Schizophrenia remains a major healthcare challenge throughout the world. According to the World Health Organisation it affects almost one in 100 people. Schizophrenia is characterized by distortions in thinking, perception, emotions, language, sense of self and behaviour. Patients with the condition have a poor quality of life and prognosis.
Antipsychotics are the main treatment but in up to a third of people with schizophrenia, the illness shows a poor response to these drugs. Particularly debilitating are cognitive symptoms of schizophrenia, such as poor decision making, attention and memory, and negative symptoms, such as social withdrawal and anhedonia, which make work and relationships difficult to sustain. Side effects of the currently approved antipsychotic drugs are also problematic, including weight gain, diabetes, heart disease, movement disorders and sexual dysfunction. There is a clear need for more effective drugs with fewer side effects.
There is increasing interest in the use of central biomarkers, based on electroencephalographic (EEG) responses to auditory stimuli, in the assessment of new mechanisms of treating schizophrenia, used alongside cognitive function testing and brain imaging (functional MRI, and positron emission tomography).
See ‘The Abandoned Illness’, a report by the Schizophrenia Commission, November 2012.
AUT00206 for the treatment of Schizophrenia
AUT00206 is a novel, orally active small molecule designed to modulate Kv3 potassium channels with increased potency and selectivity over previous compounds. Phase I testing has shown that the drug is safe and well tolerated.
Preclinical studies using models relevant to the pathophysiology of schizophrenia suggest that AUT00206 has the potential to treat cognitive and negative symptoms of schizophrenia, as well as positive symptoms with fewer side effects than current anti-psychotic drugs. Cognitive and negative symptoms are poorly treated by antipsychotic drugs and are associated with significant functional impairment and reduced quality of life for patients.
AUT00206 is currently being tested in two Phase Ib biomarker studies:
- A study in healthy volunteers employing a ketamine challenge, in collaboration with Professor Bill Deakin at the University of Manchester.
- A study in patients with schizophrenia, in collaboration with King’s College London, with Professor Oliver Howes as Principal Investigator. This study is designed to test the safety, tolerability and pharmacokinetics of AUT00206 in patients with schizophrenia, and also explores the effects of AUT00206 on relevant central biomarkers.
This project has been underpinned by a four-year collaboration with the Universities of Manchester and Newcastle, who have explored the effects of AUT00206 in preclinical models of brain pathophysiology relevant to schizophrenia.
This successful collaboration between academia and industry to explore the Kv3 modulation mechanism of action has been made possible by Innovate UK and Medical Research Council funding contributed through the UK’s Biomedical Catalyst.
Rationale for Kv3 modulation to treat schizophrenia
Accumulating evidence supports a central role for fast spiking GABAergic interneurons in the pathophysiology of schizophrenia. Dysfunction of the-se interneurons, which is associated with reductions in the calcium binding protein, parvalbumin (PV) leads to disinhibition of cortical circuitry, dysregu-lation of gamma oscillations, and is thought to contribute to cognitive defi-cits observed in patients with schizophrenia (Lewis et al. TiNS 2012; 35: 57–67).
Voltage gated, Kv3.1 potassium channels are selectively expressed by PV interneurons in cortical circuits, where they permit rapid and accurate firing necessary to synchronise the coordinated firing of pyramidal principle neu-rons at gamma frequencies. Kv3.1 channels are found to be reduced in un-medicated schizophrenia patients (Yanagi et al. Mol Psychiatry 2014; 19: 573-579). Modulation of this channel may therefore provide a means to re-store PV interneuron function in schizophrenia patients, and improve cogni-tive and perhaps, negative symptoms, an unmet clinical need.