MetaVia Inc. has unveiled promising preclinical data demonstrating that its novel GPR119 agonist DA-1241 produces enhanced hepatoprotective effects when combined with Efruxifermin, an FGF21 analogue, in treating metabolic dysfunction-associated steatohepatitis (MASH). The findings, presented at the American Diabetes Association's 85th Scientific Sessions in Chicago, represent the first demonstration of beneficial synergistic effects between these two therapeutic approaches.
Superior Efficacy in Combination Therapy
The preclinical study utilized mice fed a Gubra Amylin NASH (GAN) diet for 36 weeks to induce advanced liver pathology consistent with human MASH. Following randomization, mice received either vehicle, DA-1241 (100 mg/kg once daily, oral), Efruxifermin (1 mg/kg once weekly, subcutaneous), or the combination therapy for 12 weeks.
The combination therapy demonstrated remarkable efficacy, with 94% of mice achieving a ≥2-point improvement in the non-alcoholic fatty liver disease (NAFLD) activity score from baseline. This response rate significantly exceeded that observed with either monotherapy alone, highlighting the enhanced therapeutic potential of the combined regimen.
Weight-Independent Hepatoprotective Benefits
A notable finding was DA-1241's weight-neutral profile over the 12-week treatment period, contrasting with Efruxifermin monotherapy, which induced a statistically significant 17% reduction in body weight compared to vehicle (p < 0.05). Importantly, no additional weight loss was observed with the combination therapy, indicating that the enhanced benefits were independent of weight loss mechanisms.
Comprehensive Anti-Inflammatory and Anti-Fibrotic Effects
Liver mRNA analysis revealed substantial reductions in inflammatory markers with the combination therapy, including TNFα (-58%), CXCL10 (-56%), CCL2 (-77%), and galectin-3 (-87%). Similarly, fibrotic markers showed marked decreases, with type 1 collagen α1 reduced by 72%, α-SMA by 59%, and TIMP1 by 88%.
The combination therapy also demonstrated superior effects on liver immunohistochemistry, with significantly reduced inflammatory (galectin-3) and fibrotic (type 1 collagen and α-SMA) proteins compared to monotherapy. Additionally, hedgehog-interacting protein, a suppressor of hepatic stellate cell activation, was upregulated by 321% in the combination group.
Systemic Anti-Inflammatory Benefits
Beyond local hepatic effects, the combination therapy further reduced plasma TNFα levels, suggesting improvements in both local and systemic inflammation. This finding underscores the potential for addressing the broader inflammatory aspects of MASH pathology.
Clinical Translation Potential
"Building on the encouraging results from our Phase 2a clinical trial of DA-1241 in patients with presumed MASH, which demonstrated hepatoprotective and glucose-regulating effects, these new preclinical findings presented at the ADA further highlight the promise of combining DA-1241 with an FGF21 analogue like Efruxifermin," stated Hyung Heon Kim, President and Chief Executive Officer of MetaVia.
The company previously announced that data from its Phase 2a clinical trial of DA-1241 in patients with presumed MASH has been accepted as a late-breaking poster presentation at the European Association for the Study of the Liver (EASL) Congress 2025, scheduled for May 7-10, 2025 in Amsterdam.
Mechanism of Action
DA-1241 functions as a G-Protein-Coupled Receptor 119 (GPR119) agonist with development potential as both standalone and combination therapy for MASH and type 2 diabetes. GPR119 agonism in the gut promotes the release of key gut peptides GLP-1, GIP, and PYY, which play crucial roles in glucose metabolism, lipid metabolism, and weight regulation.
The therapeutic potential of DA-1241 has been demonstrated across multiple preclinical animal models of MASH and type 2 diabetes, where it reduced hepatic steatosis, inflammation, and fibrosis while improving glucose control. In Phase 1a, 1b, and 2a trials, DA-1241 was well tolerated in both healthy volunteers and patients with type 2 diabetes mellitus.
