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://ichgcp.net/clinical-trials-registry/NCT02286817 .

Conflict of interest statement

H.H. is the founder of NeuroFix, served on its Advisory Board and has stock or equity in neuroFix Therapeutics LLC, which is now owned by Aevi Genome Medicine Inc. H.H. was not involved with the evaluation of the study participants. All of the clinical evaluations were performed by J.E. and W.K.K. and their staff, none of whom have any competing interests, or any affiliation with neuroFix. All of the statistical analysis was done based on a predesigned SAP by an independent statistician as work for hire from a locked database. The remaining authors declare no competing financial interests.

Figures

Fig. 1

Week by week box-and-whisker plots showing the results for the CGI-I (a–d) and CGI-S (e–h) scaled inventories for all study subjects (a, e) or stratified by genetic tiers (Tier 1 (b, f), Tier 2 (c, g), and Tier 3 (d, h)). P-values denote results of the paired Student’s t-test between results from study baseline (week 1) and final (week 5). N = 30. The edges of the box plots denote 25 and 75% tiles, while the solid black horizontal line denotes the cohort median. Upper and lower whiskers denote the limits of the nominal range of the data inferred from the upper and lower quartiles (Methods section) and plotted points are outliers from these ranges

Fig. 2

Net differences in the distribution of a CGI-I, b CGI-S, c Vanderbilt, and d Brief global scales between week 1 (placebo; green) and the final (max dose; orange) week of the study shown as box plots. Patients were stratified by genetic tier group allocation. P-values denote results of the paired Student’s t-test between results from study baseline (week 1) and final (week 5) for each tier. Statistically significant comparisons are highlighted with red asterisks. N = 30. The edges of the box plots denote 25 and 75% tiles, while the solid black horizontal line denotes the cohort median. Upper and lower whiskers denote the limits of the nominal range of the data inferred from the upper and lower quartiles (see Methods) and plotted points are outliers from these ranges