Insulin Peglispro (LY2605541): A Post-Mortem Analysis of a Novel Hepato-Preferential Insulin

Executive Summary

Insulin peglispro, also known as Basal Insulin Peglispro (BIL) or by its code designation LY2605541, was a novel, long-acting basal insulin analog developed by Eli Lilly and Company. It was bioengineered with a unique "hepato-preferential" mechanism of action, intended to more closely mimic the physiological activity of endogenous insulin. The narrative of Insulin peglispro is a compelling paradox in modern pharmaceutical development: it represents a molecule that achieved unprecedented and consistent superiority in glycemic control over the then-standard-of-care, insulin glargine, yet was ultimately terminated prior to regulatory submission. Its failure was not due to a lack of efficacy but to a complex and concerning safety profile that was inextricably linked to the very innovation that made it so effective.

Across its extensive seven-trial Phase III clinical program, named IMAGINE, Insulin peglispro consistently demonstrated statistically significant and clinically meaningful reductions in glycated hemoglobin (HbA1c​) compared to active comparators in patients with both Type 1 and Type 2 diabetes. This superior glycemic control was complemented by lower glycemic variability and significant ancillary benefits, including weight loss in Type 1 diabetes and reduced weight gain in Type 2 diabetes—outcomes that are highly desirable but often elusive in insulin therapy.