HBM Holdings-B (02142) releases preclinical data of the next generation targeted ACVR2A/2B antibody LET003 for the treatment of obesity.

HBM Holdings-B (02142) announced that the Board of Directors is pleased to announce the preclinical research data of their first monoclonal antibody drug LET003 targeting ACVR2A/2B developed using the Hu-mAtrIx artificial intelligence platform. The results show that LET003 has pharmacokinetic characteristics superior to multiple competitor molecules; when used in combination with bimagrumab, it significantly enhances fat reduction effects and effectively protects lean body mass. Furthermore, at lower doses, LET003 can achieve a similar increase in lean body mass promotion as higher doses of bimagrumab, demonstrating its potential to become the best-in-class drug in the treatment of obesity. In transgenic mice and cynomolgus monkey models with human FcRn, researchers compared the blood elimination rates of LET003 with multiple competitor molecules using subcutaneous administration. The results show that the in vivo elimination rate of LET003 is significantly lower than all tested competitors, suggesting that it can achieve similar efficacy to competitor molecules with longer dosing intervals or lower doses. In an obesity model of wild-type mice, researchers administered subcutaneous injections of bimagrumab (30 nmol/kg) and LET003 (20 mg/kg) for single and combination therapy. After three weeks of treatment, the results showed that the combination therapy group had a fat reduction of 76.0% compared to the control group (P<0.0001), and a decrease in lean body mass of 6.5% compared to an increase of 5.7% in the bimagrumab monotherapy group. The data above indicate that combining LET003 with bimagrumab can significantly enhance fat reduction effects and effectively alleviate lean body mass loss that may result from bimagrumab monotherapy. In a high-fat diet-induced obesity model of transgenic mice with human FcRn, researchers administered subcutaneous injections of bimagrumab (30 nmol/kg) and LET003 (20 mg/kg) for single and combination therapy. After three weeks of treatment, the combination therapy group showed a 17.5% decrease in fat/body weight ratio compared to the control group (P<0.0001), and a 15.2% increase in lean body weight/body weight ratio compared to a 6.0% decrease in the bimagrumab monotherapy group (P=0.0127). These data further confirm that combining LET003 with bimagrumab can not only more effectively reduce body fat percentage but also significantly improve the ratio of lean body mass, achieving better body composition control. In an experiment with transgenic mice with human FcRn fed a normal diet, mice received subcutaneous injections of 20 mg/kg of LET003 or a competitor molecule weekly. After three weeks of treatment, both molecules led to an increase in lean body mass and overall weight gain in mice. Specifically: The LET003 treatment group showed an 18.3% increase in lean body weight compared to the control group (P<0.0001), and a 11.1% increase in total weight compared to a 13.5% increase with the competitor molecule. This indicates that LET003 is superior to the competitor molecule in promoting lean body weight. In another experiment with transgenic mice with human FcRn fed a normal diet, mice received subcutaneous injections of different doses (5 mg/kg, 10 mg/kg, 15 mg/kg) of bimagrumab and LET003 weekly. The results show that both molecules contribute more to the increase in lean body weight than fat accumulation. After three weeks of treatment, the 5 mg/kg dose of LET003 showed a similar effect in promoting lean body weight increase as the 15 mg/kg bimagrumab, indicating that LET003 can achieve a similar promotion of lean body weight at lower doses than higher doses of bimagrumab, demonstrating excellent therapeutic potential.