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 patientswho 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
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.
