New treatments are needed for severe asthmatics who do not respond to standard therapy with inhaled steroids, especially those with a ?type 2 low? phenotype, such as individuals with neutrophil-predominant inflammation. This solicitation is for the development and early commercialization of an inhalational formulation of the 5A apolipoprotein A-I (apoA-I) mimetic peptide that can be administered to asthmatic subjects in Phase I clinical trials and subsequently developed into a new treatment for severe asthma. ApoA-I is the major protein component of high-density lipoproteins, which mediates reverse cholesterol transport out of cells by interacting with the ATP-binding cassette subfamily member 1 (ABCA1). ApoA-I also has anti-inflammatory, anti-oxidant, and immunomodulatory properties. NHLBI investigators have shown that systemic administration of the 5A apoA-I mimetic peptide, which is a bi-helical peptide that recapitulates the ?-helical structure of apoA-I and mediates reverse cholesterol transport out of cells by interacting with ABCA1, attenuates the induction of airway inflammation, mucous cell metaplasia, and airway hyperresponsiveness in house dust mite (HDM)-challenged mice. In addition, they have shown that apoA-I has a protective effect in allergic asthma. Apoa1-knockout mice, which were sensitized and challenged with ovalbumin (OVA), have increased neutrophilic airway inflammation that was primarily mediated by increased G-CSF expression, with associated increases in type 1 (IFN-?, TNF-?) and Th17 (IL-17A) cytokines. The increased neutrophilic airway inflammation in the OVA-challenged Apoa1-knockout mice was inhibited by intranasal administration of the 5A apoA-I mimetic peptide. Lastly, serum apoA-I levels are positively correlated with FEV1 in atopic asthmatic subjects, which suggests that circulating apoA-I may improve airflow obstruction. These murine and human translational studies serve as the conceptual basis for developing the 5A apoA-I mimetic peptide into a novel inhalational treatment for severe asthma. Project Goals The overall goal of this project is to prepare, in both manufacturing processes and preclinical evaluation, an inhalational 5A apoA-I mimetic peptide that will be the subject of a future Investigational New Drug (IND) application to the US Food and Drug Administration (FDA) focused on the treatment of type 2 low phenotype asthma patients, such as those with neutrophil-predominant inflammation. Successful submission and allowance to proceed of the IND will enable the company to collaborate on the conduct of a clinical trial with intramural clinicians at the NIH Clinical Center, at the company?s discretion. During review, preference will be given to companies or teams with a demonstrated prior ability to successfully bring either a peptide therapeutic or an inhalational therapeutic to, at a minimum, Phase 1 clinical studies in the US.
