SAT028 Beneficial Effect On Intestinal Growth Of A Long-Acting GLP-2 Analog, HM15912, After Treatment Switching From Conventional GLP-2 Drug Or Other Long-Acting GLP-2 Analogs Under Clinical Development In Animal Model

Abstract

Abstract Disclosure: C. Park: Employee; Self; Hanmi Pharm. Co., Ltd. J. Choi: Employee; Self; Hanmi Pharm. Co., Ltd. E. Park: Employee; Self; Hanmi Pharm. Co., Ltd. H. Kwon: Employee; Self; Hanmi Pharm. Co., Ltd. S. Bae: Employee; Self; Hanmi Pharm. Co., Ltd. D. Kim: Employee; Self; Hanmi Pharm. Co., Ltd. Y. Kim: Employee; Self; Hanmi Pharm. Co., Ltd. I. Choi: Employee; Self; Hanmi Pharm. Co., Ltd. The widespread use of teduglutide, which is only approved GLP-2 analog drug for short bowel syndrome (SBS), may be still limited due to insufficient efficacy and leading to a significant burden for patients by daily administration. Hence, several long-acting GLP-2 analog drugs targeting once a week are currently in clinical development. Here, we investigated that HM15912, a novel long-acting GLP-2 analog, enabled to achieve additional small bowel trophic effect after switching from those existing GLP-2 analogs. To investigate additional intestinotrophic efficacy after switching from teduglutide to HM15912, C57BL/6 mice treated with twice daily administration of teduglutide for 2 weeks were switched to once-weekly administration of HM15912, or continued the typical treatment of teduglutide for the remaining 2 weeks. HM15912 treatment significantly increased wet weight of SI (72.9% over vehicle) compared to teduglutide treated group (39.4% over vehicle) after 2 weeks. After 2 more weeks treatment, while showing the maintained the increased SI weight in teduglutide treated group (58.3% at week 3 and 41.1% at week 4 over vehicle), SI weight was further increased after switching to HM15912 (61.2% at week 3 and 68.5% at week 4 over vehicle). Next, we synthesized GLP-2 analogs to have same sequences with glepaglutide and apraglutide. SD rats treated with every other day administration of these long acting GLP-2 analogs for 2 weeks were switched to HM15912 or continued the typical treatment of them for the remaining 2 weeks. HM15912 treatment significantly increased wet weight of SI compared to weekly GLP-2 analog drug treated groups after 2 weeks (84.4% versus 41.5% or 26.6% over vehicle). After 2 more weeks treatment, while showing the slight increment in SI weight in the long-acting GLP-2 analogs (50.5% and 37.4% over vehicle), SI weight was further increased after switching to HM15912 (82.1% and 90.7% over vehicle, respectively). In line with these results, D-xylose absorption capacity was also significantly increased after switching from existing GLP-2 analogs to HM15912. As a results, HM15912 significantly promoted small intestinal growth than existing GLP-2 analogs even with a less frequent dosing interval of once a week in rodents. A phase 2 clinical study of once-monthly dosing in patients with SBS is ongoing to evaluate the clinical relevance of these findings. Presentation: Saturday, June 17, 2023