Diseases and Products | Acute Exacerbations of Asthma
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Disease Overview:
Acute exacerbations of asthma are long-lasting asthma episodes in which asthma symptoms are not responsive to initial bronchodilator or corticosteroid therapy. Status asthmaticus, a severe asthma episode, is an emergency situation that can lead to death, emergency department treatment and, in some cases, hospital admission. Beta-agonist agents are the mainstays of acute treatment for these types of asthma attacks. The inhaled route is generally more effective; however, in some severe cases, there is so little airflow that inhalation does not work. In these cases, intravenous or subcutaneous administration may be used.
Market Overview:
Visits to emergency departments for asthma increased from approximately 1,500,000 in 1992 to approximately 1,800,000 in 2004. Despite significant improvements in the treatment for asthma over the past 20 years, there has not been a corresponding decrease in either hospitalizations or deaths due to asthma. Data from the National Center for Health Statistics show that 408,000 patients were hospitalized in the United States for asthma in 1980, as compared with 497,000 hospital admissions in 2004. In addition, there were approximately 2,890 deaths due to asthma in 1980, as compared with approximately 4,100 deaths in 2004. According to the National Heart, Lung and Blood Institute, the costs associated with emergency department visits and hospitalizations due to asthma were $518.0 million and $2.7 billion, respectively, in 2004. We believe that there remains an unmet medical need for a safe and effective treatment for acute exacerbations of asthma that could prevent some of these hospitalizations.
MN-221 for the Treatment of Acute Exacerbations of Asthma:
MN-221 is a novel, highly selective ß2-adrenergic receptor agonist being developed for the treatment of status asthmaticus. We licensed MN-221 from Kissei Pharmaceutical Co., Ltd. Preclinical studies conducted in vitro and in vivo showed MN-221 to be highly selective for the ß2-adrenergic receptor. In these studies, the ß1-adrenergic receptor stimulating activity of MN-221 was less than that of other ß2-adrenergic receptor agonists in isolated rat atrium and in vivo cardiac function tests in rats, dogs and sheep, thereby suggesting that the stimulating action of older, less selective ß2-adrenergic receptor agonists on the heart via ß1-adrenergic receptors may be reduced with MN-221 due to its greater ß2-adrenergic receptor selectivity. In addition, in vitro studies also suggested that MN-221 may act as only a partial ß1-adrenergic receptor agonist in cardiac tissue, while acting as a full ß2-adrenergic receptor in lung tissue. We believe that this improved receptor binding and functional selectivity may result in fewer cardiovascular side effects than are commonly observed with other ß2-adrenergic receptor agonists used to treat this condition.
Clinical Results:
We initiated a randomized, double-blind, placebo-controlled, dose escalation, multi-center Phase IIa clinical trial of MN-221 in the fourth quarter of 2006. We completed this clinical trial, which involved 23 stable mild-to-moderate asthmatics at four clinical centers in the United States, in the fourth quarter of 2007. At each dose level in the escalation, patients were randomized to receive either a 15-minute intravenous infusion of MN-221 or placebo. This clinical trial achieved statistical significance in its primary endpoint of mean change in forced expiratory volume in one second, or FEV1, from baseline to measurement at 15 minutes (the end of the infusion) at doses of 10, 16, 30 and 60 micrograms per minute of MN-221 (p-value less than or equal to 0.0006) compared to placebo. MN-221 produced a significant linear, dose-related increase in mean change in post-infusion FEV1 from baseline (p-value less than or equal to 0.0001) following a 15-minute intravenous infusion of MN-221. Significant improvements in mean change in post-infusion (15 minute) FEV 1 from baseline were observed at doses of 10, 16, 30 and 60 micrograms per minute (p-value less than or equal to 0.0006) and at the dose of 3.5 micrograms per minute (p-value=0.0106) compared to placebo. In the protocol correct population for this clinical trial, which consisted of 21 patients, the dose-related increases in FEV1 were maintained for four hours (p-value=0.0393) and at eight hours (p-value=0.0424) following the 15-minute infusion of MN-221. MN-221 was well tolerated in this Phase IIa clinical trial, with only the expected ß2-adrenergic receptor pharmacology noted in some patients (e.g., fall in serum potassium, elevation in plasma glucose, mild headache and mild tremors). There were no clinically significant cardiovascular, electrocardiogram, or ECG, or vital sign changes observed at any dose tested. In addition, no serious adverse effects were observed in this clinical trial.
Development Plans:
We have developed and studied an intravenous formulation of MN-221 appropriate for hospital use. In the first half of 2008, we initiated a second Phase IIa clinical trial in moderate to severe asthma patients to evaluate the effects of longer infusions of MN-221 and a pilot Phase IIb clinical trial in patients with status asthmaticus in an emergency department setting. We expect to complete both of these clinical trials in the second half of 2008. Upon completion of these two studies, we plan to initiate a second, larger Phase IIb clinical trial in patients with status asthmaticus in an emergency room setting, which we expect to complete in the second half of 2009. If we are successful in completing these Phase II clinical trials in a timely manner, we would plan to initiate two Phase III clinical trials of MN-221 in the second half of 2009, which we would expect to complete in the second half of 2010. If we are successful in completing these Phase III trials in a timely manner, we would then plan to file an NDA with the FDA as early as the end of 2010 to seek regulatory approval for MN-221. We also intend to conduct an advanced clinical trial of MN-221 in pediatric patients with status asthmaticus; however, we have not yet determined whether we will initiate this clinical trial in conjunction with the other planned Phase III clinical trials or after submission of the NDA.
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