Vanoglipel

What is Vanoglipel?

Vanoglipel (development code DA-1241) is an oral, first-in-class GPR119 agonist being developed by MetaVia Therapeutics (Nasdaq: MTVA, formerly NeuroBo Pharmaceuticals) under an in-license from Dong-A ST (South Korea). Important framing: vanoglipel is a small-molecule drug, NOT a peptide. Its molecular formula is C25H31F2N5O2 (MW 471.55 g/mol), with an oxadiazole-phenyl-piperidine-pyrimidine scaffold typical of small-molecule GPCR agonists. It is included on Peptide List for cross-reference because its mechanism of action operates entirely through endogenous peptide release: GPR119 activation on intestinal L-cells triggers secretion of GLP-1, GIP, and PYY, while activation on pancreatic β-cells produces direct glucose-dependent insulinotropic effects. The Phase 2a trial (NCT06054815, n=109, presumed MASH, 16 weeks) read out at AASLD 2025 (poster #4012, presenter Rohit Loomba/UCSD) with −22.8 U/L ALT reduction at 100 mg vs placebo, larger ALT effects in the baseline-ALT-40–200 U/L subgroup, improvements in CAP/VCTE/FAST/NIS-4 scores, reductions in TIMP1 and CK18 fibrosis biomarkers, −0.54% HbA1c (monotherapy) and −0.66% (combination with sitagliptin) in subjects with baseline HbA1c ~6.99%, and a tolerable safety profile with no TEAE-related discontinuations. Vanoglipel is the proposed/recommended INN; DA-1241 is the historical development code.

What Vanoglipel Is Investigated For

Vanoglipel is an oral small-molecule GPR119 agonist being developed primarily for metabolic dysfunction-associated steatohepatitis (MASH), with secondary interest in type 2 diabetes. The mechanism is genuinely interesting: rather than directly activating GLP-1R like the peptide incretins, vanoglipel activates GPR119 on intestinal L-cells to trigger endogenous release of GLP-1, GIP, and PYY — the same gut peptides that drive the metabolic effects of semaglutide and tirzepatide, but produced by the patient's own enteroendocrine cells in response to receptor signaling. The Phase 2a (NCT06054815) read out positively at AASLD 2025 with 22.8 U/L ALT reduction at 100 mg, improved CAP/VCTE/FAST/NIS-4 scores, and meaningful HbA1c reduction in a population with baseline HbA1c ~6.99%. Honest caveats are substantial. The GPR119 target has a long graveyard: GSK1292263, MBX-2982 (Metabolex), PSN821, LEZ763, JNJ-38431055, and DS-8500a (Daiichi Sankyo) all failed in Phase 2 development through tachyphylaxis, modest durability, and poor rodent-to-human translation. Whether vanoglipel's reported TFEB-autophagy and NF-κB inhibition mechanisms (preclinical data in MASH models) translate to durable clinical benefit is the question MetaVia must answer in larger Phase 2b or Phase 3 trials. As of mid-2026 MetaVia is positioning vanoglipel into the MASH space alongside resmetirom (Madrigal's THR-β agonist, the only approved MASH-specific therapy) and the broader GLP-1/glucagon incretin programs targeting liver outcomes. The strategic question is whether an oral small molecule with an incretin-stimulating mechanism can compete with directly administered incretin peptides on either efficacy or commercial positioning.

History & Discovery

DA-1241 was discovered at Dong-A ST in South Korea as part of a GPR119 small-molecule program. The Phase 1 SAD trial (NCT03061981) in type 2 diabetes completed in October 2017, with a Phase 1b MAD trial including a metformin DDI cohort (NCT03646721) completing in May 2020. The compound's preclinical mechanism work was published progressively from 2021 (β-cell preservation via ER stress and PDX1) through 2025 (TFEB-mediated autophagy and NF-κB inhibition in MASH models), gradually building a story that extended the asset's positioning from diabetes-focused GPR119 to a MASH-focused incretin-stimulating mechanism with hepatoprotective effects. NeuroBo Pharmaceuticals in-licensed DA-1241 alongside the DA-1726 dual agonist from Dong-A ST and conducted the Phase 2a MASH study (NCT06054815) at sites including UCSD with Rohit Loomba as principal investigator. The Phase 2a positive readout at AASLD 2025 (poster #4012, n=109, 16-week dosing) reported 22.8 U/L ALT reduction at the 100 mg dose, improvements in CAP/VCTE/FAST/NIS-4 liver scores, HbA1c reduction of 0.54–0.66%, and a favorable tolerability profile. NeuroBo rebranded to MetaVia Therapeutics in November 2024 and executed a 1-for-11 reverse stock split, repositioning around its dual metabolic-disease assets — vanoglipel for MASH and DA-1726 for obesity. The INN 'vanoglipel' was assigned during this period (exact WHO list reference not located). MetaVia has signaled MASH and T2D ambitions for vanoglipel and is presenting additional data at major liver and diabetes conferences through 2026. The historical context that shapes the asset's outlook is the long GPR119 graveyard — Merck's MK-1903, Metabolex's MBX-2982, GSK's GSK1292263, J&J's JNJ-38431055, Prosidion's PSN821, LEZ763, and Daiichi Sankyo's DS-8500a all failed in Phase 2 development through tachyphylaxis, modest absolute efficacy, and poor rodent-to-human translation. Vanoglipel must prove durability of effect over longer exposure windows than Phase 2a's 16 weeks to differentiate from this track record.

