Fasoracetam in adolescents with ADHD and glutamatergic gene network variants disrupting mGluR neurotransmitter signaling

Abstract

The glutamatergic neurotransmitter system may play an important role in attention-deficit hyperactivity disorder (ADHD). This 5-week, open-label, single-blind, placebo-controlled study reports the safety, pharmacokinetics and responsiveness of the metabotropic glutamate receptor (mGluR) activator fasoracetam (NFC-1), in 30 adolescents, age 12–17 years with ADHD, harboring mutations in mGluR network genes. Mutation status was double-blinded. A single-dose pharmacokinetic profiling from 50–800 mg was followed by a single-blind placebo at week 1 and subsequent symptom-driven dose advancement up to 400 mg BID for 4 weeks. NFC-1 treatment resulted in significant improvement. Mean Clinical Global Impressions-Improvement (CGI-I) and Severity (CGI-S) scores were, respectively, 3.79 at baseline vs. 2.33 at week 5 (P < 0.001) and 4.83 at baseline vs. 3.86 at week 5 (P < 0.001). Parental Vanderbilt scores showed significant improvement for subjects with mGluR Tier 1 variants (P < 0.035). There were no differences in the incidence of adverse events between placebo week and weeks on active drug. The trial is registered at https://clinicaltrials.gov/ct2/show/study/NCT02286817.

Emerging drugs for the treatment of attention-deficit hyperactivity disorder (ADHD)

“…Fasoracetam is a nonselective agonist of all mGluRs, with a non-clarified dose specificity. Fasoracetam was tested [64] in adolescents with ADHD and mutations in genes connected with the glutamatergic signaling, resulting to be tolerated and efficacious in this selected population. Four other clinical trials have been conducted with fasoracetam in the pediatric age, lasting up to summer 2019, but no results have been published and the sponsor does not have fasoracetam anymore in its pipeline.…”

The role of glutamate receptors in attention‐deficit/hyperactivity disorder: From physiology to disease

“…Memantine, an NMDA receptor antagonist, appeared to improve ADHD symptoms in patients (Findling et al, ; Surman et al, ). Fasoracetam (NFC‐1) was a nonselective metabotropic GluR activator, and adolescents with ADHD, who are carriers of mGluR risk variants, showed clinical improvement using global improvement and severity scales as well as ADHD symptom scales in response to NFC‐1 (Elia et al, ).…”

Genetics and epigenetics of attention deficit hyperactivity disorder

“…GWAS показали, что серотонинергические аллели генов ассоциированы с повышенным риском развития СДВГ, при этом каждый локус индивидуально оказывает умеренное влияние на общий риск [15]. У больных с СДВГ с мутациями в гене метаботропных глутаматных рецепторов mGluR эффективно применяется активатор метаботропных глутаматных рецепторов, устраняющий симптомы болезни [16]. Дефицит экспрессии гена NDRG2 (N-myc downstream-regulated gene-2) вовлечен в развитие СДВГ у человека и мышей.…”