Basmisanil, a highly selective GABAA-α5 negative allosteric modulator: preclinical pharmacology and demonstration of functional target engagement in man

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.

A randomized, double-blind, placebo-controlled phase II trial to explore the effects of a GABAA-α5 NAM (basmisanil) on intellectual disability associated with Down syndrome

“…The absence of an alpha peak in the baseline EEG power spectrum is in line with previous findings in adults with DS reporting a shift to lower frequencies [29][30][31]. The basmisanil-induced pharmacodynamic effects, i.e., an increase in theta power (~4 Hz), and a decrease in beta power (~20 Hz) confirm the spectral signature of basmisanil that we have found previously in healthy volunteers [19] and demonstrate brain circuit engagement. In particular, EEG power in the beta frequency range has been linked to GABA A function through pharmacology [32,33], in rare genetic conditions involving CNVs [34,35] and SNPs in GABA A receptor genes [36,37], and in modeling studies [38,39].…”

“…It is also conceivable that selective modulation of the GABA A -α5 receptor subtype or the maximal inhibitory effect of basmisanil on chloride channel current (~ 40%) [19] may not be sufficient to restore the excitatory/ inhibitory imbalance hypothesized to underlie the cognitive profile of DS [15]. Alternatively, the "excitation/ inhibition imbalance" working hypothesis may be invalid.…”

“…Dose selection was based on an integrated evaluation of pharmacokinetics (PK), pharmacodynamics, PET (BP25611; Additional file 1), and safety data from prior clinical studies with basmisanil in healthy volunteers and adults with DS, coupled with preclinical safety and efficacy data. The aim was to have two effective dosing regimens: the low dose targeted exposures that would result in receptor occupancy in all individuals above a minimum threshold of 60% expected to be required for efficacy based on preclinical models of DS [19]; the high dose was selected to reach exposures predicted to maintain receptor occupancy above a nearmaximal threshold (> 90%).…”

“…Basmisanil (RO5186582, RG1662) is a potent NAM, which combines both binding and functional selectivity at GABA A -α5 subunit-containing receptors and has been shown to improve cognition in rats and monkeys [19]. GABA A -α5 hippocampal receptor occupancy between 30-65% was required for efficacy in preclinical studies [16,19].…”

“…Basmisanil (RO5186582, RG1662) is a potent NAM, which combines both binding and functional selectivity at GABA A -α5 subunit-containing receptors and has been shown to improve cognition in rats and monkeys [19]. GABA A -α5 hippocampal receptor occupancy between 30-65% was required for efficacy in preclinical studies [16,19]. Basmisanil Given the absence of any effective therapy for the intellectual disability associated with DS, the supportive 5-week safety and tolerability profile established in individuals aged 18-30 years with DS (BP25543; Additional file 1) and the potential added benefit of earlier intervention, we aimed to assess the efficacy of extended basmisanil dosing on cognition and adaptive behavior in both adolescents and young adults with DS.…”