A group of UCL researchers is beginning a £500,000 clinical trial to examine the effects of a novel drug that modulates communication between nerve cells in the brain.
The team will study both healthy volunteers and patients with a neurological condition to determine whether the drug normalises levels of short-interval intracortical inhibition (SICI), using a measure of transcranial magnetic stimulation (TMS) a non-invasive method to cause depolarization or hyperpolarization in the neurons of the brain.
Firstly the study will investigate how the AZD7325 drug affects motor control in healthy volunteers. This will be done by studying SICI using TMS. This application of short, painless, magnetic impulses over the brain stimulates neurons and so evokes movements. This will allow the team to define a dose that enhances SICI suitable to be taken forward into clinical trials investigating neurological diseases.
The team will then study a patient population with focal dystonia, a neurological condition affecting a muscle or group of muscles in the body causing involuntary muscular contractions, abnormal posture and impaired voluntary motor control in whom SICI is abnormally reduced.
Nerve cells communicate through chemicals called neurotransmitters, which can be divided into two categories: excitatory and inhibitory. Inhibitory neurotransmitters are important as they control the stimulus of neural networks. GABA (gamma-aminobutyric acid), the chief inhibitory neurotransmitter in the central nervous system acts through various receptors. These receptors have been targeted by many medicines for the treatment of a number of very prevalent diseases including epilepsy, insomnia, anxiety and depression.
BRC-supported Professor Martin Koltzenburg, who was awarded the grant by the joint Medical Research Council/AstraZeneca scheme, said: “Previous work has shown that AZD7325 binds to a GABA receptor in the brain. We now want to use a neurophysiological biomarker to positively demonstrate that it functionally engages the relevant receptors.
“Having proof of target engagement in patients is a powerful tool in early clinical drug development. It allows us to directly compare the effect of receptor modulation with the clinical response. This approach addresses a critical point in drug development, the ‘valley of death’ as it is sometimes called. Every year hundreds of novel drugs are developed in laboratories, but less than three dozen become licensed for clinical use”.
Professor Koltzenburg concluded: “We need to understand why so many drugs do not make it. The lack of effect in a small patient cohort study is always difficult to interpret, but if we have clear proof of target engagement, the disappointment of a failed clinical trial will turn into a valuable lesson that a postulated disease mechanism may not be important or cannot be harnessed for therapy.”
