Effect of CX516, an AMPA-Modulating Compound, on Cognition and Behavior in Fragile X Syndrome: AControlled Trial

Abstract

A Phase II, 4-week randomized, double-blind, placebo-controlled clinical trial was conducted to evaluate the safety and efficacy of the Ampakine compound CX516 as a potential treatment for the underlying disorder in fragile X syndrome (FXS). After baseline screening, subjects with FXS (n = 49) underwent a 1-week placebo lead-in and then were randomized to study drug or placebo for a 4-week period. Cognitive and behavioral outcome measures were administered prior to treatment, at the end of treatment, and 2 weeks posttreatment. There were minimal side effects, no significant changes in safety parameters, and no serious adverse events. There was a 12.5% frequency of allergic rash in the CX516 group and 1 subject developed a substantial rash. There was also no significant improvement in memory, the primary outcome measure, or in secondary measures of language, attention/executive function, behavior, and overall functioning in CX516-treated subjects compared to placebo. This study did demonstrate that many outcome measures were reproducible in this test-retest setting for the FXS population, yet some were too difficult or variable. Adult subjects with FXS were able to complete an intensive clinical trial, and some valid outcome measures were identified for future FXS trial design. Problems with potency of CX516 in other studies have suggested dosing may have been inadequate for therapeutic effect and thus it remains unclear whether modulation of AMPA-mediated neurotransmission is a viable therapeutic strategy for the treatment of FXS.

Therapeutic Strategies in Fragile X Syndrome: Dysregulated mGluR Signaling and Beyond

“…A double-blind placebo-controlled trial of effects of CX516 (Cortex Pharmaceuticals) on safety and cognitive and behavioral efficacy measures was carried out in a cohort of 49 individuals with FXS (Berry- Kravis et al, 2006). CX516 is a direct AMPA receptor positive modulator or 'ampakine' known to increase LTP and raise BDNF levels, thus potentially increasing surface expression of AMPA receptors (Jourdi et al, 2009).…”

“…It is very difficult to identify good cognitive outcome measures for drug effect that can be performed by FXS subjects crossing the entire range of function because of problems with basal scores and ceilings (Berry-Kravis et al, 2006, 2009, and more work to validate appropriate measures is needed. Predicting the outcome that will improve most in a complex disorder during initial trials is essentially guesswork, when the treatment targets the underlying disorder and not a specific behavior.…”

“…Outcome measures chosen need to test a broad ability range to prevent low or high-functioning individuals from showing ceiling or floor effects, overcome problems with cooperation and variable performance, be shown to be reproducible, and quantify core defects and correlate with quality of life and true functional improvement. Only a subset of outcome measures utilized in recent trials have turned out to fulfill the majority of these criteria (Berry-Kravis et al, 2006) suggesting better, FXS-specific measures are needed. Only recently have investigators begun to develop templates to test the feasibility, reproducibility, and validity assessment before using the measure in a trial (Berry-Kravis et al, 2008b;Hessl et al, 2009;Knox and Berry-Kravis, 2009;Farzin et al, 2011).…”

The cyclic AMP phenotype of fragile X and autism

“…The basis for FX treatment with AMPAkines is to enhance the open duration of the remaining AMPA receptors to promote strengthening at the synapse (Berry-Kravis and Potanos 2004). Results from a recent clinical trial of AMPAkines were inconclusive based on low dosing (Berry-Kravis, Krause et al 2006). Pharmacologic rescue of FX Drosophila behavior by an mGluR antagonist supports the mGluR theory (McBride, Choi et al 2005).…”

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

“…That is to say, none of the aforementioned most recent clinical studies have addressed the core FXS plasticity deficit that would translate to changes in cognitive and learning measures; to date, only one study published a decade ago by Berry-Kravis and colleagues (2006) [90] targeted cognition using CX516, an AMPA activator. AMPA com pounds are potential treatments acting within the glutamate signaling pathway, which are excessively internalized as a result of increased mGlur5 signaling after the loss of FMRP.…”