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.
A COPD exacerbation is a sustained worsening of the patient’s condition, from the stable state and beyond normal day-to-day variations, that is acute in onset and necessitates a change in regular medication in a patient with underlying COPD. Exacerbations are associated with a significant increase in mortality, hospitalization and healthcare utilization.
Data from the National Center for Health Statistics show that visits to emergency departments for asthma increased from approximately 1.5 million in 1992 to approximately 1.7 million in 2006. 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 according to the National Center for Health Statistics. Data from the National Center for Health Statistics show that approximately 444,000 hospital discharges were attributed to asthma in 2006. In addition, there were approximately 2,563 deaths due to asthma during 2006. According to the National Heart, Lung and Blood Institute, the direct costs associated with hospital care due to asthma were $4.7 billion in 2007.
According to data from the Centers for Disease Control and Prevention, an estimated ten million adults had a diagnosis of COPD in the United States in the year 2000. In addition, according to the Centers for Disease Control and Prevention, in the year 2000, there were 119,000 deaths, 726,000 hospitalizations, and 1.5 million hospital emergency department visits due to COPD in the United States. According to a more recent report on respiratory diseases from the Centers for Disease Control and Prevention and National Institutes of Health, the prevalence and age-adjusted death rate for COPD increased more than 30 percent since 1980. The same report also indicated that the direct costs of health care services and indirect costs through loss of productivity related to COPD amounted to approximately $26 billion in 1998. In 2002, according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) direct costs for COPD were approximately $18.0 billion and indirect costs were approximately $14.1 billion in the United States. In 2007, according to the American Lung Association, the direct costs for COPD were approximately $26.7 billion and indirect costs were approximately $15.9 billion in the United States.
“Acute asthma exacerbations, which are asthma attacks not controlled by a patient’s medications, represent a major cause of ED visits and hospitalizations for many of the 26 million people with asthma in this country,” said lead investigator Dr. Lawrence Lewis, M.D., of Washington University and Barnes-Jewish Hospital in St. Louis, MO. “If the asthma attack can’t be effectively treated in the ED, these patients are usually admitted to the hospital for further treatment, a costly alternative for patients and a significant drain on healthcare resources. Unfortunately, we are limited to only a few medications that have been shown to help in the emergency treatment of asthma exacerbation,and often the patient has already tried most of these medications at home. There is clearly an unmet need for more effective treatments for the emergency care of this condition. We are very pleased that MediciNova will continue development of MN-221 to address this unmet medical need.”
MediciNova believes that there remains an unmet medical need for a safe and effective treatment for acute exacerbations of asthma and COPD that could prevent some of these hospitalizations.
MN-221 is a novel, highly selective ß2-adrenergic receptor agonist being developed for the treatment of exacerbations of asthma/COPD. 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 these conditions.
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.
We initiated a randomized, open-label, placebo-controlled Phase II clinical trial involved 17 patients in two dose cohorts at four clinical sites in the United States in June, 2008. We completed this clinical trial in the September, 2008. In one dosing cohort, each patient received MN-221 at a dose of 1,125 micrograms or placebo over one hour by a continuous intravenous infusion. In the other dosing cohort, each patient received MN-221 at a dose of 1,080 micrograms or placebo over two hours by a continuous intravenous infusion. Both infusion rates of MN-221 produced a marked and clinically significant improvement in FEV1. FEV1 results were expressed as "percent predicted" based on standard reference equations accounting for an individual's race, gender, age and height. At the end of the one-hour infusion, FEV1 increased by 17.5 percent predicted for MN-221 compared to an increase of 3 percent predicted for placebo. At the end of the two-hour infusion, FEV1 increased by an average of 12.1 percent predicted for MN-221 compared to an increase of 1.4 percent predicted for placebo. Per the study protocol, no inferential statistical testing was performed. MN-221 was well tolerated by the patients who received either infusion rate of MN-221. There were no clinically significant safety concerns noted among adverse events, electrocardiogram (ECG) data, vital sign data or laboratory assessments collected throughout the study.
In May, 2009 we announced final results from its Phase II clinical trial (MN-221-CL-006) evaluating MN-221 at planned escalating doses of 240 to 1,080 micrograms in patients with severe, acute exacerbations of asthma treated in Emergency Departments. The study included 29 (13 treated with standard care only and 16 treated with MN-221 plus standard care) patients with severe, acute exacerbations of asthma. All patients received standardized care consisting of inhaled albuterol, ipratropium and oral steroid treatment. No safety concerns with adding MN-221 to standardized care were identified following review of electrocardiogram (ECG), laboratory and Adverse Experience data. The hospitalization rate among patients treated with standardized care only was 46 percent (six of 13), which was the anticipated rate, compared to a hospitalization rate of 25 percent (four of 16) among patients receiving MN-221 plus standardized care. This represents a 45 percent reduction in hospitalization rate among patients treated with MN-221. All hospitalizations were due to asthma exacerbations which were judged to be unrelated to study medication and therefore do not raise safety concerns for adding MN-221 to standardized care. As specified in the protocol for this clinical trial, no inferential statistics (i.e., p-values) were calculated for this study. Improvement in forced expiratory volume in 1 second (FEV(1)) values generally appeared to be greater for patients receiving MN-221 in addition to standardized treatment.
