NeuroBo Pharmaceuticals' Novel GLP1R and GCGR Dual Agonist, DA-1726, Shown to Elicit Superior Weight Loss Efficacy Compared to Semaglutide and Tirzepatide in Preclinical Models
Preclinical Data Also Show DA-1726 Effectively Reduces Body Weight and Glycemic Control
Data Presented in One ePoster Theater Discussion and Two General Poster Presentations at the
"DA-1726, a long acting OXM analog that binds and activates both GLP-1 and glucagon receptors using a well understood mechanism, has shown weight loss efficacy, despite similar or higher food intake, in a dose-dependent manner, that is better than SEMA in diet-induced obese (DIO) rats (32.6% for DA-1726 at a high dose compared to 24.0% for SEMA, p<0.05)," stated
"In preclinical mice models, DA-1726 also showed the ability to improve plasma glucose insulin and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) as compared to Cotadutide (COTA), another OXM analog. Importantly, DA-1726 showed superior plasma triglyceride (TG) reduction and a similar reduction of total cholesterol (T-CHO) compared to COTA. In a comparative preclinical mouse study with GLP1R/glucose-dependent insulinotropic polypeptide receptor (GIPR) dual agonist, Tirzepatide (TIR), DA-1726 showed similar efficacy on weight loss, despite consuming more food. However, DA-1726 was more efficacious in improving plasma metabolic parameters such as glucose, TG, and T-CHO compared to TIR, indicating differential metabolic effects caused by GCGR agonism. Taken together, these data suggest that DA-1726 is a well-balanced GLP-1 receptor and glucagon receptor dual agonist and we anticipate that DA-1726 will have effective weight loss and glycemic control in humans," concluded
"DA-1726 is a long-acting, novel peptide drug candidate in preclinical development with therapeutic promise for obesity and NASH, in preparation for a phase 1 clinical trial for obesity," stated
Abstract Title: A Novel GLP1R/GCGR Dual Agonist, DA-1726 Elicits Weight Loss Superior to Semaglutide in Diet-Induced Obese Rats
Poster: 1676
Authors:
Presenter:
Session:
Date and Time:
Location: Poster Halls B-C
DA-1726 showed superior weight loss efficacy compared to Semaglutide (SEMA) in diet-induced obese (DIO) mice. In this study, a dose-response of DA-1726 was evaluated to determine the maximum efficacy in DIO rats which are known for translatability to human studies. The half-life of DA-1726 was longer in rats compared to mice, however the in vitro activity of DA-1726 against rat glucagon receptor was less potent than in mice, and plasma protein binding was approximately 10-fold higher in rats. Therefore, the effective dose for rats was set higher than for mice. DA-1726 was injected twice a week for approximately 4 weeks, and a dose-dependent and significant weight loss effect was observed. The minimum effective dose in DIO rats was found to be 250 nmol/kg. Then, the maximum body weight loss effects of DA-1726 (500 and 1000 nmole/kg) and SEMA were compared in the DIO rat model. DA-1726 showed an excellent weight loss effect compared to SEMA (32.6% for DA-1726 at a high dose vs. 24.0% for SEMA, p<0.05). The low-dose DA-1726 group showed a similar effect compared to SEMA in spite of consuming more food. The high-dose DA-1726 group showed similar food intake as SEMA, however it led to a higher weight loss effect. After repeated dosing, the high-dose DA-1726 increased the expression of energy metabolism-related genes (Ucp1, Ppargc1a) in white adipose tissues (WAT), supporting increased energy expenditure. In order to confirm whether this increased gene change was a direct effect leading to weight loss or an indirect effect caused by weight loss, changes in gene expression were assessed after single dosing. DA-1726 (250 and 500 nmol/kg) induced small but significant weight loss 3 days after a single injection (-7.6% and -9.5% vs. control). However, the genes expression (Ucp1, Ppargc1a) in WAT was increased only in the 500 nmol/kg-treated group suggesting a direct effect. Therefore, DA-1726 is expected to elicit significant weight loss effects in humans with a new mechanism of action.
DA-1726 showed equal or greater efficacy with higher food intake compared to Semaglutide in reducing body weight
DA-1726 showed significant increase in white adipose tissue gene expression suggesting energy expenditure's direct impact on weight loss
Abstract Title: Differentiated Metabolic Effects of DA-1726, a Balanced GLP1R/GCGR Dual Agonist
Authors:
Poster: 1668
Session: ePoster Theater
Date and Time:
Location: Exhibit Hall (ePoster Theater A)
Session: General Poster Session
Date and Time:
Location: Poster Halls A-B
The pharmacological effect of DA-1726 was evaluated compared to other competitor peptides. DA-1726 showed superior efficacy compared to another GLP1R/GCGR dual agonist, Cotadutide (COTA), in reducing body weight (14.4% for DA-1726 and 6.4% for COTA vs. diet-induced obese (DIO) mice control at 30 nmol/kg, p<0.05) and improving plasma glucose, insulin, and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) (-91% for DA-1726 vs. -52% for COTA) in DIO mice. In addition, DA-1726 showed superior plasma triglyceride (TG) reduction and similar reduction of total cholesterol (T-CHO) compared to COTA. The data suggests that the balanced dual agonist DA-1726 was superior to a GLP1R-biased dual agonist in metabolic effects. Additionally, enhanced glucagon action of GLP1R/GCGR dual agonists may increase the risk of hyperglycemia when GLP1R agonism is reduced. DA-1726 was injected for 3 weeks and a glucose tolerance test was performed at 72 hours after the last dosing. DA-1726 did not impair glucose tolerance even at minimal plasma concentrations during repeated dosing up to 100 nmol/kg. In the case of repeated dosing of 100 nmol/kg, the plasma drug concentration at 72 hours after the final injection is similar to the concentration that induces about 50% activation of receptors under 4% human albumin condition. In a comparative study with a GLP1R/glucose-dependent insulinotropic polypeptide receptor (GIPR) dual agonist, Tirzepatide (TIR), DA-1726 showed a similar maximum efficacy on weight loss (31.2% for DA-1726 and 31.3% for TIR vs. DIO control, p<0.05). However, DA-1726 was more efficacious in improving plasma metabolic parameters such as glucose, TG, and T-CHO compared to TIR, indicating differential metabolic effects caused by GCGR agonism. Taken together, this data suggests that DA-1726 is a well-balanced GLP1R/GCGR dual agonist that effectively reduces body weight and glycemic control.
DA-1726 showed similar efficacy with higher food intake compared to Tirzepatide in reducing body weight
Copies of the presentation materials are available on the
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