Abstract
BackgroundThere are currently no pharmacological therapies to address the intellectual disability associated with Down syndrome. Excitatory/inhibitory imbalance has been hypothesized to contribute to impairments in cognitive functioning in Down syndrome. Negative modulation of the GABAA-α5 receptor is proposed as a mechanism to attenuate GABAergic function and restore the excitatory/inhibitory balance.MethodsBasmisanil, a selective GABAA-α5 negative allosteric modulator, was evaluated at 120 mg or 240 mg BID (80 or 160 mg for 12–13 years) in a 6-month, randomized, double-blind, placebo-controlled phase II trial (Clematis) for efficacy and safety in adolescents and young adults with Down syndrome. The primary endpoint was based on a composite analysis of working memory (Repeatable Battery for the Assessment of Neuropsychological Scale [RBANS]) and independent functioning and adaptive behavior (Vineland Adaptive Behavior Scales [VABS-II] or the Clinical Global Impression-Improvement [CGI-I]). Secondary measures included the Behavior Rating Inventory of Executive Functioning-Preschool (BRIEF-P), Clinical Evaluation of Language Fundamentals (CELF-4), and Pediatric Quality of Life Inventory (Peds-QL). EEG was conducted for safety monitoring and quantitatively analyzed in adolescents.ResultsBasmisanil was safe and well-tolerated; the frequency and nature of adverse events were similar in basmisanil and placebo arms. EEG revealed treatment-related changes in spectral power (increase in low ~ 4-Hz and decrease in high ~ 20-Hz frequencies) providing evidence of functional target engagement. All treatment arms had a similar proportion of participants showing above-threshold improvement on the primary composite endpoint, evaluating concomitant responses in cognition and independent functioning (29% in placebo, 20% in low dose, and 25% in high dose). Further analysis of the individual measures contributing to the primary endpoint revealed no difference between placebo and basmisanil-treated groups in either adolescents or adults. There were also no differences across the secondary endpoints assessing changes in executive function, language, or quality of life.ConclusionsBasmisanil did not meet the primary efficacy objective of concomitant improvement on cognition and adaptive functioning after 6 months of treatment, despite evidence for target engagement. This study provides key learnings for future clinical trials in Down syndrome.Trial registrationThe study was registered on December 31, 2013, at clinicaltrials.gov as NCT02024789.
Highlights
There are currently no pharmacological therapies to address the intellectual disability associated with Down syndrome
This study provides key learnings for future clinical trials in Down syndrome
Chronic treatment with selective G ABAA-α5 negative allosteric modulators (NAMs)—such as α5IA [14], RO4938581 [15], and basmisanil [16]—improved synaptic plasticity and rescued cognitive and behavioral deficits in Ts65Dn mice, without inducing anxiety or convulsions, side effects observed with non-selective GABAA Negative allosteric modulator (NAM) [17, 18]
Summary
There are currently no pharmacological therapies to address the intellectual disability associated with Down syndrome. Negative modulation of the GABAA-α5 receptor is proposed as a mechanism to attenuate GABAergic function and restore the excitatory/inhibitory balance. The etiology of the cognitive disability in people with DS remains unclear, cellular and anatomical abnormalities in the prenatal and perinatal forebrain and cerebellum suggest that early brain development is altered in individuals with DS [5,6,7]. Studies have suggested that the major functional defect in the postnatal Ts65Dn brain may be an imbalance between excitatory and inhibitory circuits [11,12,13]. Inhibition of G ABAA-α5 receptors may represent an attractive mechanism to enhance cognition in individuals with DS
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