Monomeric insulin analog HALQ with BN-Inu excipient achieves ultrafast absorption and shorter duration than Fiasp in pigs.

Current insulin therapies for diabetes mellitus are fundamentally limited by insulin's tendency to self-associate into hexamers, which slows absorption from the subcutaneous depot. This delayed onset of action creates a temporal mismatch with endogenous prandial insulin physiology, often leading to early postprandial hypoglycemia followed by late hyperglycemia. This challenge necessitates novel strategies to accelerate insulin pharmacokinetics, better synchronizing with nutrient absorption and improving postprandial glycemic control. Developing an ultrafast insulin formulation that maintains stability and offers a rapid-on, rapid-off profile is a critical unmet need.

Researchers developed a materials-based strategy to stabilize HALQ, a monomeric insulin analog, using BN-Inu, a non-interacting inulin-derived excipient. They evaluated the stability of HALQ + BN-Inu under stress for 96 h and at room temperature for at least 30 days. The pharmacokinetic profile was then assessed in a porcine model of diabetes, comparing HALQ to the ultrarapid insulin aspart Fiasp and insulin lispro Lyumjev. The study measured absorption rates and duration of action. Additionally, the impact of clinically used absorption enhancers was investigated. Finally, pharmacokinetic modeling was employed to predict HALQ's performance in human physiology.

The novel excipient BN-Inu significantly mitigated aggregation and maintained HALQ stability for 96 h under stress and for at least 30 days at room temperature. In a porcine model of diabetes, monomeric HALQ exhibited significantly accelerated absorption and a shorter duration of action compared to the ultrarapid insulin aspart Fiasp. This 'fast-on, fast-off' profile aligns more closely with endogenous prandial insulin physiology, indicating faster clearance from the subcutaneous depot. The addition of clinically used absorption enhancers further accelerated HALQ's pharmacokinetic profile, producing a faster time-to-peak and reduced exposure relative to ultrarapid insulin lispro Lyumjev in the animal model. Importantly, pharmacokinetic modeling for human physiology predicted substantial improvements:

HALQ could reduce time-to-peak from 60 to 39 min and shorten the duration of action from 143 to 84 min in humans. These simulations suggest a potential step-change in the speed of insulin therapy, offering a more physiological response.