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Investigational GPR119 Agonist Shows Dual Hepatoprotective and Glycemic Benefits in MASH Patients
EASL 2025. DA-1241 significantly reduced plasma ALT levels, improved systemic inflammatory and fibrosis biomarkers, according to drug developer MetaVia.
MetaVia Inc. today announced promising phase 2a clinical trial data for DA-1241, a novel G protein-coupled receptor 119 (GPR119) agonist, demonstrating significant benefits for patients with presumed metabolic dysfunction-associated steatohepatitis (MASH). Researchers presented the findings at the European Association for the Study of the Liver (EASL) Congress 2025, May 7-11, in Amsterdam.
The 16-week trial enrolled 109 participants with presumed MASH and showed DA-1241 significantly reduced plasma ALT levels by 22.8 U/L at the 100 mg dose compared to placebo (P <.05). Investigators observed these improvements regardless of participant's diabetes status, suggesting direct hepatoprotective effects beyond glycemic control, according to a MetaVia statement.
Liver fat content, measured by controlled attenuation parameter, decreased by 23.0 dB/m with DA-1241 100 mg compared to just 1.4 dB/m with placebo. The drug also improved FibroScan-AST (FAST) scores, with average values declining from 0.559 to 0.371, indicating improvements in liver fibrosis and steatosis, MetVia stated.
"The full data from our phase 2 clinical study, as presented at the prestigious EASL Congress, confirm that DA-1241 is the first oral GPR119 agonist to demonstrate both hepatoprotective and glucose-regulating effects in presumed MASH patients," Hyung Heon Kim, MetaVita president and CEO of MetaVia, said in the statement. "Importantly, treatment with DA-1241 significantly reduced key markers of liver injury, inflammation, and fibrosis, while also improving non-invasive liver assessment scores."
The trial randomly assigned participants to receive DA-1241 50 mg, DA-1241 100 mg alone, DA-1241 100 mg with a dipeptidyl peptidase 4 inhibitor (DPP4i), or placebo in a 1:2:2:2 ratio. Researchers measured change in ALT from baseline as the primary endpoint.
Beyond liver parameters, DA-1241 demonstrated significant anti-inflammatory and anti-fibrotic activity. The 100 mg dose lowered biomarkers of systemic inflammation (hs-CRP, CCL2) and fibrosis (TIMP1) (P <.05 vs placebo). Cytokeratin 18, a marker of liver cell death, also decreased significantly by 30.5% (P <.05 vs placebo), MetaVia said.
DA-1241 was also associated with robust glycemic effects, producing rapid and significant reductions in hemoglobin A1c (HbA1c) of 0.37%, 0.41%, and 0.54% at weeks 4, 8, and 16, respectively, from a baseline of 6.99% (P <.05 vs placebo), the company reported. In the subgroup of participants with presumed MASH with type 2 diabetes, HbA1c decreased by 1.08%. When combined with a DPP4 inhibitor, DA-1241 demonstrated enhanced metabolic benefits.
"These results suggest that DA-1241's hepatoprotective effects are likely driven by its anti-inflammatory and anti-fibrotic actions rather than just glucose lowering, offering a promising multi-faceted therapeutic approach for patients at risk of progressive liver disease," Kim added.
Mechanistically, DA-1241 agonizes GPR119 in the gut, promoting the release of key gut peptides GLP-1, GIP, and PYY. These peptides influence glucose metabolism, lipid metabolism, and potentially weight management.
Safety data showed DA-1241 was well tolerated among presumed MASH study participants, with no treatment-emergent adverse events leading to discontinuation, except for one case in the placebo group.
"Based on this data, we continue to believe that the novel mechanism of action of DA-1241 supports further development as either a monotherapy or combination therapy for MASH and metabolic diseases," Kim explained. "We continue to conduct pre-clinical studies to explore other combination therapies for DA-1241, which may provide additional benefits to treat patients along the full spectrum of MASH."
MetaVia plans to review these findings at an end of phase 2 meeting with the FDA in the first half of 2025, potentially advancing this dual-action agent toward larger clinical trials for both MASH and metabolic indications.
