PI-066 - EXPLORATORY POPULATION PHARMACOKINETICS AND WEIGHT LOSS MODELING OF HRS9531, A NOVEL DUAL GLP-1/GIP RECEPTOR AGONIST IN CHINESE OBESE ADULTS

Y. Wang¹, J. Wang¹, P. Chen², Y. Zhang³, K. Shen¹, N. DJEBLI⁴; ¹Jiangsu Hengrui Pharmaceuticals, Shanghai, China, Jiangsu Hengrui Pharmaceuticals, Shanghai, China, ²Jiangsu Hengrui Pharmaceuticals, Shanghai, China, Jiangsu Hengrui Pharmaceuticals - Shanghai, China, ³Jiangsu Hengrui Pharmaceuticals, Shanghai, China, Jiangsu Hengrui Pharmaceuticals - Shanghai,, China, ⁴Luzsana / Hengrui, Luzsana Biotechnology (subsidiary of Jiangsu Hengrui Pharmaceutical), Basel, Switzerland.

Background: HRS9531, a novel dual GLP-1 and GIP receptor agonist, has shown promising weight loss efficacy in obese adults without diabetes. In RCT phase 2 study of Chinese obese adults (HRS9531-201), the mean percentage change in body weight from baseline at W24 was -5.4%, -13.4%, -14.0%, and -16.8% in the 1.0 mg, 3.0 mg, 4.5 mg, and 6.0 mg groups, respectively. The aim of this analysis was to build a population pharmacokinetic (PopPK) and exposure-response (ER) models to describe the exposure-weight loss relationship in the phase 2 study.

Methods: PK modeling data were pooled from three studies, HRS9531-101 (First in Human), HRS9531-103 (BA bridging), and the dose-ranging study HRS9531-201 (24 weeks). The derived time-varying Empirical Bayesian Estimates (EBEs) of PK parameters from HRS9531-201 were used in a sequential PK-PD modeling of exposure-weight loss effect. The total body weight was considered as the sum of FFM (Fat Free Mass) and FM (Fat Mass).

Results: A total of 8763 PK observations from 321 patients covering a dose range from 0.1 to 8.1 mg were used to build the PopPK model, which is represented by a two-compartment distribution model with linear clearance from the central compartment. The ER data included 3128 FFM and FM observations from 199 patients of active groups. Indirect response model with drug concentrations inhibiting the formation rate of either FFM or FM were used to capture the weight loss effect. The inhibitory effect of HRS9531 was best described by an Emax model. HRS9531 primarily reduces FM rather than FFM: the Emax for FM (Emax_FAT) is larger than in FFM Emax_FFM (i.e. 0.663 versus 0.265, respectively), resulting in an Emax ratio of 2.5. The estimated elimination rate constant (Kout) for both FFM and FM were 0.0782 week⁻¹, associated to a typical half-life for body weight loss of ~ 8.7 weeks, with a treatment duration of about 30 weeks to be close to reaching the steady-state body weight. A higher body weight loss was identified in females: 65.8% lower ED50 and 32.1% E0_FAT (the inhibitory effect on FM without drug) in females as compared to males.

Conclusion: A PopPK and E-R body weight loss modeling was built to describe the exposure-weight loss relationship of HRS9531. The final model is being used to support further development of HRS9531 in the obese indication.