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Abstract Background There 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. Methods Basmisanil, 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. Results Basmisanil 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. Conclusions Basmisanil 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 registration The study was registered on December 31, 2013, at clinicaltrials.gov as NCT02024789.

Abstract GABAA-α5 subunit-containing receptors have been shown to play a key modulatory role in cognition and represent a promising drug target for cognitive dysfunction, as well as other disorders. Here we report on the preclinical and early clinical profile of a novel GABAA-α5 selective negative allosteric modulator (NAM), basmisanil, which progressed into Phase II trials for intellectual disability in Down syndrome and cognitive impairment associated with schizophrenia. Preclinical pharmacology studies showed that basmisanil is the most selective GABAA-α5 receptor NAM described so far. Basmisanil bound to recombinant human GABAA-α5 receptors with 5 nM affinity and more than 90-fold selectivity versus α1, α2, and α3 subunit-containing receptors. Moreover, basmisanil inhibited GABA-induced currents at GABAA-α5 yet had little or no effect at the other receptor subtypes. An in vivo occupancy study in rats showed dose-dependent target engagement and was utilized to establish the plasma exposure to receptor occupancy relationship. At estimated receptor occupancies between 30 and 65% basmisanil attenuated diazepam-induced spatial learning impairment in rats (Morris water maze), improved executive function in non-human primates (object retrieval), without showing anxiogenic or proconvulsant effects in rats. During the Phase I open-label studies, basmisanil showed good safety and tolerability in healthy volunteers at maximum GABAA-α5 receptor occupancy as confirmed by PET analysis with the tracer [11C]-Ro 15-4513. An exploratory EEG study provided evidence for functional activity of basmisanil in human brain. Therefore, these preclinical and early clinical studies show that basmisanil has an ideal profile to investigate potential clinical benefits of GABAA-α5 receptor negative modulation.

ABSTRACTObjective:The primary objective of this study was to investigate the drug–drug interaction potential of dalcetrapib on drugs metabolized via major cytochrome P450 (CYP) isoforms using both in vitroand clinical approaches. A secondary objective was to investigate the safety and tolerability of dalcetrapib alone or co-administered either with a combination of five probe drugs or with rosiglitazone.Research design and methods:Human liver microsomes and a panel of substrates for CYP enzymes were used to determine IC50for inhibition of CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. In addition, two drug–drug interaction studies were conducted in healthy males: dalcetrapib 900 mg plus the Cooperstown 5  1 drug cocktail, which includes substrates for CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4, and dalcetrapib 900 mg plus rosiglitazone, a substrate for CYP2C8. Pharmacokinetic and safety parameters were assessed.Results: In vitro, dalcetrapib was inhibitory to all CYP enzymes tested. IC50values ranged from 1.5 ± 0.1 μM for CYP2C8 to 82 ± 4 μM for CYP2D6. Co-administration of dalcetrapib plus drug cocktail showed no clinically relevant effect of 900 mg dalcetrapib on activity of CYP1A2, CYP2C19, CYP2D6, CYP2C9, or CYP3A4 following repeated administration. Co-administration of dalcetrapib plus rosiglitazone showed no clinically relevant effect of dalcetrapib 900 mg on activity of CYP2C8. Dalcetrapib was generally well tolerated.Conclusions: Although in vitrostudies indicated that dalcetrapib inhibits CYP activity, two clinical studies showed no clinically relevant effect on any of the major CYP isoforms at a 900 mg dose, which is higher than the 600 mg dose being explored in phase III studies. Dalcetrapib was generally well tolerated in these studies. However, these studies were limited to a small number of healthy males; additional, larger studies are necessary to study its safety. [ABSTRACT FROM AUTHOR]