

BACKGROUNDnGSP301 nasal spray is a fixed-dose combination of the antihistamine olopatadine hydrochloride and the corticosteroid mometasone furoate intended for seasonal allergic rhinitis (SAR) treatment.nnnOBJECTIVEnTo evaluate the efficacy and safety of once-daily or twice-daily GSP301 in a ragweed pollen environmental exposure chamber.nnnMETHODSnIn this randomized, double-blind, double-dummy study, adults (18-65 years old) with SAR were equally randomized to 665 μg of olopatadine and 25 μg of mometasone (twice-daily GSP301), 665 μg of olopatadine and 50 μg of mometasone (once-daily GSP301), a US Food and Drug Administration-approved formulation of 137 μg of azelastine and 50 μg of fluticasone twice-daily (AzeFlu), a US Food and Drug Administration-approved formulation of 665 μg of olopatadine twice-daily, or placebo (twice-daily). During 2 visits (baseline and end of 14-day treatment), participants assessed SAR symptoms at specified time points. The primary end point-mean change from baseline in instantaneous total nasal symptom score (iTNSS) for twice-daily or once-daily GSP301 vs placebo-was analyzed by analysis of covariance. Onset of action, ocular symptoms, and adverse events were assessed.nnnRESULTSnA total of 180 participants were randomized. Treatment with twice-daily or once-daily GSP301 provided statistically significant improvements in iTNSS vs placebo (twice-daily GSP301: least squares mean difference, -3.60; 95% confidence interval [CI], -4.89 to -2.30; once-daily GSP301: least squares mean difference, -3.05; 95% CI, -4.35 to -1.76; P < .0001 for both). Significant improvements in iTNSS with twice-daily GSP301 occurred by 10 minutes after dosing (-1.26; 95% CI, -2.30 to -0.21; Pu202f=u202f.02) and were maintained at all later time points except one (2.5 hours). Treatment-emergent adverse events occurred in 22.2%, 30.6%, 25.0%, 22.2%, and 16.7% of participants in the twice-daily GSP301, once-daily GSP301, AzeFlu, olopatadine, and placebo groups, respectively.nnnCONCLUSIONnIn an environmental exposure chamber model, twice-daily and once-daily GSP301 treatments were well tolerated and provided statistically significant and clinically meaningful SAR symptom improvement vs placebo.nnnTRIAL REGISTRATIONnClinicalTrials.gov Identifier: NCT03444506.

Pharmacokinetics of intranasal olopatadine in the fixed-dose combination GSP301 versus two monotherapy intranasal olopatadine formulations

BACKGROUNDnGSP301 is a fixed-dose combination of the antihistamine olopatadine hydrochloride and the corticosteroid mometasone furoate developed as a single nasal spray.nnnOBJECTIVEnTo assess the relative bioavailability of olopatadine administered as GSP301 versus two olopatadine monotherapy nasal spray formulations.nnnMETHODSnIn this single-dose, open-label, crossover study, healthy adults (18-65 years old) were equally randomized to one of six treatment sequences for three 48-hour treatment periods with GSP301 (olopatadine 665 μg-mometasone 50 μg), the olopatadine monotherapy component of GSP301 (OLO-sponsor; 665 μg) and U.S. Food and Drug Administration approved olopatadine (OLO; 665 μg); each treatment was administered as a single dose (two sprays in each nostril). To assess the relative bioavailability of olopatadine in the fixed-dose nasal spray versus two monotherapies, pharmacokinetic (PK) estimates, maximum plasma concentration (Cmax), area under the plasma concentration time curve (AUC) from time 0 to the last time point with measurable concentration (AUC0-t), and AUC from time 0 to time infinity (AUC0-∞) were compared by analysis of variance. Safety and tolerability were also evaluated.nnnRESULTSnA total of 30 healthy adults (mean age, 43.1 years) were randomized. The majority of the subjects were white men. The geometric mean ratios for natural log transformed Cmax, AUC0-t, and AUC0-∞ of olopatadine in GSP301 and OLO-sponsor were 86.63, 86.92, and 92.83, respectively. For GSP301 and OLO, geometric mean ratios for Cmax, AUC0-t, and AUC0-∞ were 84.68, 87.87, and 93.80, respectively. The percentage of subjects who reported treatment-emergent adverse events (AE) for GSP301, OLO-sponsor, and OLO were 13.8, 10.3, and 10.0%, respectively, with mild AEs reported. One subject withdrew from the study due to an AE (minor oropharyngeal pain) during OLO treatment, before receiving GSP301.nnnCONCLUSIONnOlopatadine bioavailability with GSP301 was comparable with OLO-sponsor and OLO. The presence of mometasone in GSP301 did not considerably affect the PK of olopatadine. GSP301 was well tolerated, with only mild AEs reported.

