NeuroBo Pharmaceuticals' DA-1241 in Combination with Semaglutide Improves Liver Fibrosis and Demonstrates Additive Hepatoprotective Effects in Pre-Clinical MASH Models Compared to Either Treatment, Alone
Data Will be Presented in Two Posters at the
"The data being presented at EASL further strengthen the pre-clinical evidence that DA-1241's activation of GPR119 has therapeutic potential for the reduction of hepatic steatosis, inflammation, fibrosis, and improved glucose control," stated
- Abstract Title: Additive Hepatoprotective Effects of DA-1241, a Novel GPR119 Agonist, in Combination with Semaglutide in the GAN Diet-Induced Obese and Biopsy-Confirmed Mouse Model of MASH
- Authors: Monika Lewinska,
Malte H. Nielsen ,Susanne Pors ,Henrik B. Hansen ,Il Hoon Jung ,Hyung Heon Kim ,Michael Feigh ,Mi-Kyung Kim - Presenter
Name : Dr.Michael Feigh , Vice President Scientific Research, Gubra - Abstract Number: 1950
- Abstract ID: THU-232
- Session: Poster - MASLD: Experimental and pathophysiology
- Session Date:
Thursday, June 6, 2024 - Session Time:
8:30 am –6:00 pm CET
Male C57BL/6JRj mice were fed the GAN diet for 36 weeks before treatment initiation. Only biopsy-confirmed
DA-1241 and semaglutide monotherapy each improved NAS (≥2-point) in 21% of mice, whereas combination treatment led to marked improvements (≥2-point in 80% of mice and ≥1-point in all mice), driven by reduction in steatosis and lobular inflammation scores. Correspondingly, combination therapy synergistically promoted quantitative histology for steatosis (%-area of liver lipids, % lipid-laden hepatocytes) compared to monotherapies. While treatments did not significantly influence quantitative markers of fibrosis (PSR, Col1a1), DA-1241 and semaglutide in monotherapy lowered α-SMA levels with further improvement in combination treatment, suggesting additive inhibitory effects on fibrogenesis. Liver transcriptome analysis demonstrated a significant increase in the number of differential expressed genes with prominent signature changes in lipid metabolism, chemokine signaling, and fiber proteins following combination therapy compared to monotherapies.
- Abstract Title: DA-1241, a GPR119 Agonist, Combined with Semaglutide Synergistically Improved Liver Fibrosis in Mice with CCl4 Induced Liver Fibrosis
- Authors: Il
Hoon Jung, Tae Hyoung Kim ,Sujin Lee ,Yuna Chae ,Hyung Heon Kim ,Mi-Kyung Kim - Presenter
Name : IIHoon Jung ,Dong-A ST Research Center - Abstract Number: 117
- Abstract ID: THU-531
- Session: Poster - Fibrosis / Stellate cell biology
- Session Date:
Thursday, June 6, 2024 - Session Time:
8:30 am –6:00 pm CET
Liver fibrosis mice were generated by feeding a western diet in adjunctive with CCl4 injections. After administering CCl4 twice weekly for 3 weeks, mice with elevated plasma ALT levels were allocated to receive DA-1241 (oral) or semaglutide (subcutaneous) alone and in combination for 4 weeks. At the end of treatment, semaglutide reduced body weight by approximately 17% (p < 0.05 vs. vehicle control), while DA-1241 (-2.8%) showed little effect. There was no additional weight loss in the combination group (-19%, p < 0.05) compared to semaglutide alone. After four-week-treatment, three drug-treated groups had significantly lower plasma ALT levels than the vehicle control group, suggesting alleviation of liver damage.
Collagen fiber deposition was prominent in mice treated with vehicle compared to the normal control group. However, DA-1241 or semaglutide alone lowered collagen-positive area compared to the vehicle-treated group (17.8%, 17.1% vs. 25.8%, p < 0.05), and their combination therapy elicited a further reduction to 6.05% (p < 0.05) compared with each treatment alone, which was recapitulated in changes of fibrosis score. Hepatic hydroxyproline contents and gene expression of various collagen subtypes (Col1a1, Col3a1, Col5a1, Col6a1) were also altered correspondingly, supporting the beneficial combination effects against the liver fibrogenesis. Notably, gene expression of Hedgehog-interacting protein (Hhip), a suppressor of hepatic stellate cell activation, was lower in mice with liver fibrosis than in normal mice, and were increased by DA-1241 or semaglutide alone. Intriguingly, their combination therapy fully restored the gene expression of Hhip. Additionally, the expression of inflammatory cytokines (Tnfa, IL1b, Ccl2, Cxcl10) was significantly reduced by each monotherapy, and combination treatment reduced gene expression of Tnfa and Cxcl10 more than monotherapy. These data indicate that liver inflammation status has improved as well.
After the presentations, the posters will be accessible within the "Presentations" section of NeuroBo's website at: https://www.neurobopharma.com/events-presentations/presentations.
About DA-1241
DA-1241 is a novel G-Protein-Coupled Receptor 119 (GPR119) agonist with development optionality as a standalone and/or combination therapy for both MASH and type 2 diabetes (T2D). Agonism of GPR119 in the gut promotes the release of key gut peptides GLP-1, GIP, and PYY. These peptides play a further role in glucose metabolism, lipid metabolism and weight loss. DA-1241 has beneficial effects on glucose, lipid profile and liver inflammation, supported by potential efficacy demonstrated during in vivo preclinical studies. The therapeutic potential of DA-1241 has been demonstrated in multiple pre-clinical animal models of MASH and T2D where DA-1241 reduced hepatic steatosis, inflammation, fibrosis, and improved glucose control. Furthermore, in Phase 1a and 1b trials, DA-1241 was well tolerated in both healthy volunteers and those with T2DM.
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Forward Looking Statements
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