In this Phase 2 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 0.6 - 3.0 mM, i.e., from U-100 to U-500 strengths. We anticipate that a U-500 formulation of Fluorolog will be of particular benefit to the treatment of Type 2 diabetes mellitus (T2DM) in the setting of marked insulin resistance. Such patients are disproportionately members of underprivileged minority communities, including African-Americans, Hispanic Americans, and Indigenous Americans. T2DM represents a major component of health-care disparities in American society. Our Phase 1 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-PheB24) can at the same time (i) protect the insulin monomer from degradation and (ii) modulate mitogenicity such that untoward effects of AspB10 on cellular proliferation in culture and on cross-binding to the IGF receptor are each mitigated. In Phase 2 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 2 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 (2-F-PheB24). 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 3 mM (in contrast to the impaired PK properties of wild-type insulin), making feasible a rapid-acting formulation at a strength of U-500 or higher. We seek to advance this project toward human studies with special attention to the unmet needs of disadvantaged minority populations.

Agency
National Institute of Health (NIH)
Type
Small Business Innovation Research Grants (SBIR) - Phase II (R44)
Project #
2R44DK092041-02A1
Application #
8645450
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Arreaza-Rubin, Guillermo
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Thermalin Diabetes, LLC
Department
Type
DUNS #
City
Cleveland
State
OH
Country
United States
Zip Code
44106