P435 Olopatadine/mometasone combination nasal spray improves seasonal allergic rhinitis symptoms in a ragweed environmental exposure chamber

In patients with allergic rhinitis (AR), combining intranasal antihistamines and corticosteroids may provide improved symptom relief over monotherapy treatment. GSP301 nasal spray is a fixed-dose combination of the antihistamine olopatadine hydrochloride and the corticosteroid mometasone furoate. In this Proof-of-Concept study, efficacy and safety of GSP301 once-daily (QD) or twice-daily (BID) were evaluated in a ragweed pollen Environmental Exposure Chamber (EEC).

Poster 2000: A case study in effective innovative strategic multi-modal recruitment strategies in difficult-to-recruit patient populations: study of safety and tolerability of novel SLIT in an adolescent population

Background Poor subject recruitment is a major cause of cost overruns, extended finish dates, and delayed agency submissions. Failure to meet recruitment targets is particularly common in allergy immunotherapy studies where unique challenges such as allergen seasonality, lengthy study durations and studying allergen specific populations are necessary. Historically, standard modalities of advertising in newspaper, radio, and television have been employed with mixed success. Increasing availability of communication and sharing technologies, and social media availabilities, affords innovative approaches and tools to customize the recruitment of subjects, especially difficult populations.

S101 – Mometasone Reduces Congestion in Acoustic Rhinometry Study

Objectives In a double-blind placebo-controlled study of ragweed-sensitive subjects with seasonal allergic rhinitis (SAR), mometasone furoate nasal spray (MFNS) was evaluated for improvement in nasal congestion, reportedly the most bothersome symptom of SAR. Methods On Day 1, 310 subjects were exposed to ragweed pollen in an environmental exposure chamber (EEC) for 2 hours pre-dose, given MFNS 200 mcg or placebo, and studied for 6 hours post-dose. Acoustic rhinometry (AcR) was used to measure congestion before and after exposure. Subjects (n=155) who received MFNS or placebo for 7 additional days returned to the EEC on Day 8 for 4 additional hours of pollen exposure at 24, 26, and 28 hours post-dose. Results On Day 1, after 2 hours of EEC exposure pre-dose, minimal cross-sectional areas (MCAs) of each nostril measured with AcR decreased significantly for all subjects. At 6 hours post-dose, MFNS significantly reduced congestion (increased nasal patency) vs. baseline (P equal to/less than 0.00001) and placebo (P equal to 0.005). On Day 8, MFNS significantly decreased congestion vs. placebo pre-EEC pollen exposure (P equal to 0.04) and at 2 and 4 hours (P equal to 0.01 and 0.0008, respectively). MFNS protected subjects against nasal congestion throughout EEC pollen exposure on Day 8, while congestion continued to increase in subjects receiving placebo. Conclusions A single treatment of MFNS demonstrated significantly reduced nasal congestion, as assessed by AcR, a sensitive, objective measure of nasal patency. MFNS effectively reduced allergen-induced nasal congestion, even at trough levels.