Effect of Two Doses of Basimglurant on Behavioral Symptoms in Adolescent and Adult Patients with Fragile X Syndrome; Results from Fragxis, a Double-Blind, Placebo Controlled Study

Background:  Recent research in Fragile X syndrome (FXS), an X-linked condition caused by a CGG-repeat expansion in the FMR1 gene, has focused on the metabotropic glutamate receptor 5 (mGlu5) antagonism as a mechanism to treat the behavioral and cognitive impairments observed in FXS.  Preclinical evidence has shown that chronic treatment of FMR1knockout mice with an mGlu5-negative allosteric modulator (NAM) rescues a broad range of phenotypes associated with FXS.  Basimglurant, a potent, selective mGlu5-NAM, has previously shown a trend for improvement in a placebo-controlled study of 40 adult patients with FXS, warranting further investigation.

Objectives:  To evaluate the efficacy, safety and tolerability of basimglurant MR 12-week treatment versus placebo in patients with FXS.

Methods:  Adolescents and adults (age 14 to 50 years) with FXS were randomized to basimglurant 0.5 mg, basimglurant 1.5 mg, or placebo for 12 weeks. The primary efficacy endpoint was the change from baseline to week-12 in the ADAMS total score. The secondary efficacy endpoints were Clinical Global Impression–Severity and Improvement Scales (CGI-S and CGI-I), Aberrant Behavior Checklist (ABC) total and factor scores, ADAMS factor scores, Social Responsiveness Scale (SRS), Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)–Immediate Memory, Vineland Adaptive Behavior Scale II (VABS) total and domain scores, Clinical response (ABC total improvement ≥25% + CGI-I ≤2) and the Visual Analog Scale (VAS)-Most Troubling Behavioral Symptoms. Safety outcomes included the incidence of spontaneously reported adverse events (AE), clinical assessment of suicidality, clinical laboratory tests, vital signs, weight, Tanner staging, menstrual status and ECGs. Efficacy in biomarker subgroups (either FMR1 methylation status, FMR1mRNA delta count, or Fragile X Mental Retardation Protein (FMRP) concentration) and subgroups based on age and sex were also explored.

Results:  A total of 185 patients were randomized from 39 centers in North America, Latin America and Europe: 60 to basimglurant 0.5 mg, 62 to basimglurant 1.5 mg and 63 to placebo.  63 were adolescents (14 -17 years) and 122 were adults (18-50 years). Basimglurant treatment groups showed no improvement over placebo in the primary efficacy endpoint.  Basimglurant did not demonstrate meaningful improvement over placebo in any of the secondary efficacy measures and biomarker subgroups.  Neither subgroup analysis, males versus females nor adolescents versus adults, showed any improvements for basimglurant over placebo. The incidence of AEs was similar across treatment groups and they were mostly mild to moderate in severity. The most common AEs were vomiting, nasopharyngitis, and headache.  A higher number of patients discontinued due to psychiatric adverse events in the basimglurant 0.5 and 1.5mg groups (n=4 for both groups) as compared to placebo (n=1). No clinically relevant changes in any of the other safety outcomes were observed.  

Conclusions:  Basimglurant showed no improvement over placebo in either the primary and secondary efficacy endpoints or the biomarker subgroups.  Treatment with basimglurant was generally safe and well tolerated in adolescents and adults (aged 14 to 50 years) with FXS.