AUT00206 / Autifony Therap - LARVOL DELTA

Targeted therapy improves cellular dysfunction, ataxia, and seizure susceptibility in a model of a progressive myoclonus epilepsy. (PubMed, Cell Rep Med) - "A Kv3-specific positive modulator (AUT00206) selectively enhances the firing frequency of Kv3.1-expressing neurons and improves motor function and seizure susceptibility in Kcnc1-Arg320His/+ mice. This work identifies a cellular and circuit basis of dysfunction in EPM7 and demonstrates that Kv3 positive modulators such as AUT00206 have therapeutic potential for the treatment of EPM7."

Journal • Ataxia • CNS Disorders • Epilepsy • Movement Disorders

A Potent and Novel Potassium Channel Positive Modulator AUT00201 Attenuates Cellular Dysfunction, Ataxia, and Seizure Susceptibility in a Mouse Model of Progressive Myoclonus Epilepsy Type 7 (AES 2023) - "Previously, we demonstrated that the complex features of EPM7 correlate with the dysfunction of Kv3.1-expressing neurons in distributed brain regions in a novel mouse model of EPM7, Kcnc1-p.Arg320His/+ (H/+) mice, and investigated the therapeutic potential of a Kv3 channel positive modulator, AUT00206. Kcnc1-p.Arg320H/+ mice exhibit progressive ataxia and enhanced seizure susceptibility, and hence reproduce key disease features of, and represent a model for, the study of EPM7. Impaired excitability of Kv3.1-expressing neurons in vitro and indices of cerebellar dysfunction and seizure susceptibility in vivo could be ameliorated with the potent Kv3-channel modulator AUT00201, which may demonstrate therapeutic potential for the treatment of human patients with EPM7."

Preclinical • Ataxia • CNS Disorders • Epilepsy • Movement Disorders

Pharmacological modulation of Kv3 voltage-gated potassium channels regulates fear discrimination and expression in a response-dependent manner. (PubMed, Prog Neuropsychopharmacol Biol Psychiatry) - "We determined the effect of the positive Kv3 modulator AUT00206 given systemically to female rats undergoing limited or extended auditory fear discrimination training, which we have previously shown results in more discrimination or generalization, respectively, based on freezing at retrieval...These results indicate that pharmacological Kv3 modulation regulates fear discrimination and expression in a response-dependent manner. They also raise the possibility that targeting Kv3 channels may ameliorate perturbed cognition and emotional regulation in psychiatric disease."

Journal • CNS Disorders • Mental Retardation • Mood Disorders • Psychiatry • Schizophrenia

Potassium channel modulators and schizophrenia: an overview of investigational drugs. (PubMed, Expert Opin Investig Drugs) - "Early data suggests that dysfunctional GABA interneurons can be ameliorated through modulators of Kv3.1 and Kv3.2 channels. AUT00206 has been shown to improve dopaminergic dysfunction induced by ketamine and PCP, improve resting gamma power in patients with schizophrenia, impact dopamine synthesis capacity in a subgroup of individuals with schizophrenia, and affect reward anticipation-related neural activation."

Journal • CNS Disorders • Psychiatry • Schizophrenia

Targeting GABAergic dysfunction in schizophrenia: potassium channel modulation (KV3.1/2) as treatment targets in schizophrenia - imaging and electrophysiological biomarker findings from a first in patient study. (SIRS 2023) - "This presentation documents three experiments which tested the effects of a novel compound AUT00206, which targets voltage-gated potassium 3.1 (Kv3.1) and 3.2 (Kv3.2) channels expressed on GABAergic parvalbumin-containing neurons, on imaging and electrophysiological biomarkers in people with schizophrenia...Keyword Keywords Parvalbumin Interneurons GABAergic interneurons dopamine synthesis reward anticipation resting state EEG Poster Award No Please list all co-authors for this poster submission. * Presenting Author First Name Last Name Affiliation Stephen * Kaar * Institute of Psychiatry, King's College London Ilinca Angelescu Institute of Psychiatry 2Matthew Nour Max Planck UCL Centre for Computational Psychiatry and Ageing Research, University College London Judith Nottage Institute of Psychiatry, King's College London Tiago Reis Marques King's College London, Institute of Psychiatry, Psychology & Neuroscience, London, UK Charles Large Autifony..."

Biomarker • Clinical • CNS Disorders • Schizophrenia

Gamma Oscillations and Potassium Channel Modulation in Schizophrenia: Targeting GABAergic Dysfunction. (PubMed, Clin EEG Neurosci) - "We also found a significant reduction in frontal gamma power (t = 3.635, P = .003) from baseline in patients who received AUT00206. This provides initial evidence that the Kv3.1/3.2 potassium channel modulator, AUT00206, may address gamma oscillation abnormalities in schizophrenia."

