A pilot open label, single dose trial of fenobam in adults with fragile X syndrome

Abstract

Objective:A pilot open label, single dose trial of fenobam, an mGluR5 antagonist, was conducted to provide an initial evaluation of safety and pharmacokinetics in adult males and females with fragile X syndrome (FXS). Methods: Twelve subjects, recruited from two fragile X clinics, received a single oral dose of 50-150 mg of fenobam. Blood for pharmacokinetic testing, vital signs and side effect screening was obtained at baseline and numerous time points for 6 h after dosing. Outcome measures included prepulse inhibition (PPI) and a continuous performance test (CPT) obtained before and after dosing to explore the effects of fenobam on core phenotypic measures of sensory gating, attention and inhibition.Results: There were no significant adverse reactions to fenobam administration. Pharmacokinetic analysis showed that fenobam concentrations were dose dependent but variable, with mean (SEM) peak values of 39.7 (18.4) ng/ml at 180 min after the 150 mg dose. PPI met a response criterion of an improvement of at least 20% over baseline in 6 of 12 individuals (4/6 males and 2/6 females). The CPT did not display improvement with treatment due to ceiling effects. Conclusions: Clinically significant adverse effects were not identified in this study of single dose fenobam across the range of dosages utilised. The positive effects seen in animal models of FXS treated with fenobam or other mGluR5 antagonists, the apparent lack of clinically significant adverse effects, and the potential beneficial clinical effects seen in this pilot trial support further study of the compound in adults with FXS.Fragile X syndrome (FXS) is the most common inherited form of intellectual disability, autism, and learning disability, with a broad range of severity and full mutation gene frequency of 1/2500.1 FXS results from an unstable trinucleotide repeat expansion of .200 CGG repeats (full mutation) in the promoter of the FMR1 (fragile X mental retardation-1) gene 2 which leads to transcriptional silencing of FMR1 and thus, absence or significant reduction of the FMR1 protein (FMRP). 3Because FMR1 is located on the X chromosome, females with a full mutation are more mildly affected than males, due to production of FMRP from the normal FMR1 allele on the non-mutated X chromosome. FMRP is an RNA binding protein which modulates dendritic maturation and synaptic plasticity through mechanisms including inhibition of group 1 metabotropic glutamate receptor (mGluR1 and mGluR5) mediated mRNA translation in dendrites. [4][5][6][7]

Review of targeted treatments in fragile X syndrome

“…In an open label, single-dose trial of fenobam in 12 adults with FXS (6 males and 6 females), half of the subjects showed at least 20% improvement in prepulse inhibition (PPI) -a measure of sensory gating -within 1 hour of dosing, and most subjects showed clinical improvement in areas of hyperactivity and anxiety (21). It was also well tolerated in these participants and no serious adverse events were reported.…”

Neurobehavioral features and targeted treatments in fragile X syndrome: Current insights and future directions

“…Fenobam single-dose was found to be safe in a small pilot trial of adults with FXS. The trial showed improvements in hyperactivity and anxiety, and in prepulse inhibition [86]. As noted earlier, this work is important to delineate neurobiological phenotypes within FXS but can be only demonstrated through double-blind, randomized, placebo-controlled studies.…”

Fragile X syndrome due to a missense mutation

“…6 This mimics excessive group 1 metabotropic glutamate receptor signaling, which is an insight that has initiated several FXS clinical trials with therapeutic approaches directly targeting this pathway. [7][8][9] FXS is almost exclusively diagnosed by molecular testing for CGGrepeat expansion, even though the causal link to FXS is not directly because of repeat expansion but rather because of the loss of the encoded FMR protein. This CGG-repeat test is among the most frequently ordered genetic tests and is standard of care for any child not meeting developmental milestones.…”