2847-LB: PT403, a Once-Monthly Long-Acting Semaglutide: Preclinical Efficacy and Interim Safety and Tolerability in Healthy Subjects

by sugaradmin



Introduction and Objective: GLP-1 receptor agonists (GLP-1RAs) effectively treat type 2 diabetes and obesity but frequent injections may limit adherence. PT403 is a long-acting semaglutide formulation based on biodegradable poly(lactic-co-glycolic acid) (PLGA) microspheres designed for once-monthly administration. This study evaluated the pharmacological efficacy, safety, and tolerability of PT403 and explored its translational development potential as a once-monthly semaglutide formulation.Methods: PT403 was formulated by encapsulating semaglutide in biodegradable PLGA microspheres using ultrasonic spray-drying for sustained release. Preclinical efficacy was evaluated in a high-fat diet-induced obesity (DIO) mouse model with dosing regimens maintaining equivalent daily exposure while varying injection intervals. In a randomized, open-label pilot study, 16 healthy adults received either weekly semaglutide (0.5 mg once weekly for four weeks; n=8) or a single subcutaneous dose of PT403 (4 mg; n=8). Safety and adverse events were monitored for 57 days.Results: In the DIO mouse model, PT403 demonstrated sustained body weight reduction. A -30% reduction at week 4 was achieved in the PT403 Q2W and Q3W groups, whereas semaglutide QD and Q3D groups did not reach this target. In the pilot study, 69 adverse events were reported (PT403: 27; reference: 33). Therapeutic intervention was required for 45.5% of ADRs with weekly semaglutide vs 29.6% with PT403. Nausea and vomiting occurred with weekly semaglutide but not with PT403. PT403 ADRs were mild injection-site reactions and decreased appetite. No serious adverse events were reported.Conclusion: PT403 demonstrated sustained pharmacodynamic efficacy in preclinical models and favorable safety and tolerability in a pilot study. These findings suggest that PT403 has the potential to be developed as a differentiated long-acting GLP-1RA formulation that may reduce injection burden, improve tolerability, and enhance long-term treatment adherence.

Disclosure

M. Choi: None. H. Jeong: None. S. Kim: Employee; Current; Peptron. Y. Shin: None. J. Lee: None. S.W. Kim: None. S. Chang: None. H. Choi: None.



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