Journal • CNS Disorders • Psychiatry • Schizophrenia

Targeted Therapy Corrects Cellular Dysfunction, Ataxia, and Seizure Susceptibility in a Mouse Model of a Progressive Myoclonus Epilepsy (AES 2022) - "We tested the effect of augmenting Kv3 current with a novel Kv3 channel modulator AUT00206 (AUT6; Autifony Therapeutics Limited) at various concentrations in vitro and in vivo... Kcnc1-p.Arg320H/+ mice exhibit seizure susceptibility and progressive ataxia, and hence represent a model with construct- and face-validity with which to study EPM7. We identified ion channel, cellular, and synaptic dysfunction of Kv3-expressing neurons throughout the brain. Deficits could be reversed with the novel Kv3-channel modulator AUT6, which demonstrates therapeutic potential for the treatment of human patients with EPM7."

Preclinical • Ataxia • CNS Disorders • Epilepsy • Movement Disorders • CLSPN,

The effect of AUT00206, a Kv3 potassium channel modulator, on dopamine synthesis capacity and the reliability of [F]-FDOPA imaging in schizophrenia. (PubMed, J Psychopharmacol) - "These findings support further investigation of Kv3 channel modulators for schizophrenia treatment. [F]-FDOPA PET imaging showed very good test-retest reliability in patients with schizophrenia."

Biomarker • Journal • CNS Disorders • Psychiatry • Schizophrenia

The effects of AUT00206, a novel Kv3.1/3.2 potassium channel modulator, on task-based reward system activation: a test of mechanism in schizophrenia. (PubMed, Psychopharmacology (Berl)) - "Following treatment with AUT00206, there was a significant increase in reward anticipation-related activation in the left associative striatum (t = 4.23, peak-level p(FWE) < 0.05)), but no significant effect in the ventral striatum. This provides preliminary evidence that the Kv3.1/3.2 potassium channel modulator, AUT00206, may address reward-related striatal abnormalities in schizophrenia."

Journal • CNS Disorders • Psychiatry • Schizophrenia

AUT00206, a Novel Kv3.1/3.2 Positive modulator, Normalizes Gamma Oscillations in Patients with Schizophrenia (SIRS 2022) - P1 | "AUT00206 is a novel Kv3.1/Kv3.2 positive modulator that reduced the impact of ketamine on BOLD responses in healthy volunteers (Deakin et al. Treatment with AUT00206 led to a reduction in gamma power (35-45Hz) in frontal and posterior regions during resting state, and to an increase in power of induced gamma oscillations during an oddball paradigm. In contrast, PLF in the gamma range remained unaffected by the treatment. Treatment with AUT00206 was associated with a shortening of the latency to peak power and PLF in the 40 Hz ASSR paradigm without affecting power or PLF in general."

Clinical • CNS Disorders • Schizophrenia

AUT00206, a First-In-Class Kv3 Modulator, Improves Auditory Processing in Patients With Schizophrenia (ACNP 2021) - P1 | "AUT00206 is a novel Kv3.1 modulator that reduced the impact of ketamine on BOLD responses in healthy volunteers [Deakin et al. Treatment with AUT00206 improved measures of auditory information processing at different levels of the auditory system in patients with schizophrenia, consistent with a critical role for Kv3.1 channels in high fidelity information processing and transfer. Treatment with Kv3.1 modulators may not only correct information processing at higher cortical levels, but also ameliorate sensory deficits across all modalities – a novel, but long overdue approach that may help improve symptoms and quality of life through a bottom-up effect in patients with schizophrenia. These results provide the first evidence that targeting PV+ interneuron through modulation of their intrinsic ion channels is an important new approach to the treatment of information processing disorders, such as schizophrenia."

Clinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Psychiatry • Schizophrenia

AUT00206, a First-In-Class Kv3 Modulator, Improves Auditory Processing in Patients With Schizophrenia (ACNP 2021) - P1 | "AUT00206 is a novel Kv3.1 modulator that reduced the impact of ketamine on BOLD responses in healthy volunteers [Deakin et al. Treatment with AUT00206 improved measures of auditory information processing at different levels of the auditory system in patients with schizophrenia, consistent with a critical role for Kv3.1 channels in high fidelity information processing and transfer. Treatment with Kv3.1 modulators may not only correct information processing at higher cortical levels, but also ameliorate sensory deficits across all modalities – a novel, but long overdue approach that may help improve symptoms and quality of life through a bottom-up effect in patients with schizophrenia. These results provide the first evidence that targeting PV+ interneuron through modulation of their intrinsic ion channels is an important new approach to the treatment of information processing disorders, such as schizophrenia."

Clinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Psychiatry • Schizophrenia

[VIRTUAL] AUT00206, a Novel Treatment for Schizophrenia, Improves Auditory Mismatch Negativity and Hearing Performance in Patients (SIRS 2021) - "AUT00206 is a novel Kv3.1 modulator that reduced the impact of ketamine on BOLD responses in healthy volunteers (Deakin et al. Treatment of sensory deficits represents a novel, but long overdue approach that could lead to improvements in the quality of life of patients with schizophrenia. Auditory deficits may be associated with underlying pathology and so targeting Kv3 channels may have a broader efficacy across symptom domains."

Clinical • CNS Disorders • Schizophrenia

[VIRTUAL] AUT00206, a Novel Treatment for Schizophrenia, Improves Auditory Mismatch Negativity and Hearing Performance in Patients (SIRS 2021) - "AUT00206 is a novel Kv3.1 modulator that reduced the impact of ketamine on BOLD responses in healthy volunteers (Deakin et al. Treatment of sensory deficits represents a novel, but long overdue approach that could lead to improvements in the quality of life of patients with schizophrenia. Auditory deficits may be associated with underlying pathology and so targeting Kv3 channels may have a broader efficacy across symptom domains."

Clinical • CNS Disorders • Schizophrenia

[VIRTUAL] AUT00206, a Novel Treatment for Schizophrenia, Improves Auditory Mismatch Negativity and Hearing Performance in Patients (SIRS 2021) - "AUT00206 is a novel Kv3.1 modulator that reduced the impact of ketamine on BOLD responses in healthy volunteers (Deakin et al. Treatment of sensory deficits represents a novel, but long overdue approach that could lead to improvements in the quality of life of patients with schizophrenia. Auditory deficits may be associated with underlying pathology and so targeting Kv3 channels may have a broader efficacy across symptom domains."

Clinical • CNS Disorders • Schizophrenia

[VIRTUAL] AUT00206 improves speech in noise recognition in patients with schizophrenia (ECNP 2020) - "AUT00206 is a novel Kv3.1 modulator that reduced the impact of ketamine on BOLD responses in healthy volunteers [5]. Treatment of sensory deficits represents a novel, but long overdue approach to managing and improving the quality of life of patients with schizophrenia. Although not considered a core symptom of schizophrenia, central auditory deficits may be associated with underlying pathology and thus targeting Kv3 channels may have a broader efficacy across symptom domains."

Clinical • CNS Disorders • Psychiatry • Schizophrenia

Boehringer calls off €627M deal with GSK spinout, passing on schizophrenia drug option (Endpoints News) - "Boehringer Ingelheim has walked away from a schizophrenia program it once called an 'unprecedented therapeutic concept,' taking €627.5 million off the table for its biotech partner. Stevenage, UK-based Autifony noted that over the past three years, it’s collaborated with Boehringer to demonstrate target engagement, biomarker data and safety for its lead Kv3 modulator, AUT00206, as well as moving a second molecule into Phase I."

Licensing / partnership • CNS Disorders • Schizophrenia

A Novel Treatment for Cognitive Impairment Associated With Schizophrenia by Enhancing the Activity of Parvalbumin Interneurons (SIRS 2019) - "We have shown that positive modulation of Kv3 channels with a novel drug, AUT00206 can enhance the activity of PV interneurons and rescue cognitive function in animal models...The interim analysis of the phase 1b CANTAB data, an exploratory endpoint, in about 2/3 of the intended sample support previous findings that patients with schizophrenia are heterogeneous. In light of this finding, we will explore the data for correlations between baseline cognitive performance and treatment outcome"

CNS Disorders • Schizophrenia

AUT00206, a Novel Kv3 Channel modulator, Reduces Ketamine-Induced Bold Signalling in Healthy Male Volunteers: A Randomised Placebo-Controlled Crossover Trial (SIRS 2019) - "The results are also consistent with results from the rodent ketamine-challenge model. These results are promising for the potential use of AUT00206 in the treatment of disorders associated with reduced cortical inhibitory function, such as schizophrenia."

Clinical • CNS Disorders • Schizophrenia • MRI

Safety, Tolerability and Pharmacokinetics of AUT00206 in Patients With Schizophrenia, and Also Explores the Effects of AUT00206 on Relevant Central Biomarkers. (clinicaltrials.gov) - P1; N=24; Completed; Sponsor: Autifony Therapeutics Limited; Active, not recruiting ➔ Completed; Trial completion date: Aug 2019 ➔ Apr 2019

Biomarker • Clinical • Trial completion • Trial completion date

Safety, Tolerability and Pharmacokinetics of AUT00206 in Patients With Schizophrenia, and Also Explores the Effects of AUT00206 on Relevant Central Biomarkers. (clinicaltrials.gov) - P1; N=24; Active, not recruiting; Sponsor: Autifony Therapeutics Limited; Recruiting ➔ Active, not recruiting

Biomarker • Clinical • Enrollment closed