Diseases and Products | Asthma
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Disease Overview:
Asthma is a chronic inflammatory disorder of the airways in which many cell types play a role, in particular tissue mast cells, circulating eosinophils and T lymphocytes. In susceptible individuals, this inflammation causes recurrent episodes of wheezing, breathlessness, chest tightness and cough, particularly at night and/or in the early morning. These symptoms are usually associated with airflow limitation that is at least partly reversible either spontaneously or with treatment.
According to the National Institute of Allergy and Infectious Diseases (NIAID), approximately 7% of Americans currently suffer from asthma. Both prevalence and mortality rates have risen since 1982. The American Academy of Allergy, Asthma and Immunology (AAAAI) and the Centers for Disease Control (CDC) note that 13.6 million physician office visits are for treatment of asthma, and 497,000 hospital admissions, plus 1.8 million emergency visits, are attributed to this disease. Approximately 5 million asthmatics are under the age of 18 and there are nearly 5,000 deaths from asthma annually. Despite the prevalence and significant medical and economic consequences of asthma, relatively few novel therapies have been introduced in the last 10 years.
Market Overview:
Asthma is a chronic inflammatory disease of the airways in which symptom control is the key to effective disease management. Alleviation of acute asthmatic symptoms and blocking of late phase inflammation are both important to asthma therapy. According to the National Center for Health Statistics and the Global Initiative for Asthma, there are approximately 20,000,000 asthma patients in the United States and 300,000,000 asthma patients worldwide.
Sales of asthma therapeutics, with over 160,000,000 retail prescriptions written in 2004, increased to over $13.0 billion in 2005. Leading treatments currently include inhaled corticosteroids, bronchodilators and leukotriene antagonists. Worldwide sales of inhaled corticosteroids were $2.3 billion in 2005. Combination products, consisting of inhaled corticosteroids plus long acting beta agonists, added an additional $6.5 billion in sales in 2005. Inhaled steroids, such as fluticasone (Flovent®) and beclomethasone (Vanceril®), are more broadly effective in blocking late phase inflammation, but their general side effects require careful monitoring. Leukotriene antagonists, such as montelukast (Singulair®) or zafirlukast (Accolate®), became available as a new asthma therapy in the late 1990s. These drugs block the actions of leukotrienes, which are pro-inflammatory chemical mediators, and the subsequent inflammation caused by eosinophil migration to the lungs. According to Merck & Co., Inc.’s 2006 Annual Report, worldwide sales of montelukast (Singulair®), a leading leukotriene antagonist, were $3.6 billion in 2006.
MN-001 for the Treatment of Asthma:
MN-001 is a novel, orally bioavailable compound under development for the treatment of bronchial asthma. MN-001 combines the positive attributes of the leukotriene (LT) antagonists and inhaled steroids while maintaining an acceptable clinical safety profile. In vitro receptor binding and enzyme inhibition assays have identified several mechanisms by which MN-001 may produce its anti-asthma activity in preclinical models, including LT receptor antagonism and inhibition of phosphodiesterases III and IV, 5-lipoxygenase, phospholipase C and thromboxane A2. Preclinical animal pharmacology studies have demonstrated that MN-001 inhibits the airway hyper-reactivity that causes bronchoconstriction through a reduction of airway inflammation. In addition, MN-001 was shown to be well tolerated in extensive rodent and dog toxicology testing.
The diagram above shows the asthma cascade. Mast cells can be stimulated to release pro-inflammatory chemical mediators by either extrinsic/allergic or intrinsic (e.g., cold, exercise) triggers. MN-001 has been shown to block these chemical mediators and inhibit eosinophil infiltration, and therefore inhibit acute bronchoconstriction and chronic inflammation in the lung as illustrated above. Thus, MN-001 has the potential to alleviate acute asthmatic symptoms and to block late phase inflammation.
Clinical Results:
MN-001 has proven to be well tolerated in early clinical testing. Treatment-related adverse effects, primarily consisting of gastrointestinal discomfort such as diarrhea, loose stools, nausea and upper abdominal pain, were mild, transient and reversible. These adverse effects were consistent with findings in preclinical studies.
We conducted a randomized, double-blind, placebo-controlled, multi-center Phase II clinical trial in patients with mild-to-moderate asthma, which was completed in the fourth quarter of 2005. In this clinical trial, 147patients were randomly assigned to receive placebo or MN-001 tablets in one of three oral dosing regimens for four weeks. The primary endpoint of the trial was achieved with a statistically significant improvement in mean forced expiratory volume in one second or, FEV1, after four weeks of treatment with 500 mg of MN-001 at three times daily dosage, or TID, compared to placebo (p-value=0.021; intent-to-treat, observed cases). A similar trend was observed for the 750 mg two times daily dosage, or BID, of MN-001 (p-value=0.058). Positive trends in secondary outcome measures were also observed in the 500 mg TID treatment group, including serial spirometry, morning and evening peak flow rates, and provocative concentration causing a 20% fall in FEV1, or PC20, values in a methacholine challenge test, each of which is a common measure of respiratory function. MN-001 was well tolerated in this clinical trial with 89% of patients completing four weeks of treatment. There was no apparent difference between placebo and any of the active treatment groups in adverse events leading to discontinuation or in adverse events attributable to treatment.
Development Plans:
We initiated a Phase III clinical trial in asthma with MN-001 in the fourth quarter of 2006 and used a 1,500 mg total daily dose. We terminated this clinical trial in the second quarter of 2007 to pursue development of a once-per-day oral dosing formulation of MN-001 and to focus our resources on our two prioritized product candidates, MN-221 and MN-166. We have developed a prototype once-per-day oral dosing formulation for MN-001 for potential future clinical trials. We will limit our development efforts on MN-001 for the treatment of asthma to those activities necessary to maximize MN-001’s value while pursuing a variety of initiatives to monetize this product candidate.
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