Fluorolog: A Rapid-Acting Ultra-Concentrated Insulin Formulation

DESCRIPTION provided by applicant In this Phase SBIR application we seek to advance toward human clinical trials a rapid acting and ultra concentrated monomeric insulin analog of novel halogen based protein design Designated Fluorolog this analog was found in Phase I studies to exhibit rapid acting PK PD properties irrespective of protein concentration in the range mM i e from U to U strengths We anticipate that a U formulation of Fluorolog will be of particular benefit to the treatment of Type diabetes mellitus T DM in the setting of marked insulin resistance Such patients are disproportionately members of underprivileged minority communities including African Americans Hispanic Americans and Indigenous Americans T DM represents a major component of health care disparities in American society Our Phase studies validated a key hypothesis underlying design of Fluorolog that introduction of a single fluorine atom at the receptor binding surface of insulin para F PheB can at the same time i protect the insulin monomer from degradation and ii modulate mitogenicity such that untoward effects of AspB on cellular proliferation in culture and on cross binding to the IGF receptor are each mitigated In Phase we seek to extend these studies to obtain data required in an IND application To this end pilot stability data willbe enlarged to include formal testing of the individual aspects of chemical and physical degradation such as disulfide cleavage covalent polymer formation and fibrillation by procedures and under conditions customarily provided in an IND application Similarly pilot cell culture data wil be extended to analysis of tumor xenograft growth rates in nude mice and by formal toxicity studies in Sprague Dawley rats The overarching goal of this Phase application is thus the submission of an appropriate and well documented IND application PUBLIC HEALTH RELEVANCE We propose to build on the promising Phase I results characterizing Fluorolog a truly monomeric insulin analog whose physical and biological properties have been optimized by a site specific fluoro aromatic substitution F PheB In the course of the Phase I studies we discovered that this analog retains its fast acting pharmacokinetic properties even at protein concentrations as high as mM in contrast to the impaired PK properties of wild type insulin making feasible a rapid acting formulation at a strength of U or higher We seek to advance this project toward human studies with special attention to the unmet needs of disadvantaged minority populations