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Autifony Therapeutics Continues Evaluation of AUT00206 for the Treatment of Schizophrenia

Posted on 12 January 2017

Autifony Therapeutics recently presented a poster at the American College of Neuropsychopharmacology (ACNP) Annual Meeting following their first human Phase I study in healthy male volunteers to investigate a novel treatment for the positive, negative and cognitive symptoms of schizophrenia. AUT00206 is an oral molecule that was designed to selectively modulate Kv3 potassium channels, which are thought to be associated with the brain circuits that are dysfunctional in schizophrenia.

Impaired cognition (specifically decision making, attention and memory) is a core feature of schizophrenia and as yet no pharmacological treatment has been approved for the treatment of these symptoms, highlighting the importance of this research. CANTAB tests were used alongside clinical rating scales, ERPs and imaging, at various time points to explore the cognitive effects in the target patient population. The study results supported the continuation of AUT00206, and the next phase will examine the compound in a population of patients who have been diagnosed with schizophrenia in the past 5 years.


Abstract as presented at ACNP:

T161. Early Clinical Evaluation of AUT00206, a Novel Selective Kv3 Channel Modulator for the Treatment of Schizophrenia

John Hutchison*, Anil Sajjala, Omair Sahgal, Bill Deakin, Oliver Howes, Colin Dourish, Giuseppe Alvaro, Charles Large
Autifony Therapeutics, London, United Kingdom

Background:

It is universally acknowledged that there is a pressing need for novel treatments for schizophrenia, particularly in respect of negative and cognitive symptoms which are not well served by current therapeutic options (Keef et al Arch. Gen. Psychiatry 2007; 64:633-647). Here we present the first clinical data for AUT00206, a novel selective modulator of the Kv3 channel which has exhibited promising activity in preclinical models of schizophrenia (Large et al, Neill et al, this meeting). We also describe the translational medicine approach we have adopted to bridge from preclinical studies to clinical trials in patients.

Methods:

The first in human study was a randomised, double-blind, placebo-controlled study of single and multiple ascending oral doses of AUT00206 in healthy male volunteers, which also incorporated an evaluation of food effect. The primary objective was to explore the safety, tolerability (adverse events: AEs) and pharmacokinetics (PK) of AUT00206, with pharmacodynamic (PD) biomarkers as exploratory outcome measures. In Part A, 3 cohorts of 8 subjects participated in up to 5 dosing sessions, in which they received single oral doses of AUT00206 or placebo (6:2 ratio) in a dose escalating design. Progression from one dose level to the next was made after a medical review of the safety, tolerability and PK of the previous dose. The highest dose achieved by one cohort was repeated in the first dosing session of the next. The effect of food on the PK of AUT00206 was assessed in the first cohort and all subsequent treatments were administered in the fed state. In Part B, 4 cohorts of 8 subjects (6:2 ratio) received multiple oral doses of AUT00206 once or twice daily for 14 days in the fed state. Pharmaco-EEG (PhEEG) was performed in all subjects predose and at several timepoints post dosing. The 3 higher dose groups in Part B also had cognitive function assessments (using the CANTAB battery) and assessments of Event-Related Potentials (ERPs). The ERPs included mismatch negativity (MMN), P300 oddball paradigm (P300) and gamma response to an auditory tone pre- and post- dosing, as exploratory biomarkers. Results: AUT00206 was considered to be safe and well tolerated at all dose levels tested in Parts A and B of the study. The data remain blinded at the time of writing, however somnolence was more common following high single doses, compared to lower doses in Part A and headache was more prevalent at the higher dose levels in Part B. There were no deaths, serious AEs or severe AEs in either part of the study. Treatment-related AEs were more common in the Nervous System, compared to other system organ classes. There were no dropouts relating to treatmentemergent AEs. The PK analyses revealed a significant food effect, with Cmax and AUC0-inf increased 4 fold and 2 fold respectively in the presence of food. Following single doses in the fed state, exposure increased in a slightly less than dose proportional manner with low inter-individual variability. Half-life ranged from 10-15 h, compatible with once daily dosing. The accumulation ratio (Racc) following multiple doses was approximately 1.5, with steady state achieved within 2-3 days in Part B. Data from the PhEEG, cognitive battery and ERPs assessments are currently being analysed.

Conclusions:

The first in human data both support and inform the continued development of AUT00206, as plasma exposure in the single and multiple dose parts of the study achieved levels in the range predicted to be pharmacologically active, based on preclinical studies. Two dose levels from Part A have been chosen to explore the effects of AUT00206 on blood oxygen-level dependent (BOLD) fMRI and short term memory (N-Back) in healthy volunteers given a low i.v. dose ketamine challenge, in a randomised double-blind, placebo-controlled 4-way single dose crossover study. This study will explore whether signals identified in a previous rodent ketamine challenge model translate to humans and is due to commence shortly in Manchester, UK. The top dose level from Part B will be employed in an experimental study in patients diagnosed with schizophrenia within the last 5 years, who are taking no more than 2 recognised antipsychotics. This will be a randomised doubleblind, placebo-controlled study (part inpatient, part outpatient) with daily dosing for 28 days. The study will be conducted jointly at King’s College and Hammersmith Medicines Research, both in London, UK. In addition to clinical rating scales, cognitive function (CANTAB), ERPs (MMN, P300, ASSR) and imaging (18 F-DOPA PET, BOLD fMRI) will be performed at various timepoints to investigate PD effects in the target patient population. This study will commence later in the year.

Disclosure: Autifony: Employee and Shareholder, Self; Autifony: Employee, Self; Hammersmith Medicines Research: Employee, Self, University of Manchester: Consultancy and Grant, Self; Kings College London: Consultancy and Grant, Self; P1Vital: Employee and Shareholder, Self; Autifony: Employee and Shareholder, Self; Autifony: Employee and Shareholder, Self.

More information can be found in Autifony’s recent press release on this study

Read more abstracts from Poster Session II at ACNP