We seek to develop a rapid-acting U-500 insulin analog formulation for patients with Type 2 and Type 1 diabetes mellitus (T2DM and T1DM). Such a novel product would improve treatment in two contexts: (i) for T2DM patients with marked insulin resistance (as associated with "diabesity," secondary to corticosteroid treatment, the mitochondrial diabetes syndrome MIDD, or lipodystrophies), a rapid-acting U-500 formulation would enhance safety, convenience, and efficacy of prandial or pump therapy and could, by reducing injection volume- associated pain, improve patient compliance;(ii) for patients without insulin resistance (i.e., the majority of patients with T1DM) or for T2DM patients who want the convenience of a patch-pump, a rapid acting U-500 formulation would extend by fivefold the reservoir life of current disposable pumps and/or would enable miniaturization of these disposable pumps without decreasing reservoir life. An innovative structural approach is proposed based on "electrostatic engineering." Only a single U-500 product is currently available (Lilly Humulin R U-500, containing wild-type human insulin);its pharmacokinetic and pharmacodynamic (PK/PD) properties are so prolonged that they resemble U- 100 NPH insulin. Experimental U-500 versions of Humalog likewise exhibit prolonged PK/PD and so are suboptimal for prandial or pump use. The key barrier to design of a rapid-acting U-500 formulation is posed by concentration-dependent hexamer-hexamer interactions. Such interactions retard disassembly of insulin hexamers in the subcutaneous depot and so block capillary absorption. The insulin hexamer is doughnut-shaped. Linear stacking of successive hexamers (the predominant mode of crystal packing) is mediated by trimer-related protein surfaces at the top and bottom of the doughnut. We have discovered that a rapid-acting U-500 formulation (designated Hexalog-1) is made possible by combining the "lispro" substitutions of Humalog? with a two-residue acidic extension of the B-chain: residues GluB31 and GluB32. Compatible with native potency, these negative charges are positioned to cause electrostatic repulsion between opposing hexamer surfaces. As a further potential benefit, the acidic extension (opposite in charge from the ArgB31-ArgB32 extension in the reportedly mitogenic basal analog insulin glargine;Lantus?) reduces cross-binding to the mitogenic IGF receptor. Speed of disassembly may be further enhanced by an optional chloro-aromatic substitution at the para position of PheB24 (Hexalog-Cl). Dr. B. Frank (PI) was co-inventor of Humalog? during his prior career at Eli Lilly. Thermalin Diabetes, LLC has an exclusive license to U500- related IP, which is owned by CWRU. Project Description

Public Health Relevance

A rapid-acting ultra-concentrated (U-500) insulin analog formulation would benefit both(A) T2DM patients with marked insulin resistance (who experience injection pain, late post-prandial hypoglycemia, and poor glycemic control with existing U-100 formulations and for whom the only current such product (Lilly Humulin R U500) exhibits protracted action (12-16 hours) and so is inappropriate for prandial or pump use), many of whom are disadvantaged minorities, and (B) T1 or T2 DM patients seeking to use disposable insulin pumps enhanced by either (i) miniaturization or (ii) long-lasting high-capacity reservoirs. We have invented rapid-acting U-500 insulin analog formulations (designated Hexalog-1 and Hexalog-Cl) that exhibit (1) absorption kinetics as fast as or faster than Humulin(R) U-100 and (2) decreased cross-binding to the mitogenic IGF receptor and hence are less likely to be associated (on long-term, high-dose use) with carcinogenesis than is wild-type hyperinsulinemia. This phase I project will take Hexalog-1 or -Cl through proof-of-concept testing.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Small Business Innovation Research Grants (SBIR) - Phase I (R43)
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Special Emphasis Panel (ZRG1-EMNR-E (10))
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Arreaza-Rubin, Guillermo
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Thermalin Diabetes, LLC
United States
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