PEGBIO CO-B (02565) announced that CR059, its novel GLP-1 receptor agonist developed using a circular RNA (CircRNA) protein replacement technology and an AI-assisted molecular design platform, has completed single-dose administration in subjects and yielded one-month clinical observation results. CR059 is part of a staged development strategy for the PB-2309 triple-receptor (GLP-1/GIP/GCG) agonist program, serving as the lead candidate for initial clinical validation of the GLP-1 receptor activation mechanism.
Utilizing a lipid nanoparticle (LNP) delivery system, CR059 enables sustained in vivo expression of the GLP-1 receptor agonist, aiming to achieve long-lasting metabolic intervention. This approach is expected to extend dosing intervals and improve patient compliance. In db/db mouse models, under head-to-head study conditions with semaglutide as a control, CR059 demonstrated stronger metabolic intervention effects and a clear dose-response relationship, supporting its ability to produce stable GLP-1 receptor activation via in vivo expression.
In a spontaneous type 2 diabetes rhesus monkey model, once-monthly subcutaneous administration of CR059 (on Day 1 and Day 32) significantly reduced fasting blood glucose, with metabolic improvement effects persisting across dosing intervals. By Day 88, glycated hemoglobin (HbA1c) showed continued improvement from baseline, indicating the potential of the circular RNA-based sustained protein expression strategy to support extended dosing regimens.
In healthy rhesus monkey models, a single subcutaneous injection of CR059 maintained metabolic intervention effects for several weeks (approximately 11.8% body weight reduction 5 weeks post-dose), further supporting the low-frequency dosing strategy and providing evidence for a shift from repeated exogenous administration to sustained in vivo expression for chronic metabolic diseases.
The company is currently conducting a first-in-human clinical study to evaluate the safety, tolerability, and pharmacokinetic/pharmacodynamic (PK/PD) profile of CR059 in subjects with type 2 diabetes (T2DM). Beyond assessing the safety and preliminary efficacy of CR059 alone, this FIH study also explores the clinical feasibility of using circular RNA-based protein replacement technology to achieve sustained in vivo expression and low-frequency dosing in chronic metabolic diseases.
Clinical observations four weeks after a single dose showed: sustained improvement in HbA1c and fasting blood glucose from baseline; increased time-in-range (TIR) for blood glucose control within the target range (4-10 mmol/L) as shown by continuous glucose monitoring (CGM), reflecting overall improved glycemic control; and a significant reduction in average blood glucose levels.
The human study results indicate a trend of continued metabolic improvement after a single dose of CR059, supporting the feasibility of low-frequency dosing via the circular RNA-based sustained in vivo expression strategy for chronic metabolic diseases and providing human-level signals for long-term systemic treatment models.
These preliminary human observations also suggest that the circular RNA-based sustained in vivo protein expression strategy may have the potential to support long-term systemic intervention for chronic metabolic diseases. The company's circular RNA platform achieves efficient circularization through optimized codon structure design, avoiding the introduction of exogenous ligases or chemical modifications. Combined with high-expression IRES elements and translation-enhancing sequences, the platform enables stable and sustained protein translation from circular RNA even without a 5' cap or poly(A) tail.
This design helps extend the effective in vivo expression time of therapeutic proteins, thereby supporting a protein replacement therapy strategy that shifts from repeated exogenous administration to sustained in vivo expression. It offers a technical pathway for low-frequency dosing in indications requiring long-term systemic intervention, such as chronic metabolic diseases. This approach holds promise for providing a new treatment paradigm that transitions chronic disease management from frequent external dosing to continuous internal expression.