SBIR-STTR Award

Asthma is a complex inflammatory disease of the airway. Current treatments employ the use of inhaled bronchodilators and corticosteroids. While these medicines are effective for most cases of asthma, they are less effective in severe forms of the disease. Moreover, the chronic use of corticosteroids has been associated with side effects in a subset of patients. Therefore the development of novel medications that are effective in suppressing the asthmatic response and lack the pharmacological properties of corticosteroids is desirable for the treatment of this disorder. We have identified a novel class of low molecular weight molecules that have potent effects on blocking lymphocyte heterotypic aggregations in vitro. in vivo data suggest that these compounds have potent activity in suppressing asthmatic-like responses to antigen in rodent models of asthma. Using combinatorial approaches and structure activity relationships in vitro, we have developed new analogs of the prototype that have more potent activity in suppressing lymphocyte aggregation in vitro. The aims of this grant are: 1) prepare analytically pure preparations of the aminosterol prototype and its analogs for in vivo toxicity studies; and 2) perform in vivo studies with these compounds to determine their efficacy in suppressing asthmatic-like responses to antigen. PROPOSED COMMERCIAL APPLICATIONS: The use of novel low molecular weight compounds that are able to suppress the asthmatic response to antigen via non-corticosteroidal mechanisms have a broad potential for commercialization as new anti- inflammatory and asthma medicines. It is our intent to pursue the generation and development of these aminosterol compounds as an aerosol or oral medication for the treatment of asthma. Magainin is in a unique position to develop compounds of this class because of our intellectual property position, which is secured by multiple patents that cover composition of matter and their use in a broad range of indications.

Phase II research will emphasize continuing in vitro and in vivo data collection to identify Genaera aminosterol library compounds useful in treating atergen-induced respiratory inflammation, with a focus on asthma. Lead compounds will first be defined using in vitro endpoints for interference with lymphocyte function, emphasizing the additional collection of trans-epithelial monolayer barrier penetration data as a surrogate for possible oral activity. Careful pharmacokinetic and activity data measurements for lead compounds in an Aspergillus fumigatus spore-induced murine model of airway inflammation using both oral and intratracheal routes of aminosterol administration will subsequently be taken to select a few aminosterols for formal preclinical development. These compounds will be compared to the water soluble lead compounds MSI-1 432 and MSI-f 828 shown active in phase I research for intratracheal delivery, while discovery of an orally active aminosterol is given priority in parallel experimentation. Preparation and formulation of a single lead aminosterol to GMP standards will then be rapidly instituted for delivery by the preferred route of administration, along with necessary supporting analytical method development, and a first acute rat toxicity GLP study will be initiated as the first of a series of preclinical safety studies to support use in humans. The eventual goal is to enter human clinical trials in asthma patients by 2004 with an orally delivered aminosterol emerging from the phase Il SBIR research. PROPOSED COMMERCIAL APPLICATION: Asthma affects more than 14?15 million U.S. citizens" 5 million of whom are children, and more than 5,000 die of asthmatic disease each year. The health related costs of asthma are estimated for the year 2000 to exceed $14.5 billion, and asthma (and asthma costs) are on the rise among inner city residents. There is a significant need for better and more novel treatments for asthma, notably those with fewer side effects and that are easier for patients to use. Aminosterols are a new class of anti-inflammatory agents discovered by Genaera Corporation that are preferentially active with Th2-type T cells and that may offer several advantages to asthma patients, including the ability to self-administer.