Safety of the intranasal toll-like receptor 4 agonist CRX-675 in allergic rhinitis

Background: CRX-675 is an aqueous formulation of a toll-like receptor 4 agonist and an inducer of T,l responses. Studies in allergic dogs showed that pretreatment with CRX-675 reduced nasal congestion induced by allergen challenge. Objective: To study the safety of intranasal CRX-675 treatment in patients with seasonal allergic rhinitis. Methods: We conducted a single-center, randomized, double-blind, placebo-controlled, dose-escalating safety trial of single doses of CRX-675 given intranasally before intranasal ragweed challenges. Patients with ragweed-induced seasonal allergic rhinitis received increasing concentrations of ragweed to determine the dose that would result in a 30% reduction in nasal volume (PD30) during screening. Two weeks later, each patient was rechallenged with their assigned PD30 ragweed dose. Fourteen days later, patients were treated with either placebo (n = 16) or CRX-675 (2, 20, 100, or 200 mu g intranasally, n = 12 per arm) 24 hours before a subsequent PD30 ragweed challenge. Patients were rechallenged with ragweed 14 days thereafter. Results: No serious or severe adverse events were reported. Most adverse events were mild (grade 1) and either were considered unrelated to CRX-675 or resolved without intervention. The adverse event profile of CRX-675-treated patients was similar to that of placebo-treated patients, and no dose-related toxic effects were observed. There was no clear trend in the ability of CRX-675 to inhibit nasal allergen challenge responses, but improvement in nasal symptom scores was observed at 100 jig. Conclusions: This preliminary trial suggests that intranasally applied CRX-675 is safe at the doses tested. Appropriate dosing and timing will ultimately define its potential therapeutic role for allergies.