Safety and Exploratory Efficacy of Basimglurant in Pediatric Patients with Fragile X Syndrome: A Randomized, Double-Blind, Placebo-Controlled Study

Background:  Fragile X syndrome (FXS) is the most commonly inherited cause of mental retardation due to a mutation on the 5’-untranslated region of the FMR1 gene in the X chromosome.  It has been hypothesized that metabotropic glutamate receptor 5 (mGlu5) antagonism may revert the pathophysiological abnormalities observed in FXS.  Preclinical evidence showed that chronic treatment of FMR1knockout mice with an mGlu5-negative allosteric modulator (NAM) rescues a broad range of phenotypes associated with FXS.  Basimglurant is a potent, selective mGlu5 NAM with good oral bioavailability, brain penetration, and high in-vivo potency.

Objectives:  The primary objective was to evaluate the safety and tolerability of modified release basimglurant in comparison with placebo in pediatric patients with FXS.  The secondary objective was to explore the efficacy and pharmacokinetics of 12-week treatment of basimglurant.

Methods:  This is a phase IIa, randomized, double-blind, parallel arm, 12-week study of basimglurant or placebo, once daily, in children 5 to 13 years old with FXS.  Doses of basimglurant were selected to target exposures in the pediatric population to match the adult steady state exposures at 0.5 mg (dose A) and 1.5 mg (dose B).  Safety outcomes assessed included the incidence of spontaneously reported adverse events, clinical assessment of suicidality, clinical laboratory tests, vital signs, weight, Tanner staging, menstrual status and ECG assessments. Exploratory efficacy assessments included the Anxiety, Depression, and Mood Scale, Clinical Global Impression – Improvement and Severity scales, Aberrant Behavior Checklist, Repeatable Battery for the Assessment of Neuropsychological Status – Immediate Memory, Visual Analog Scale – Most Troubling Symptom, Global Behavior Assessment Scale, and Expressive Language.  Blood samples were collected to explore the drug effect in the biomarker subgroups (FMR1 methylation, RNA and FMRP). Pharmacokinetic was also explored.

Results:  A total of 47 patients at 14 centers in the United State were randomized to basimglurant dose A (n=15), basimglurant dose B (n=15) or placebo (n=17).  Overall, the incidence of adverse events (AE) were similar across treatment arms except for aggression which was more frequent in the basimglurant arms and headache which occurred more in the placebo arm.  The most common AEs were upper respiratory tract infection, aggression, vomiting, headache, and pyrexia.  The majority of AEs were mild or moderate in intensity. There were no serious AEs, no reports of suicidality and no AEs that led to withdrawal of study treatment.  No clinically relevant changes in any of the other safety outcomes were observed.  The statistical analyses of the mean change from baseline at week 12 for basimglurant dose A and dose B compared with placebo did not reveal relevant differences on any of the exploratory efficacy measures or within any biomarker subgroups. 

Conclusions:  Basimglurant was generally safe and well tolerated in children age 5 to 13 years old with FXS.  The overall incidence of AEs was similar across treatment arms except for aggression which occurred with higher frequency in the basimglurant dose arms compared to placebo.  In the exploratory efficacy analyses, basimglurant dose A and dose B were not statistically different from placebo.