Enabling implantable artificial pancreas pumps with heat-stable, ultra-rapid insulin

Project Summary We seek to develop an ultra stable ultra fast insulin analog formulation for use in advanced smart pumps in the treatment of diabetes mellitus A commercially available insulin formulation that is stable at body temperature for at least days and at room temperature for a year would respectively make practical a implantable intraperitoneal closed loop pumps for the treatment of T DM T DM and b pre filled patch pumps for the treatment of T DM The economics of the latter market makes practical the development of a critical enabling technology for an implanted artificial pancreas AP device linked to a continuous glucose monitor Ultra fast pharmacokinetic dynamic PK PD promises to improve the safety and efficacy of the feedback algorithms employed in such closed loop systems The current barrier to the development of more stable insulin formulations is the temperature dependent susceptibility of insulin to undergo fibrillation such physical degradation leads to a pro inflammatory amyloid At body temperature fibrils can form in commercial insulin formulations in as little as one week on gentle agitation as in a pump reservoir Once fibrillation begins a seeded nucleation growth process promotes the rapid conversion of the native insulin molecules into amyloid activity declines exponentially making dosing inaccurate and leaving deposits that lead to catheter occlusion To overcome this barrier an innovative structural approach is proposed based on a single chain insulin SCI platform that is fully potent and yet refractory to fibrillation and chemical degradation Design of this platform is based on i recent crystallographic studies of how insulin interacts with its primary binding site in the insulin receptor Site and ii molecular models of insulin fibrils In particular we have discovered that a properly constructed residue linker between the C terminus of the B chain ThrB and N terminus of the A chain GlyA can prevent fibril formation for andgt year on gentle agitation at oC while preserving native biological activity Such an SCI is stable both in a zinc free monomeric formulation and in a zinc based hexameric formulation thus providing marked flexibility in choice of excipients for the simultaneous optimization of stability and rate of absorption fast ON We will extend such optimization to engineer fast OFF pharmacodynamics PD through modification of insulin s ancillary receptor binding surface cognate to Site in the fibronectin homology domains of the receptor subunit An ultra stable fast ON fast OFF SCI formulation would provide a major advance in AP technology We therefore propose to synthesize and characterize five such SCIs as candidate formulations Dr B H Frank principal investigator was co inventor of Humalog during his prior career at Eli Lilly Thermalin Diabetes LLC has an exclusive license to SCI related IP which is owned by CWRU Project Narrative Single chain insulin SCI analogs provide a general platform for ultra stable formulations with appropriate design of a foreshortened connection domain residue and optimization of A and B domain sequences we can construct an ultra rapid absorbing insulin analog that can be formulated at high concentrations e g up to U and is refractory to fibril formation and stable at body temperature for andgt days This technology promises to make practical an implanted artificial pancreas system whose reservoir requires refilling only once every days The five variants of Stablelog Rapid that we have developed promise to enable both implanted and pre filled disposable insulin pumps in this project we propose to characterize these analogs in preparation for commercial development of the best performing candidate