Pomaglumetad methionil

Mechanism of action#

Pomaglumetad methionil is itself pharmacologically inactive: it is an L-methionine amide prodrug hydrolyzed by peptidases to pomaglumetad (LY-404039), a structurally novel, conformationally constrained glutamate analog that is a potent, selective orthosteric agonist at the Gi/o-coupled group II metabotropic glutamate receptors mGlu2 and mGlu3 (Ki 149 nM and 92 nM at recombinant human receptors; Ki 88 nM at native rat mGlu2/3), with >100-fold selectivity over ionotropic glutamate receptors, glutamate transporters, and monoaminergic targets of existing antipsychotics. Agonism at predominantly presynaptic mGlu2/3 autoreceptors dampens excessive glutamate release in limbic and forebrain circuits — LY-404039 suppressed evoked excitatory activity in striatum and serotonin-induced glutamate release in prefrontal cortex, and showed antipsychotic-like activity in rodents without D2 occupancy, prolactin elevation, extrapyramidal symptoms, or weight gain. The clinical hypothesis was a first-in-class non-dopaminergic antipsychotic; the Phase 3 failure with later subgroup/pharmacogenetic signals (HTR2A rs7330461, early-in-disease patients) reframed it as a candidate for biomarker-guided redevelopment.

Formulations#

Pomaglumetad methionil for Schizophrenia#

DiscontinuedDiscontinuedSchizophrenia indication →

Pomaglumetad methionil (LY2140023, DB103) for schizophrenia — the field's defining test of the mGlu2/3-agonist hypothesis, and now a biomarker-rescue candidate. Lilly's Phase 2 proof-of-concept (HBBD, published Patil et al. Nature Medicine 2007) showed statistically significant improvement in PANSS versus placebo at 4 weeks without prolactin elevation, EPS, or weight gain. The dose-ranging HBBI (2009) was an inconclusive failed trial in which neither pomaglumetad nor the olanzapine control separated from placebo. The pivotal HBBM study missed its primary PANSS endpoint in July 2012 in both the overall population and a prospectively defined HTR2A genetic subpopulation, and on 2012-08-29 Lilly stopped all Phase 3 development (HBBN, HBDE, HBBO and extensions) after an independent futility analysis of HBBN; the adjunctive negative-symptoms study HBCO also missed. Post hoc analyses kept the mechanism alive: significantly greater responses in patients early in disease (≤3 years) or previously treated with predominantly D2-antagonist antipsychotics at 40 mg BID (Kinon 2015), a pharmacogenetic association with HTR2A SNP rs7330461 T/T homozygotes across 1,115 genotyped patients (Nisenbaum 2016), and later target-engagement studies suggesting the tested doses were likely too low (Krystal 2020). Denovo Biopharma licensed exclusive global rights from Lilly on 2015-03-03 (all IP and data transferred; Lilly retained a buy-back option exercisable after a successful trial) and is redeveloping the asset as DB103 under its Denovo Genomic Marker platform — a 2026 CNS Drugs review reports 23 HTR2A SNPs associated with treatment response, though Denovo has published no primary biomarker data. On 2026-02-11 Denovo announced a partnership with Orygen (Parkville, Australia; PI Patrick McGorry) for an open-label Phase 2 investigator-initiated feasibility study of 40 mg BID for 12 weeks in patients aged 18-25 with first-episode psychosis insufficiently responsive to a first-line antipsychotic or with persistent clinical-high-risk symptoms (Royal Melbourne Hospital HREC Project 2024.289). As of 2026-08-12 no new trial is registered on ClinicalTrials.gov or ANZCTR and Denovo's own pipeline page lists DB103 at the biomarker-discovery stage, so the program is recorded as discontinued per registered reality; a registry entry for the Orygen study would flip it back to active Phase 2.

Clinical trials#