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June 7, 2026

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

Key Points

This study aims to evaluate the pharmacological efficacy, safety, and tolerability of PT403, a long-acting semaglutide formulation.
Encapsulation of semaglutide in biodegradable PLGA microspheres using ultrasonic spray-drying for sustained release.
Preclinical efficacy tested in a diet-induced obesity mouse model with varying dosing regimens.
Randomized pilot study involving 16 healthy adults receiving either weekly semaglutide or a single dose of PT403.
PT403 induced a -30% body weight reduction at week 4 in the DIO mouse model, outperforming daily semaglutide.
69 adverse events noted across both groups, with PT403 reporting 27 and semaglutide 33.
No serious adverse events for PT403; mild side effects included injection-site reactions and decreased appetite.

Abstract

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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