Close-loop systems of insulin delivery-comprising an insulin pump, continuous glucose monitor, and feedback-based control algorithm-provide a promising technology to enable tight glycemic control in Type 1 diabetes mellitus with improved patient convenience and compliance. The safety and efficacy of such coupled devices (also known as an "artificial pancreas") would be enhanced by the development of novel insulin analog formulations that coupled rapid absorption with prompt "turn off" of insulin signaling. Whereas multiple technologies are under investigation to accelerate absorption (approaches based on pharmacokinetics;PK), it is not known how to foreshorten the intrinsic cellular duration of insulin signaling once a productive hormone- receptor complex has been formed in target tissues (approaches based on pharmacodynamics;PD). Because a key challenge in closed-loop systems is recovery from transient over-delivery events. An ideal pump insulin would combine rapid PK with foreshortened PD. Our invention of a dual PK-PD optimized insulin analog formulation was inspired by recent structural insights into the molecular basis of how insulin binds to the insulin receptor (IR). An international team of academic investigators, co-led by the laboratory of M. A. Weiss at Case Western Reserve University School of Medicine, has defined how insulin binds to its primary binding site (designated Site 1) in the IR ectodomain (in press in Nature (2013)). Elucidation of Site 1 coupled with biochemical probes of ancillary Site 2 enabled design of novel insulin analogs with abbreviated PD duration in a rodent model of Type 1 diabetes (streptozotocin- treated Sprague-Dawley rats). Dual Site 1/Site 2 co-optimization provides an innovative paradigm for insulin analog design. Our product is designated Tryptolog as an essential element is substitution of leucine position A13 (a non- conserved residue on the back surface of insulin adjoining Site 2) by tryptophan. We hypothesize that this bulkier aromatic residue foreshortens molecular communication between the hormone-triggered IR ectodomain and its intracellular tyrosine-kinase domains, in turn abbreviating the insulin signal. In this Phae 1 SBIR application we seek support for (i) the further optimization and characterization of Tryptolog products by co- modification of Site 1 sites A8 and B24 and (ii) their comparative validation in a pig model more relevant to human patients than Sprague-Dawley rats. Pig studies will be conducted at Legacy Health Systems (Portland, OR) by Dr. W. K. Ward, an expert on closed-loop systems and experienced pig investigator.
Following a new paradigm for optimizing insulin action for safe and effective use in closed-loop systems (smart pumps), we go beyond the focus of existing analogs on accelerating pharmacokinetics (PK) to co- optimize PK and pharmacodynamic (PD) properties by creating an analog with reduced binding to Site 2 on the insulin receptor (IR), thereby foreshortening molecular communication between the hormone-triggered IR ectodomain and its intracellular tyrosine-kinase domains and in turn abbreviating the insulin signal. In a rat model this invention provides significantly shortened duration of action, promising a novel approach to creating the kind of ultra-rapid-acting insulin formulation needed for closed loop insulin pumps. This project will evaluate Tryptolog and Tryptolog-Cl, then select one for further development that promises to provide significantly improved clinical benefits relative to other fast-acting analogs in present use or (to our knowledge) in development with application to the safety and efficacy of closed-loop systems.