Drug Discovery Opinion

Last week, Roche reported data from a 320 patient phase II proof-of-concept study with its first-in-class investigational glycine transporter-1 (GlyT-1) inhibitor, RG1678. Dysfunction of neurotransmission at the NMDA-type glutamate receptor has been implicated in the pathophysiology of schizophrenia, suggesting that enhancement of receptor function may be effective in treating schizophrenia; GlyT-1 inhibitors increase glycine levels and hence NMDA signalling.

Schizophrenia is a chronic, severe and disabling mental health problem that is found all over the world, affecting roughly one per cent of the population. Although men and women are equally affected, men tend to experience symptoms at a slightly earlier age than women, often in their late teens. The symptoms of schizophrenia can be broadly classified as positive, negative or cognitive. Positive symptoms are psychotic behaviours including hallucinations, particularly hearing voices; delusions, or false yet strongly held personal beliefs; and disorders of thinking. Negative symptoms, which are harder to recognise and can be mistaken for depression, include blunted emotions; lack of motivation; an inability to take an interest in, or enjoy, life; and poor social functioning. Cognitive symptoms include problems with working memory and trouble focusing or paying attention.

Antipsychotic medications, which have been available since the mid-1950s and work primarily by suppressing dopamine activity, are the current mainstay of treatment for schizophrenia. These are generally able to reduce hallucinations and delusions and allow patients to function more effectively and appropriately. They are, however, less helpful with negative symptoms such as reduced motivation and emotional expressiveness, which for many patients contribute more to poor quality of life and functional disability than do positive symptoms.

When given as an add-on treatment to patients who were stable on antipsychotic therapy and suffered mainly from negative or disorganised thought symptoms, RG1678 was well tolerated at all doses tested and was able to improve negative symptoms and patients’ personal and social performance, reaching statistical significance on primary and secondary endpoints. The company believes that RG1678, which is being co-developed globally with Chugai, has the potential to enable patients to better establish social relationships and participate in functional activities, reducing the burden for caregivers and patients alike.

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