Profiling novel GABA agonists

‘Pharmacological activity at different subunits of the GABA-A receptor is responsible for the various clinical CNS effects of non-selective GABA agonists such as benzodiazepines,’ says Dr Gabriel Jacobs, Research Director in Psychiatry. ‘We know that the α1 subunit mediates undesirable GABA-ergic effects, such as drowsiness and memory impairment. In contrast, converging evidence from preclinical and clinical experiments suggests that the α2 and α3 subunits might be implied in the anxiolytic and antiepileptic effects of GABA agonists.’

Several companies are currently developing compounds with selective activity at the α2 and α3 subunits of the GABA-A receptor. ‘We’ve had the opportunity to study a number of these compounds on behalf of various clients in recent years,’ says Dr Laura Borghans, neuropsychologist and Senior Clinical Scientist in the Psychiatry group. ‘It’s exciting to investigate whether novel subtype-selective GABA compounds live up to the promise shown in preclinical studies.’

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NeuroCart and EEG

‘In 2022, we conducted studies with two different selective GABA-A α2,3,5 positive allosteric modulators (PAMs),’ says Dr Pauline Nettesheim, Clinical Scientist and Research Physician. ‘Engrail Therapeutics, the client developing these compounds, was keen to know more about their clinical CNS profile in humans and whether this would turn out to be much different from the non-selective GABA PAMs.’ Drawing on previous experience with GABA PAMs, such as TPA023, NS11821, AZD7325/6280 and darigabat, the team was able to set up studies to profile both agents.

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‘We followed a very similar protocol for both agents, which meant that we could compare the results,’ says Borghans. In addition to a thorough investigation of pharmacokinetics, the team used EEG and NeuroCart® measures to gain additional insight into drug effects. EEG measurements can provide useful information about the CNS characteristics of a compound. In addition, the NeuroCart offers several measures that can be used to identify desired and undesired effects. For example, body sway can indicate drowsiness and reduced psychomotor control (fall risk). In addition, saccadic eye movements can indicate an anxiolytic effect — especially in the absence of drowsiness, as measured using visual analogue scales.

In both studies, the drug was administered over several days, reaching a plateau in blood levels. ‘This approach is expected to correspond to the potential indication of each compound as maintenance treatment for anxiety disorders and/or epilepsy,’ says Borghans. EEG and NeuroCart measurements were performed prior to administration of the drug, on the first day of treatment, and at plasma steady state. ‘We’re currently interpreting the results of the two studies. Although we can’t draw definitive conclusions yet, it’s clear that we’ve been successful in characterising these compounds, providing the client with valuable insight.’

Carbon dioxide inhalation challenge

Moving into patient populations requires significant financial investment. As a result, clients are often seeking additional confidence in the potential efficacy of novel CNS drugs in the earlier phases of development. CHDR supports clients by offering experimental medicine models to demonstrate relevant drug effects in healthy volunteers. One such model is the carbon dioxide (CO2) inhalation challenge. In combination with EEG and NeuroCart measures, this challenge model can shed light on the anxiolytic efficacy of a compound in healthy volunteers, and can be used to derisk compounds with regard to unwanted effects.

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‘The principle is rather straightforward,’ explains Dr Koshar Safai Pour, Clinical Scientist and Research Physician. ‘In approximately 50% of people without a personal or family history of anxiety or depression, inhaling air with a relatively high ratio of CO2 to oxygen will trigger symptoms resembling those of a panic attack. In our clinical studies, we can use this to compare the occurrence and the intensity of CO2-induced panic under placebo to its occurrence following administration of an active drug.’ The model is most informative if the compound has reached steady state plasma concentrations. Therefore, subjects are asked to take the medication for a certain period of time to achieve steady state before the challenge test.