Mavoglurant: Mechanism, Trials, and Future Outlook

Mavoglurant is a small molecule drug, an indole derivative, that has undergone significant scientific and medical investigation. It has been explored as a potential treatment for various medical conditions.

How Mavoglurant Interacts with the Brain

Mavoglurant operates by selectively targeting the metabotropic glutamate receptor 5 (mGluR5) in the brain. This compound functions as a selective non-competitive antagonist of mGluR5, meaning it binds to a different site on the receptor than glutamate and reduces its activity. mGluR5 is a G-protein coupled receptor that plays a role in modulating synaptic transmission and neuronal excitability within the central nervous system.

Activation of mGluR5 by glutamate initiates a signaling cascade that involves Gq proteins and phospholipase C (PLC), leading to the production of second messengers like inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). These messengers influence various kinases, ion channels, and intracellular calcium stores. By blocking mGluR5, mavoglurant modulates glutamatergic signaling, reducing abnormal neuronal activity linked to neurological disorders. This modulation aims to restore the balance of excitatory and inhibitory signals within the brain.

Conditions Under Investigation

Mavoglurant has been primarily investigated for treating Fragile X Syndrome (FXS). FXS is a genetic disorder caused by a mutation in the FMR1 gene, resulting in a deficiency of the fragile X mental retardation protein (FMRP). This deficiency leads to excessive activation of mGluR5 pathways, contributing to synaptic dysfunction and symptoms such as intellectual disability, anxiety, hyperactivity, and seizures. Mavoglurant aims to mitigate these symptoms by inhibiting mGluR5, improving quality of life for individuals with FXS.

Beyond FXS, mavoglurant has also been explored for other conditions. It was in phase II clinical trials for levodopa-induced dyskinesia, a movement disorder associated with Parkinson’s disease treatment, and has been studied for obsessive-compulsive disorder (OCD) and cocaine use disorder (CUD).

Clinical Trial Outcomes and Safety Profile

In preclinical studies for Fragile X Syndrome, mavoglurant showed positive neuronal and behavioral effects, but human trials presented mixed results. Two 12-week, randomized, placebo-controlled, double-blind, phase IIb studies in adults (aged 18-45 years) and adolescents (aged 12-19 years) with FXS did not meet their primary endpoint of significant improvement in abnormal behaviors (measured by ABC-C_FX). Despite these outcomes, an earlier small-scale phase IIa trial suggested efficacy in a subpopulation of FXS patients with a fully methylated FMR1 gene.

Mavoglurant was well tolerated in these studies, with no new safety signals identified in long-term extension trials. Most patients experienced at least one adverse event, predominantly mild or moderate and often considered unrelated to the drug. Five percent of adults and 16.9 percent of adolescents discontinued treatment due to adverse events. Serious adverse events were infrequent; 11 patients experienced one, with four possibly related to treatment. The dosage used in these studies was up to 100 mg twice daily.

For cocaine use disorder, mavoglurant was studied in 68 participants aged 18 to 57 years. Participants received mavoglurant or placebo pills twice daily for 14 weeks. The study found that mavoglurant users reported using cocaine on fewer days compared to the placebo group. No serious adverse events were reported, and non-serious adverse events were similar between groups, with headache being most common.

Current Research Status and Future Directions

Novartis discontinued development of mavoglurant for Fragile X Syndrome in April 2014 due to disappointing trial results, and for other indications by 2017. However, Stalicla, a biotech company, recently acquired worldwide rights from Novartis to continue developing mavoglurant for substance use and neurodevelopmental disorders.

Stalicla plans to advance mavoglurant into phase 3 studies for cocaine use disorder, building on promising phase 2 results showing the drug induced abstinence without withdrawal liability. The company also plans to use its artificial intelligence platform to identify patient subgroups within neurodevelopmental disorders who might respond well to mavoglurant. This renewed interest indicates a potential future for mavoglurant in targeted therapeutic approaches.

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