Dual C20 Fatty Acid-Conjugated Insulin Analog LPJT-026: Enhanced HSA Binding, Prolonged PK/PD Profiles, and Reduced Hypoglycemia Risk for Biweekly Diabetes Therapy

Purpose: This research aimed to develop a next-generation ultra-long-acting insulin analog with dual long-chain fatty acid conjugation, addressing unmet needs of frequent injections and hypoglycemia risk in diabetes therapy. Methods: LPJT-026, a dual C20 fatty acid-modified insulin (LysA22 and LysB29), was designed, synthesized and characterized. Head-to-head comparisons with marketed insulin icodec (Awiqli®) were performed via in vitro binding assays (HSA/INSR/IGF-1R) and in vivo PK/PD evaluations in STZ-induced type 1 diabetic (T1D) rats and Beagle dogs. Long-term efficacy (HbA1c reduction) and safety (hypoglycemia-related mortality) were assessed in 8-week repeated-dose studies. Results: LPJT-026 (purity ≥ 98%) bears C20 fatty acid chains at LysA22 and LysB29, exhibiting significantly higher human serum albumin (HSA) binding affinity (KD = 139 nM vs. 510 nM for Insulin Icodec) and favorable insulin receptor binding (KD = 134 nM). Animal studies demonstrated superior PK/PD profiles: LPJT-026 sustained glucose-lowering effects for 96 h (vs. 72 h for Insulin Icodec) with significantly lower hypoglycemia-related mortality (10% vs. 40%, p < 0.05) in T1D rats, dose-proportional PK profiles in Beagle dogs (AUC_0-∞ = 75,851–301,529 h·ng/mL at 0.1–0.4 mg/kg concentration with subcutaneous administration) and cross-species plasma stability (t_1/2 > 373 min) supporting translational potential. Conclusions: Dual fatty acid conjugation enables LPJT-026 to form a stable HSA-binding reservoir, achieving biweekly dosing potential, superior glycemic control, and improved safety. LPJT-026 represents a promising next-generation therapy for insulin-dependent diabetes.