blixeprodil (GM-1020) / Gilgamesh Pharma - LARVOL DELTA

First-in-human pharmacological characterization of the novel NMDA receptor antagonist GM-1020: a single ascending dose study in healthy participants (ECNP 2025) - "Ketamine, a non-competitive and non-selective N-methyl-D-aspartate receptor (NMDAR) antagonist, rapidly induces antidepressant effects in treatment-resistant MDD patients. Conclusion Collectively, CNS biomarkers sensitive to NMDAR antagonism provide clinical evidence of target engagement (EEG) at 60 mg without undesirable CNS effects. Dissociation and sedation were dose-dependent and mild at doses of 220 mg and below; supporting 60–220 mg as the optimal pharmacologically active oral dose range for GM-1020 in future clinical trials."

Clinical • First-in-human • P1 data • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

Gilgamesh Announces Initiation of Phase 2a Trial of GM-1020 in Major Depressive Disorder (PRNewswire) - "Gilgamesh Pharmaceuticals...announced the initiation of patient dosing with GM-1020 in a Phase 2a study in Major Depressive Disorder (MDD) to assess safety, tolerability, and efficacy. GM-1020 is a novel, orally bioavailable NMDA receptor antagonist with reduced sedative and dissociative side effects. The study will include an initial placebo-controlled crossover phase followed by a 2-week multiple dose period....Initial results of the Phase 2a trial anticipated to be available in the 2nd half of 2024."

P2a data • Trial status • Major Depressive Disorder

A Clinical Study to Evaluate of Single and Multiple Oral Doses of GM-1020 in Patients With MDD (clinicaltrials.gov) - P2 | N=30 | Recruiting | Sponsor: Gilgamesh Pharmaceuticals

New P2 trial • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

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

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

Gilgamesh Pharmaceuticals Successfully Completes Phase 1 SAD/MAD Clinical Trials of GM-1020 (PRNewswire) - "Gilgamesh Pharma...proudly announces the successful completion of its Phase 1 Single Ascending Dose (SAD) and Multiple Ascending Dose (MAD) trials for GM-1020...currently in clinical development. This next-generation therapy is poised to potentially transform the treatment landscape for major depression, bipolar disorder, obsessive-compulsive disorder (OCD), and other debilitating mental health conditions....Following the successful completion of the Phase 1 SAD/MAD trials, Gilgamesh Pharma will initiate a Phase 2a study in major depressive disorder (MDD) patients during the second half of 2023."

New P2a trial • Trial completion • Bipolar Disorder • CNS Disorders • Depression • Major Depressive Disorder • Obsessive-Compulsive Disorder