How It Works

GPR119 is a receptor found on gut cells (called L-cells) and on insulin-producing cells in the pancreas. When GPR119 is activated by vanoglipel, gut L-cells release GLP-1, GIP, and PYY — the same hormones that injectable weight-loss drugs like Ozempic and Mounjaro mimic. Pancreatic cells release more insulin when blood sugar is high. The net effect is improved blood sugar, reduced liver fat, and lower liver enzymes. Vanoglipel itself is a pill, not an injection, and is a small molecule rather than a peptide.

Vanoglipel (DA-1241) is a small-molecule agonist of GPR119, a Gαs-coupled G-protein-coupled receptor with restricted expression: intestinal L-cells (where it triggers GLP-1, GIP, and PYY release) and pancreatic β-cells (where it produces direct glucose-dependent insulinotropic action). Endogenous GPR119 ligands include oleoylethanolamide (OEA) and other lipid-derived signaling molecules. The expected metabolic effects are downstream of three signals: (1) GLP-1 release reduces appetite, slows gastric emptying, and improves glycemic control; (2) GIP release contributes additional insulinotropic and possibly weight-relevant effects; (3) PYY release further suppresses appetite and modulates gut motility; (4) direct β-cell stimulation increases glucose-dependent insulin secretion. Preclinical work in MASH models (PMIDs 34678732, 35052026, 37657264, 40153257) extends the mechanistic picture beyond incretin release: DA-1241 was reported to inhibit hepatic gluconeogenesis, preserve pancreatic β-cell function via ER stress suppression and increased PDX1 expression, suppress NF-κB-mediated hepatic inflammation, and upregulate TFEB-mediated autophagy to reduce hepatic steatosis. These mechanism-of-action findings are preclinical and require clinical confirmation. The small-molecule nature has practical consequences. Vanoglipel is dosed orally, with established pharmacokinetics characterized in Phase 1 SAD (NCT03061981) and Phase 1b MAD (NCT03646721) including a metformin DDI cohort. Bioanalytical methods for plasma quantification have been validated (PMID 41243172). Compared to peptide incretin agonists, the small-molecule profile offers oral convenience and potentially lower manufacturing cost, but introduces standard small-molecule considerations: CYP metabolism, drug-drug interactions, and the receptor pharmacology challenges (tachyphylaxis, modest peak efficacy) that have historically limited the GPR119 target class.

Evidence Snapshot

Research Gaps & Open Questions

What the current literature has not yet settled about Vanoglipel:

• 01Durability of effect beyond 16 weeks — the critical Phase 2b/3 question given the GPR119 graveyard.
• 02MRI-PDFF liver fat reduction — only CAP/VCTE/FAST/NIS-4 reported, not direct MRI-PDFF measurement.
• 03Direct head-to-head comparison versus resmetirom (the only approved MASH therapy) and versus incretin-class MASH-targeting agents (survodutide, semaglutide, tirzepatide).
• 04Phase 2b dose optimization — Phase 2a tested 50 mg and 100 mg; whether higher or alternate dosing improves efficacy is unknown.
• 05Tachyphylaxis assessment in extended dosing — the recurring failure mode of prior GPR119 agonists.
• 06Cardiovascular outcomes — no CV outcomes trial planned at this stage.
• 07Liver histology endpoints — Phase 2a relied on non-invasive scores; Phase 2b/3 will require biopsy-based MASH resolution and fibrosis improvement endpoints to support a regulatory MASH label.

Forms & Administration

Oral. Phase 2a tested 50 mg and 100 mg daily, alone or combined with sitagliptin 100 mg. Investigational; no FDA-approved formulation.

Dosing & Protocols

The ranges below reflect protocols commonly discussed in the literature and by clinicians — not a prescription. Actual dosing for any individual should be determined by a qualified healthcare provider who knows the patient.

Vanoglipel is not FDA-approved for any indication. Doses and schedules above reflect published clinical trial protocols and are not prescriptions. Legitimate access is limited to enrollment in registered clinical trials.

Timeline of Effects

Common Questions

Who Vanoglipel Is NOT For

Drug & Supplement Interactions

No FDA-labeled interaction profile because vanoglipel is not approved. CYP-mediated drug-drug interactions are expected as standard small-molecule considerations and were assessed in Phase 1b (NCT03646721) including a metformin DDI cohort. The therapeutic combination with sitagliptin (DPP-4 inhibitor) in Phase 2a is intentional and mechanistically synergistic — sitagliptin extends GLP-1 half-life, amplifying the GPR119-driven endogenous GLP-1 release. Combination with insulin or sulfonylureas would likely require downward titration of the concomitant hypoglycemic agent given vanoglipel's glucose-lowering effect.

Safety Profile

Legal Status

Regulatory status changes over time. Verify current local rules with a qualified professional.

Myths & Misconceptions