In March, 2010 we announced final results from a Phase Ib clinical trial (MN-221-CL-010) evaluating MN-221 in 48 moderate-to-severe COPD patients who received a one (1) hour intravenous infusion of MN-221 at three different escalating dose levels (300 micrograms, 600 micrograms, or 1200 micrograms) or placebo. Based on preliminary findings, all doses of MN-221 produced a clinically significant improvement in FEV(1)(L) as compared to the baseline and placebo. At the end of the one hour infusion, FEV(1)(L) increased as compared to baseline by an average of 21.5% (p=0.0025) for the 1200 microgram dose, 16.2% (p=0.020) for the 600 microgram dose, and 9.2% (p=NS) for the 300 microgram dose compared to a decrease of 4.0% for the placebo. MN-221 was well tolerated by all patients who received infusions of MN-221.
MN-221-CL-007 was a randomized, double-blind, placebo-controlled Phase 2 clinical trial which enrolled 175 patients in the United States. The trial enrolled patients who presented to the emergency department with an acute exacerbation of asthma and did not initially respond to complete standard-of-care pharmacotherapy including inhaled albuterol, inhaled ipratropium, and steroids. In order to be eligible for enrollment, patients needed to have baseline FEV1 (% predicted), after initial standard therapy, of <50% and therefore considered “severe” exacerbation subjects. Enrolled patients were randomized 1:1 to placebo vs. 1200 micrograms MN-221 i.v. infused over 1 hour.
MN-221 showed a significant benefit over placebo for FEV1 (liters) Area Under the Curve (AUC Hour 0-1, 0-2, 0-3) of change from baseline (p=0.043, p=0.050, p=0.066 respectively) in the data set defined below. The trial also demonstrated a reduction in hospital admissions with MN-221 added to standard drug treatments. Moreover, there was a significant improvement in clinical symptoms with MN-221 treated patients and the safety profile of MN-221 continues to be positive as no safety/tolerability issues of clinical significance were observed.
The data set presented below includes more than 85% of the 164 efficacy evaluable patients in the trial. This includes patients from all of the sites that enrolled a minimally sufficient number of patients (greater than three) and for whom all efficacy data were available including FEV1, dyspnea, respiratory rate, and hospitalization.
Highlights of MN-221-CL-007 Trial:
MN-221-CL-012 is a randomized, double-blind, placebo-controlled, multi-center Phase 1b clinical trial in patients with stable, moderate-to-severe chronic obstructive pulmonary disease (COPD) involving multiple administrations of intravenous (i.v.) MN-221 over several days in typical patients with concomitant illnesses.
A total of 25 subjects were randomized to placebo (5 subjects) or MN-221 (20 subjects) treatment groups; with similar enrollment at each of two clinical research units. The patient group included those who had concomitant illnesses and were using other medications that are typical in this disease population.
Preliminary efficacy results indicated moderately improved pulmonary function (FEV1) in the MN-221 recipients but not the placebo recipients. Moreover, the improvement of FEV1 on subsequent MN-221 dosing days was as good as or better than on Day One. Regarding other strategic objectives, comparison of the simple hand-held FEV1 monitor with the spirometer machine used in our other clinical trials of MN-221 indicated good correlation and pharmacokinetic analyses indicated no significant accumulation of plasma MN-221 over the multiple dosing intervals.
The data from this trial will aid in the design of a future Phase III program, if warranted.
MediciNova intends to design pivotal trial(s) that will include technological and operational improvements and further controls for medications that are not typically used in the treatment of acute exacerbations of asthmay. Accordingly, MediciNova has filed an End-of-Phase 2 meeting request with the Division of Pulmonary, Allergy, and Rheumatology Products at FDA which has been granted for the date of October 22nd, 2012.
MediciNova's intravenous beta-agonist MN-221 program had seven poster presentations scheduled during the Annual Meeting of the American College of Chest Physicians in Vancouver, Canada. The presentations are related to MediciNova’s development of MN-221 for potential utility in acute exacerbations of asthma or chronic obstructive pulmonary disease (COPD). Please click on the poster titles to view.
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