2662-P: IBI3046, an INHBE siRNA, Enables High Quality and Long-Lasting Weight Control in Preclinical Study

Introduction and Objective: INHBE is a genetically validated gene that regulats lipid storage and mobilization in adipose tissue, emerging as a promising therapeutic target obesity. IBI3046, an INHBE-silencing RNAi therapeutic, designed to enhance adipose lipolysis with sustained effects. Combining IBI3046 with GLP-1RAs may synergistically enhance fat loss while mitigating key limitations of current anti-obesity regimens. Methods: IBI3046 was designed to target conserved regions in human and monkey homologs, with GalNAc conjugation for hepatic delivery; The in vitro study was conducted on Hep3B and primary human hepatocytes. Furthermore, in vivo knockdown efficacy was verified in hINHBE gene knock in (KI) mice. The anti-obesity studies were performed in DIO mouse models harboring human INHBE. Body weight was monitored and body composition was quantified via DEXA scan. Lipolytic genes in adipose tissues were assessed at the end. The PD study was conducted in cynomolgus monkeys (n=4). Results: IBI3046 demonstrated potent and durable mRNA knockdown in hINHBE KI mouse model. In the efficacy study, IBI3046 (9 mg/kg, QWx4) resulted in a 13% reduction in body weight and a 50% decrease in fat mass relative to control. In combination therapy, IBI3046 administered with a low dose of GLP-1RA achieved 20% body weight loss, which is comparable to that achieved with a high-dose GLP-1RA alone. Regarding fat mass reduction, the combination therapy resulted in a 70% decrease, superior to the high-dose GLP-1RA monotherapy. In a sequential treatment regimen, IBI3046 extended the duration of suppressed weight regain following GLP-1RA withdraw. Conclusion: 1. IBI3046 is a potent and durable RNAi therapeutic agent capable of silencing hepatic INHBE mRNA expression in mice. 2. IBI3046 demonstrates greater efficacy at reducing body weight and Fat mass compared to Benchmark siRNA. 3. In combination with a GLP-1RA, IBI3046 exhibits enhanced potency relative to GLP-1RA monotherapy 4. Following drug withdrawal, IBI3046 shows more durable effects than GLP-1 RA. Disclosure X. Zhang: None.