95-LB: Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of a Novel Oral Small Molecule GLP-1 Receptor Agonist (HRS-7535) in Healthy Subjects —A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Single- and Multiple-Ascending Dose Study

• Published in: Diabetes (New York, N.Y.) Vol. 72; no. Supplement_1; p. 1
• Main Authors: WU, JINGYING, HU, WEI, DU, YIJUN, ZHANG, QIAN, ZHOU, RENPENG, ZHANG, QIN, QIN, HUILING, YE, ZI, XU, YIMEI, FENG, SHENG, SHU, CHANG, SHEN, YU, FAN, YANG
• Format: Journal Article
• Language: English
• Published: New York American Diabetes Association 20.06.2023
• Subjects: Agonists; Body mass index; Body weight; Clinical trials; Dosage; Food availability; Food consumption; GLP-1 receptor agonists; Glucagon; Glucagon-like peptide 1; Glucose tolerance; Insulin secretion; Metabolic syndrome; Pharmacodynamics; Pharmacokinetics; Placebos; Safety; Titration; Vomiting
• DOI: 10.2337/db23-95-LB
• ISSN: 0012-1797

Background: HRS-7535, a novel, oral small molecule glucagon-like peptide-1 receptor (GLP-1R) agonist, has demonstrated no strict food restriction, and has been found to obviously improve glucose tolerance, promote insulin secretion, and reduce food consumption in preclinical studies. This study aimed to assess the safety, tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of single and multiple ascending doses (SAD and MAD) of HRS-7535 in healthy subjects. Methods: This was a randomized, double-blind, multi-part, phase 1 trial (NCT05347758). Overtly healthy adults 18-55 yrs were eligible, with the body mass index of 19.0-28.0 kg/m2 and the HbA1c of <6.2%. In the SAD, healthy subjects were randomized (6:2) to receive HRS-7535 (15, 60, and 120 mg) or placebo. In the MAD, healthy subjects were randomized (18:6) to receive daily HRS-7535 (120 mg [30/60/90/120 mg titration scheme]) or matching placebo for 4 wks. Results: 24 subjects participated in SAD and 24 participated in MAD, respectively. Most common treatment-emergent adverse events in both SAD and MAD were nausea and vomiting; all TEAEs were mild in severity. PKs were approximately proportional; In SAD, the median Tmax was 5.98-5.99 h and geometric mean t1/2 was 5.28-9.08 h across the HRS-7535 dosing range. In MAD, the median Tmax was 5.98-10.98 h and geometric mean t1/2 was 6.48-8.42 h on Day 28 across the HRS-7535 dosing range. In MAD, the mean reduction in body weight from baseline on Day 29 was 4.38 kg in subjects with HRS-7535. Conclusion: Both SAD and MAD of HRS-7535 showed acceptable safety profile and favorable PKs/PDs. The obvious reductions in body weight could be observed in healthy subjects. These finding support further clinical exploration of HRS-7535 in patients with metabolic syndromes.