Allergic rhinitis - R112
Seasonal allergic rhinitis, or hay fever, is caused by an allergy to otherwise harmless substances such as pollen, pet hair and dust, which inflames the mucus membranes. Symptoms include sneezing, runny and stuffy noses, coughing, postnasal drip, an itchy nose and throat, dark circles under the eyes, and itchy, watery and swollen eyes. In severe cases, patients can suffer asthma attacks.
Seasonal allergic rhinitis, or hay fever, is caused by an allergy to otherwise harmless substances such as pollen, pet hair and dust, which inflames the mucus membranes. Symptoms include sneezing, runny and stuffy noses, coughing, postnasal drip, an itchy nose and throat, dark circles under the eyes, and itchy, watery and swollen eyes. In severe cases, patients can suffer asthma attacks.
It is modulated by immunoglobulin E (IgE), to which the allergen binds. This then in turn binds to the receptors on the surface of mast cells and basophils, which causes the release of histamine, leukotrienes and other inflammation causing substances. Targeting the interaction of IgE with cell surface receptors is thus a potential route for treating allergic rhinitis.
Rigel is investigating the possibility of inhibiting spleen tyrosine kinase, or Syk, a novel drug target which is involved in IgE signalling in mast cells. These cells play important roles in both early and late phase allergic reactions, and so Syk inhibitors could prevent both of these phases.
Rigel's lead investigational drug, R-112, is an inhibitor of Syk. It enters the mast cells, binding to an intercellular target, thus interrupting the signal from the IgE receptor. This prevents downstream signalling, and hence stops the release of the chemical mediators such as histamine and leukotrienes.
In a Phase II randomised, placebo controlled study in 319 patients, R-112 was shown to reduce the global nasal allergy symptom score by 38%, compared to 29% for those given placebo, on the first day. Similar reductions were seen on the second day. No significant drug related adverse events were seen, and statistically significant improvements over placebo were seen within half an hour of dosing, and dramatic improvements in chronic nasal congestion were also seen.
In a double blind, randomised crossover trial, single doses of R-112 were given to 20 out of season volunteers who suffered from grass or ragweed pollen induced allergic rhinitis.1 A single dose was given intranasally, and 15 minutes later a nasal allergen challenge was given. The active reduced prostaglandin D2 and tryptase levels, but not histamine. It improved rhinorrhoea, but symptom scores were not significantly different between the two groups, and trials continue.