Introduction and Objective: ALK7 plays a crucial role in adipose homeostasis, with genetic variants linked to obesity in human GWAS. This study examines the pharmacodynamic effects of SGB-ALK7 in cynomolgus monkeys and its therapeutic potential in an obese mouse model.Methods: SanegeneBio is developing Ligand and Enhancer Assisted Delivery (LEAD™) technology, which utilizes a receptor-mediated internalization mechanism to power biodistribution to adipocytes and de-target liver. Based on this platform, SGB-ALK7s were developed to degrade and silence ALK7 in the adipose tissues of mice and monkeys, respectively.Results: We demonstrate durable and tissue-selective adipocyte mRNA inhibition after administration of a single S.C. dose in nonhuman primates. In DIO mice, a research analog of SGB-ALK7 resulted in body weight loss comparable to Semaglutide but with near-complete preservation of lean mass. Notably, we observed significantly reduced long-term body weight gain after Semaglutide withdrawal. Furthermore, SGB-ALK7 boosted Semaglutide’s weight-loos effects, achieving full efficacy at 1/3 of the standard dose.Conclusion: SGB-ALK7 is a potent siRNA therapeutic that silences adipose ALK7, reduces fat mass while preserving lean mass, and promotes weight loss, supporting the clinical development of SGB-ALK7, along with other adipocyte-targeted LEAD™ siRNAs, for the treatment of obesity.
P. Zhang: None.
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