CYT003, a TLR9 agonist, in persistent allergic asthma - a randomized placebo-controlled Phase 2b study.

BACKGROUND: New treatment options are required for patients with asthma not sufficiently controlled with inhaled therapies. In a Phase 2a trial, CYT003, a Toll-like receptor-9 agonist immunomodulator, improved asthma control during inhaled glucocorticosteroid reduction in patients with allergic asthma. This double-blind Phase 2b study assessed the efficacy and safety of CYT003 in patients with persistent moderate-to-severe allergic asthma not sufficiently controlled on standard inhaled glucocorticosteroid therapy with/without long-acting beta-agonists (LABAs). METHODS: Overall, 365 patients received seven doses of subcutaneous CYT003 (0.3, 1, or 2 mg) or placebo as add-on therapy to conventional controller medication. Change from baseline in Asthma Control Questionnaire (ACQ) score was the primary outcome; secondary outcomes included change in forced expiratory volume, Mini Asthma Quality of Life Questionnaire, and safety. RESULTS: All groups, including placebo, showed a clinically important improvement in ACQ score; however, there was no significant difference between the CYT003 and placebo groups at week 12 (least-squares mean difference 0.3 mg: -0.027 [95% confidence interval -0.259 to 0.204]; 1 mg: 0.097 [-0.131 to 0.325]; 2 mg: 0.081 [-0.148 to 0.315]). No significant differences were seen in secondary outcomes. CYT003 was well tolerated; the most common treatment-emergent adverse events were injection site reactions. Due to lack of efficacy, the study was prematurely terminated at the end of the treatment phase with no further follow-up. CONCLUSIONS: Toll-like receptor-9 agonism with CYT003 showed no additional benefit in patients with insufficiently controlled moderate-to-severe allergic asthma receiving standard inhaled glucocorticosteroid therapy with or without LABAs.

Assessment of clinical efficacy of CYT003-QbG10 in patients with allergic rhinoconjunctivitis: a phase IIb study.

BACKGROUND: Allergic symptoms are generally caused by exposure to substances to which people have become sensitized. Associated with this is an 'unbalanced' Th1/Th2 immune response with T cell responses skewed towards the production of Th2 cytokines, IL-4, 5, and 13 and high levels of IgE antibodies. Current immune modulating therapies require the use of allergens, carrying the risk to induce potentially severe allergic reactions. OBJECTIVE: Goal of the present study was to assess the safety and efficacy of an allergen-free immune modulator in patients suffering from perennial allergy. METHODS: In order to be protected from immediate degradation upon injection, a toll-like receptor 9 (TLR9) agonist was packaged into virus-like particles. These nanoparticles loaded with TLR9 ligands (CYT003-QbG10) were injected six times, at weekly intervals, into patients with house dust mite allergy in an attempt to ameliorate allergic symptoms by modifying the immune response towards allergens. Two different doses were compared against placebo in this double-blind, randomized phase IIb study (n=299). Public trial registry: http://clinicaltrials.gov (NCT00800332). RESULTS: The treatment was safe and generally well tolerated. Rhinoconjunctivitis symptoms were significantly lower in patients treated with high dose of CYT003-QbG10 as compared with placebo (scores 0.31 vs. 0.52, P=0.04) based on a standardized average combined symptom and medication score. Furthermore, patients in the high dose group reported a significantly better quality of life score post-treatment than patients on placebo (scores 0.71 vs. 1.21, P=0.02). The conjunctival provocation test revealed a median 10-fold increase in allergen tolerance in the high dose group while in the placebo group it remained unchanged. CONCLUSION AND CLINICAL RELEVANCE: Treatment with high-dose CYT003-QbG10 improved disease symptoms and reduced medication use in allergic individuals thus providing first evidence for a new potential immunotherapeutic.