Effect of the mGluR5-NAM Basimglurant on Behavior in Adolescents and Adults with Fragile X Syndrome in a Randomized, Double-Blind, Placebo-Controlled Trial: FragXis Phase 2 Results

Abstract

Preclinical data suggest that inhibition of the metabotropic glutamate receptor 5 (mGluR5) receptor might hold therapeutic benefits in Fragile X syndrome (FXS). Treatment of Fmr1 knockout mice with mGluR5-negative allosteric modulators (NAMs) has been reported to correct a broad range of phenotypes related to FXS. The early short-term clinical trials with mGluR5 NAMs, including basimglurant, assessing the effects in individuals with FXS, were supportive of further exploration in larger, well-controlled trials. We evaluated basimglurant, a potent and selective mGluR5 NAM, in a 12-week, double-blind, parallel-group study of 183 adults and adolescents (aged 14-50, mean 23.4 years) with FXS. Individuals with an FMR1 full mutation were randomized to placebo or one of two doses of basimglurant. The primary efficacy endpoint was the change from baseline in behavioral symptoms using the Anxiety Depression and Mood Scale (ADAMS) total score. All treatment arms showed marked behavioral improvements from baseline to week 12 with less improvement in the basimglurant 1.5 mg arm than placebo; however, basimglurant 0.5 mg was inferior to placebo in the ADAMs total score. Treatment with basimglurant was overall well-tolerated. A higher incidence of adverse events classified as psychiatric disorders were reported in patients treated with basimglurant, including three patients with hallucinations or psychosis. In this phase 2 clinical trial, basimglurant did not demonstrate improvement over placebo. Evaluation of the overall risk-benefit in younger patient populations is an important consideration for the design of potential further investigations of efficacy with this class of medications.

Figure 1

Change from baseline in ADAMS Total scores at each visit (ITT). A decrease in the ADAMS total score indicates improvement. Both basimglurant treatment groups showed no improvement over placebo.

Figure 2

Biomarker analysis of FMR1 promoter methylation, FMR1 mRNA and FMRP in study patients. The figure shows the frequency distribution of biomarker data. Data of patients were distributed over 50 bins and frequency of appearance is depicted on the Y-axis. Male-derived samples are in solid black and Female in blue bars. (a) Levels of FMRP in whole blood in pM. Most of the male patients had no detectable levels of FMRP in the blood (0 pM). (b) Levels of FMR1 mRNA expressed as delta CT values. Note that delta Ct values over 6 are not considered to represent quantifiable levels of mRNA but rather unspecific noise as judged by the CP curves. (c) Methylation of the FMR1 promoter expressed in percent methylation of analyzed methylation sites.