1859-LB: PG-102, a Novel Bispecific GLP-1R/GLP-2R Fc-Fused Agonist—Data on Safety, Tolerability, and Pharmacokinetics (PK) in Single Ascending Dose Trial in Healthy Subjects and Preliminary Population PK Modeling

• Published in: Diabetes (New York, N.Y.) Vol. 73; no. Supplement_1; p. 1
• Main Authors: HAN, SEUNGHOON, HAN, SUNGPIL, SON, KYOUNG-HWA, SUNG, YOUNGCHUL
• Format: Journal Article
• Language: English
• Published: New York American Diabetes Association 14.06.2024
• Subjects: Agonists; Clinical trials; Diabetes mellitus; Dosage; Dyspepsia; Fc receptors; Fused protein; Metabolic disorders; Nausea; Pharmacodynamics; Pharmacokinetics; Placebos; Vomiting
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db24-1859-LB

PG-102, a novel bi-specific GLP-1R/GLP-2R Fc-fused agonist, exhibits promising therapeutic option for metabolic disorders, particularly obesity and diabetes, showing superior efficacy in preclinical studies. In this Phase 1a study, we conducted a randomized placebo-controlled, and double-blind study to evaluate the safety, tolerability, pharmacokinetics (PK), and preliminary pharmacodynamics (PD) of single ascending doses of PG-102 in healthy subjects. Additionally, we employed PK/PD modeling to propose preliminary dosing intervals for further clinical studies. Forty volunteers (33 men, 7 women; mean age 30.1 years, mean BMI 23.8 kg/m2) received PG-102 (5, 15, 30, and 60 mg) or placebo in an 8:2 ratio. PG-102 demonstrated acceptable safety and a favorable PK profile. Treatment-emergent adverse events (TEAEs) were primarily gastrointestinal, including dyspepsia, nausea, and vomiting, consistent with the GLP-1RA drug class. Notably, no nausea or vomiting occurred up to the 30 mg dose and TEAEs were generally mild to moderate in severity. The PK profile demonstrated a prolonged sustenance effect of PG-102, enabling sustained high concentrations in the bloodstream, thereby contributing to its prolonged effectiveness compared to other Fc-fused protein agonist. Utilizing basic population PK modeling with simulated human PK profiles, we proposed efficacious doses and dosing intervals for PG-102. PK/PD modeling suggests weekly injections of 5 mg and 15 mg, and biweekly or longer interval for 30 mg and 60 mg doses. Additionally, simulated dose of 90 mg* are expected to have monthly intervals. These findings will be further refined and updated with the results from the ongoing multiple ascending dose study. *50% dose of NOAEL in toxicity study