Discovery of a Novel Long-Acting Urocortin 2 Analog for Improving Body Composition in Obese Mice

Introduction and Objective: Urocortin 2 (UCN2) has been shown to reduce fat mass and increase muscle mass. While GLP-1-based therapies have demonstrated significant weight loss, they may lead to muscle mass reduction with long-term use. The objective of this study was to identify a novel, long-acting UCN2 analog that could enhance body composition when combined with the GLP-1 analog ecnoglutide in diet-induced obese (DIO) mice. Methods: UCN2 peptides were designed and tested in HEK293 reporter cells expressing the CRF1 or CRF2 receptor (CRF1R or CRF2R), followed by assessed in SD rats through single injections and in DIO mice via once-daily injections for 21 days to assess body weight (BW) reduction. The most promising peptide was selected for evaluation of its impact on body composition in combination with ecnoglutide in DIO mice via once-daily injections for 21 days. Pharmacokinetics were assessed in minipigs. Results: Among the peptides, XW4475 showed great potency and efficacy in both CRF2R based cell assay and BW reduction in rodents. The EC50 for XW4475 was 0.0175 nM (vs 0.295 nM for wild-type UCN2) in the CRF2R assay without stimulating CRF1R. In SD rats, 30 nmol/kg XW4475 induced -3.8% BW loss at 24 h post-injection, and in DIO mice, BW loss on Day 22 was -27.9% for a combination of 3 nmol/kg ecnoglutide and 30 nmol/kg XW4475, compared to -17.2% for 3 nmol/kg ecnoglutide. In body composition analysis in DIO mice, muscle mass on Day 22 was 65.2% of BW for a combination of 3 nmol/kg ecnoglutide and 3 nmol/kg XW4475, compared to 55.9% of BW for 3 nmol/kg ecnoglutide; meanwhile, fat mass was 12.8% of BW for the combination, compared to 25.9% of BW for ecnoglutide. In minipigs, XW4475 exhibited a half-life of 100 hours. Conclusion: The novel UCN2 analog XW4475 demonstrated great selectivity and efficacy, favorable pharmacokinetics, and a significant impact on improving body composition. These findings suggest that XW4475 could offer a more balanced and sustainable approach to weight management. Disclosure: H. Zou: Employee; Sciwind Biosciences. R. Zhu: Employee; Sciwind Biosciences. Y. Wang: Employee; Sciwind Biosciences. J. Zhao: Employee; Sciwind Biosciences. X. Wu: Employee; Sciwind Biosciences.