AUT-00063

AUT00063 is an experimental new medicine that has been demonstrated to suppress spontaneous hyperactivity by modulating the action of voltage-gated potassium-channels in central auditory cortical neurons of a rodent model. This neurobiological property makes it a good candidate for treating the central component of subjective tinnitus but this has not yet been tested in humans. The main purpose of the QUIET-1 (QUest In Eliminating Tinnitus) trial was to examine the effect of AUT00063 on the severity of tinnitus symptoms in people with subjective tinnitus. The trial was a randomised, placebo-controlled, observer, physician and participant blinded multi-centre superiority trial with two parallel groups and a primary endpoint of functional impact on tinnitus 28 days after the first drug dosing day. The trial design overcame the scale and logistical challenges of delivering a scientifically robust, statistically powered multi-centre study for subjective tinnitus within the National Health Service in England. The trial was terminated early for futility. Overall, 212 participants consented across 18 sites with 91 participants randomised to groups using age, gender, tinnitus symptom severity and hearing status as minimisation factors. While the pharmacokinetic markers confirm the uptake of AUT00063 in the body, within the expected therapeutic range, with respect to clinical benefit findings indicated that AUT00063 was not effective in alleviating tinnitus symptoms (1.56 point change in Tinnitus Functional Index). In terms of clinical harms, results indicated that a daily dose of 800 mg capsules of AUT00063 taken for 28 days was safe and well tolerated. These findings provide significant advances in the drug development field for hearing sciences, but raise questions about the predictive validity of certain rodent models of noise-induced hearing loss and tinnitus, as least for the mechanism evaluated in the present study. Trial Registration: (EudraCT) 2014-002179-27; NCT02315508.

Temporal processing by cochlear implant listeners is degraded and is affected by auditory deprivation. The fast-acting Kv3.1 potassium channel is important for sustained temporally accurate firing and is also susceptible to deprivation, the effects of which can be partially restored in animals by the molecule AUT00063. We report the results of a randomised placebo-controlled double-blind study on psychophysical tests of the effects of AUT00063 on temporal processing by CI listeners. The study measured the upper limit of temporal pitch, gap detection, and discrimination of low rates (centred on 120 pps) for monopolar pulse trains presented to an apical electrode. The upper limit was measured using the optimally efficient midpoint comparison (MPC) pitch-ranking procedure; thresholds were obtained for the other two measures using an adaptive procedure. Twelve CI users (MedEl and Cochlear) were tested before and after two periods of AUT00063 or placebo in a within-subject crossover study. No significant differences occurred between post-drug and post-placebo conditions. This absence of effect occurred despite high test-retest reliability for all three measures, obtained by comparing performance on the two baseline visits, and despite the demonstrated sensitivity of the measures to modest changes in temporal processing obtained in other studies from our laboratory. Hence, we have no evidence that AUT00063 improves temporal processing for the doses and patient population employed.