GM1020 / Genervon - LARVOL DELTA

GM-1020: a novel, orally bioavailable NMDA receptor antagonist with rapid and robust antidepressant-like effects at well-tolerated doses in rodents. (PubMed, Neuropsychopharmacology) - "The NMDA receptor (NMDAR) antagonist ketamine has shown great potential as a rapid-acting antidepressant; however, its use is limited by poor oral bioavailability and a side effect profile that necessitates in-clinic dosing. Electroencephalography (EEG) was performed to determine indirect target engagement and provide a potentially translational biomarker. These results demonstrate that GM-1020 is an orally bioavailable NMDAR antagonist with antidepressant-like efficacy at exposures that do not produce unwanted motor effects."

Journal • Preclinical • CNS Disorders • Depression • Psychiatry

GM-1020: An Oral NMDA Receptor Antagonist for Depression Demonstrates Target Engagement at Doses That Do Not Cause Dissociation, Ataxia or Sedation in a Phase 1 Single Ascending Dose Study (ACNP 2023) - "Esketamine (Spravato®) an intranasal formulation of the more potent S-isomer of ketamine, has been approved for patients with treatment-resistant depression, but still requires supervised administration due to its sedative and dissociative effects. The oral bioavailability and the ability of GM-1020 to produce significant quantitative and subjective pharmacodynamic evidence of NMDA receptor antagonism without causing dissociation, sedation or ataxia at exposures expected to have antidepressant effects. This distinguishes this novel molecule from existing ketamine-based therapies. Consistent with the preclinical characterization of this molecule, GM-1020 produced significant changes in low and high frequency EEG power at doses below those associated with ataxia or sedation."

P1 data • Ataxia • CNS Disorders • Depression • Mood Disorders • Pain • Psychiatry

Preclinical and translational profile of GM-1020, a novel, orally bioavailable NMDA antagonist (Neuroscience 2023) - "Despite ketamine providing rapid and sustained antidepressant efficacy, patient access is limited by poor bioavailability and sedative and dissociative side effects. Here we describe the novel NMDA receptor (NMDAR) antagonist, GM-1020 which was designed to be orally bioavailable and cause limited sedation and dissociation at therapeutic doses.GM-1020 displaces [3H]MK-801 binding in rat cortex (Ki = 3.25 µM) and is a voltage-dependent antagonist of human GRIN1/GRIN2A-containing NMDAR (IC50 = 1.19 µM at -70 mV and 265.21 µM at +60 mV)...After dosing with GM-1020 EEG spectral power changed in a plasma concentration-dependent manner indicating that decreases in low frequency and increases in high frequency power provide translational biomarkers of NMDA receptor target engagement. Quantitative EEG can be used clinically to determine whether significant target engagement can be achieved without causing dissociation or sedation."

Preclinical • Ataxia • CNS Disorders • GRIN2A

GM-1020 is a Novel, Orally Bioavailable NMDA Antagonist With Improved Separation Between Antidepressant and Ataxic Doses Compared to Ketamine (SOBP 2023) - "Methods The affinity of GM-1020 at NMDAR was determined using displacement of [3H]MK-801 binding in rat cortex. Conclusions GM-1020 is a voltage-dependent NMDA antagonist that shows improved oral bioavailability compared to ketamine. GM-1020 fully reversed the effects of CMS at doses well below those causing ataxia suggesting a superior therapeutic window compared to (R,S)-ketamine."

Alzheimer's Disease • Ataxia • CNS Disorders • Cognitive Disorders • Depression • Mood Disorders • Psychiatry • GRIN2A

GM-1020: A Novel, Orally Bioavailable NMDA Receptor Antagonist With Rapid and Robust Antidepressant Effects and Reduced Ataxia in Rodents (ACNP 2022) - " The binding affinity of GM-1020 at NMDAR was determined using displacement of [3H]MK-801 from rat cortical tissue homogenates... GM-1020 has a good oral bioavailability in non-clinical species and predicted bioavailability of >60% in humans. In the CMS model of depression, the minimum antidepressant-like dose of GM-1020 was 1.5 mg/kg, with robust efficacy observed after the first dose and maintained for 14 days after the final dose. The ED50 for ataxia was ~13-fold higher, while no effect on locomotion was observed even at >20-fold higher doses than the minimum efficacious dose in CMS."

Preclinical • Alzheimer's Disease • Ataxia • CNS Disorders • Depression • Mood Disorders • Psychiatry • GRIN2A