819-P: A Novel Premix Insulin GZR101 for Diabetes Management

Introduction: Inadequate glycemic control in patients with premix insulin regimen is often due to the short half-life and pronounced peak-to-trough ratio of basal insulin. This necessitates the development of a premix insulin containing basal insulins with an extended half-life and steady pharmacokinetic (PK) profile.

Objective: This study evaluated and characterized GZR33, an ultra-long half-life basal insulin, and GZR101 which is composed by GZR33 and insulin aspart.

Methods: The binding affinity of GZR33 to the human insulin receptor (hIR) was analyzed in vitro using surface plasmon resonance. IR activation was examined in CHO cells in the presence and absence of human serum albumin (HSA). Adipogenesis was measured in 3T3L1 MBX cells. Potency was tested in vivo in streptozotocin-induced T1DM rats and db/db T2DM mice, using insulin degludec (iDeg) and iDegAsp as controls. PK studies were assessed in Sprague-Dawley rats.

Results: GZR33 was constructed by linking a C22 fatty diacid side chain to desB30 human insulin via a 6×OEG linker. GZR33 exhibited strong hIRA and hIRB binding (dissociation constants: 2.86E-6 M and 1.28E-6 M). It activated IRA and IRB with EC₅₀ of 370.13 ± 94.86 nM and 477.48 ± 64.28 nM, respectively, in 0.5% HSA, and induced adipogenesis with an EC₅₀ of 2.45 ± 0.81 nM. PK studies showed a dose-dependent increase in maximum concentration and exposure, with a T_½ of 5.45 h for GZR33 (2.3 h for iDeg). In T1DM rats and T2DM mice, GZR33 outperformed iDeg in reducing HbA1c and FBG, demonstrating a potency at least three-fold higher than iDeg. Additionally, GZR101's glucose-lowering effect was proportional to the GZR33 dosage in diabetic models.

Conclusion: Traditional basal insulins display a 24-hour glucose-lowering effect with noticeable peaks, leading to fluctuating blood glucose in patients. However, a basal insulin with over 3-day longevity and once-daily dosing, like GZR33, can achieve a nearly peak-less PK profile at steady-state. Consequently, GZR101 emerges as a promising once-daily premix insulin candidate.