IGF::OT::IGF

Technolgy Holding, Llc, Salt Lake City UT

Investigators

Abstract

Summary 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.