asthma

Asthma is a lung disease characterized by airway obstruction, airway inflammation, and increased airway responsiveness to a variety of stimuli. Typical symptoms include

shortness of breath, cough and wheezing in response to particular stimuli. The

disease varies in severity from a mild intermittent form to a severe persistent form.

While asthma cannot be cured, most people with asthma are able to be treated so that

they are able to live active lives.

While spasmatic constriction of the airways, or bronchospasm, is an important aspect

of the disease, there is believed to be an underlying inflammatory process that triggers

bronchospasm when a patient is exposed to certain stimuli. The inflammation results

in narrowed, swollen airways, increased mucus and frequently is accompanied by

constriction of the smooth muscle in the airways, or bronchoconstriction, causing

difficulty breathing and the familiar wheeze often associated with the disease.

Relevant inflammatory cells are believed to include the bronchial mucosal mast cell,

lymphocytes and eosinophils.

The ion channel target for senicapoc is a potassium channel that is expressed in

mast cells, lymphocytes, eosinophils, airway epithelial cells and other cell types. This potassium channel facilitates the influx of calcium into certain cells in the immune and inflammatory systems, thus contributing to the activation of these cells during immune and inflammatory responses to certain stimuli. Blocking this channel in these cells decreases the calcium-dependent activation. Moreover, this potassium channel has also been shown to be expressed at increased levels in activated T-lymphocytes and, when inhibited by selective blockers, to decrease T-cell proliferation in a dose-dependent manner.

According to the National Heart Lung and Blood Institute, about 20 million people have been diagnosed with asthma in the United States, nearly 9 million of whom are children. A variety of drugs are used for the treatment of asthma, including inhaled beta

agonists, inhaled and oral corticosteroids, cromolyn and leukotriene inhibitors. Sales of drugs used for the treatment of asthma exceeded $8.0 billion in 2007, according to data from Datamonitor.

Drugs currently approved for the treatment of asthma include both inhaled and orally available therapies. Inhaled agents include beta agonists, inhaled corticosteroids, and cromolyn, while orally available agents include systemic corticosteroids and leukotriene inhibitors such as Singulair. These drugs are believed to work through a variety of mechanisms, including relaxation of the bronchial smooth muscle and inhibition of the inflammatory process. Many patients require combination therapy to adequately control their asthma symptoms. These drugs are therefore typically utilized in a stepwise manner, with inhaled agents used for patients with more mild asthma on a “rescue” basis and oral agents typically added to inhalation therapy for those with more severe and persistent forms of asthma. Each of these drugs is associated with certain side effects, the most problematic of which are caused by the corticosteroids when administered orally on a chronic basis. In addition, many patients do not respond adequately to orally available leukotriene inhibitors, leaving a large group of patients without a satisfactory long-term orally available therapy.

Senicapoc

Senicapoc is a novel small molecule potassium channel inhibitor that we are developing for the treatment of asthma, for which we recently completed Phase I clinical studies. The company expects to initiate a Phase II clinical trial in patients with allergen-induced asthma at selected sites in the UK during the fall of 2008.  Senicapoc targets a particular potassium channel that is expressed on a number of cells believed to be important in the pathogenesis of asthma, including various cells of the immune and inflammatory system and airway epithelial cells. Senicapoc is taken orally and is being developed for once-a-day dosing. We retain all worldwide rights to senicapoc.

A sheep model demonstrating naturally occurring bronchoconstriction and airway hyperreactivity in response to exposure to a certain antigen was used in preclinical efficacy studies. Following exposure to the natural antigen, this model demonstrates an early and a late antigen response characterized by increases in airway resistance and airway hyperreactivity. In controlled studies conducted in this model, senicapoc was demonstrated to reduce the antigen induced changes in both late phase airway resistance and airway hyperreactivity following both intravenous and inhalation administration. These results were statistically significant. Furthermore, in the intravenous study, in which two different doses were tested, the results were dose dependent and at the high dose, there was additionally a statistically significant reduction in the early phase airway resistance.