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.
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.