754-P: Antifibrotic Potential of a Novel Long-Acting Glucagon/GIP/GLP-1 Triple Agonist (HM15211) in Preclinical Models of IPF

Idiopathic pulmonary fibrosis (IPF) is an irreversible and progressive pulmonary disorder in which scarring of lung tissue eventually leads to death. A large of studies have demonstrated that the core mechanisms in fibrosis across various organs are similar. Previously, excellent preclinical efficacy of HM15211, a novel long-acting Glucagon/GIP/GLP-1 triple agonist, on liver fibrosis was confirmed (the major distribution tissues of HM152were liver and lung) . These findings prompted us to hypothesize that HM152might be also a promising drug candidate for IPF. Its effect on pulmonary function and mortality was evaluated in bleomycin (BLM) -induced mouse model of lung fibrosis. BLM was instilled intratracheally to assess the therapeutic benefits of HM152over pirfenidone (PIRF) and nintedanib (NINT) (FDA-approved drugs for IPF) . Briefly, HM152was administered 7 days post BLM instillation, and then saturation of peripheral oxygen (SpO₂) and survival rate were monitored until day 14 and day 21, respectively. 1.5 U/kg BLM mice showed markedly impaired lung function at day 7 as indicated by SpO₂ (84.0 vs. 95.6% for normal) , which was further exacerbated until day 14 (77.1% vs. 96.0% for normal) . Interestingly, while PIRF (81.9%) and NINT (81.3%) prevent additional lung function impairment without any reversal effects, HM152treatment significantly restored impaired lung function (91.5%) at day 14. In addition, at 21 days after 2.5 U/kg BLM treatment, substantial decline in survival rate (17%) was effectively inhibited by HM15211, NINT, and PIRF. Notably, HM152 (61%) showed more improved survival rate than NINT (33%) , and PIRF (28%) , suggesting potential superiority of HM152over current IPF drugs.

In conclusion, HM152may be a novel therapeutic potential for pulmonary fibrosis over current standard of care for IPF. Further evidences from the mechanistic studies will shed light on a direct inhibitory effect of HM152on pulmonary fibrosis.