AUT-00063: Development and Clinical Evaluation of a Kv3 Channel Modulator for Hearing Disorders

1. Introduction and Overview

AUT-00063 (also designated AUT00063) is an investigational small molecule drug developed by Autifony Therapeutics.[1] It was designed as a positive modulator of voltage-gated potassium channels of the Kv3 subfamily, particularly Kv3.1.[2] These channels play a critical role in regulating neuronal firing patterns, especially in the auditory system. Based on preclinical evidence suggesting that enhancing Kv3 channel function could ameliorate deficits associated with hearing loss and tinnitus, AUT-00063 was advanced into clinical development for these indications.[3] Phase I studies were initiated in 2013 [3], followed by Phase II trials exploring its efficacy in age-related hearing loss (ARHL), subjective tinnitus, and cochlear implant users.[2] Despite demonstrating a favorable safety profile, the Phase II clinical trials ultimately failed to show significant efficacy in these patient populations, leading to the cessation of development for these specific indications around 2019.[1]

2. Mechanism of Action and Preclinical Rationale

The therapeutic rationale for AUT-00063 stemmed from the crucial role of Kv3 voltage-gated potassium channels, particularly the Kv3.1 subtype, in the auditory system. These channels are characterized by their high activation threshold and rapid activation/deactivation kinetics, properties that enable neurons to sustain high-frequency firing with temporal precision.[4] This fast-spiking phenotype is critical for neurons involved in processing complex auditory information, including speech perception in noisy environments and the encoding of temporal cues.[4] Kv3 channels are highly expressed in key auditory processing centers, including the cochlear nucleus, inferior colliculus (IC), and auditory cortex, as well as in fast-spiking, parvalbumin-positive (PV+) inhibitory interneurons that modulate cortical circuit synchronization.[4]

Dysfunction or decline in Kv3 channel activity has been implicated in hearing disorders. Age-related decline in Kv3.1 channel expression and function may contribute to deficits in central auditory processing observed in ARHL.[5] Furthermore, noise-induced neuronal hyperactivity in auditory centers, a proposed mechanism underlying subjective tinnitus, might be linked to altered Kv3 channel function.[6] Auditory deprivation, such as that experienced before cochlear implantation, can also negatively impact Kv3.1 channel expression and temporal processing capabilities.[4]

AUT-00063 was developed as a novel small molecule designed to selectively enhance Kv3 channel function.[4] In vitro studies confirmed its activity as a positive modulator, demonstrating its ability to increase the amplitude of potassium currents mediated by recombinant human Kv3.1 channels.[4] The hypothesis was that by enhancing Kv3 channel activity, AUT-00063 could restore more precise high-frequency firing in auditory neurons, thereby improving temporal processing and potentially alleviating symptoms of ARHL and tinnitus.[4]

Preclinical studies provided support for this hypothesis. In rodent models:

• AUT-00063 suppressed noise-induced spontaneous hyperactivity in neurons of the dorsal cochlear nucleus (DCN) and inferior colliculus (IC).[4]
• It partially reversed the degradation of temporal coding (assessed by phase locking to acoustic chirps) in the IC and auditory cortex of mice with auditory nerve damage.[4]
• It improved behavioral measures of temporal resolution (gap detection using gap-prepulse inhibition, gap-PPI) in aged rats, which exhibit deficits compared to younger animals.[4]
• AUT-00063 (and the related compound AUT00202) also had a suppressive effect on the acoustic startle response (ASR) in aged rats, with the effect being dose- and age-dependent.[5]

Collectively, these preclinical findings indicated that AUT-00063 could influence intrinsic neuronal firing properties and improve auditory temporal processing, providing a strong rationale for investigating its therapeutic potential in human hearing disorders characterized by deficits in temporal processing or neuronal hyperactivity.[4]

3. Clinical Development Program

Following promising preclinical results and successful completion of Phase I studies establishing initial safety and tolerability [3], Autifony Therapeutics advanced AUT-00063 into Phase II clinical trials targeting specific hearing disorder populations. The clinical program aimed to provide proof-of-concept for the Kv3 modulation strategy in humans.

Three key Phase II trials were conducted:

1. QUIET-1 (NCT02315508): A Phase IIa, randomized, double-blind, placebo-controlled, multi-center trial designed to evaluate the efficacy and safety of AUT-00063 in patients with subjective tinnitus.[2]
2. CLARITY-1 (NCT02345031): A Phase IIa, randomized, double-blind, placebo-controlled, parallel-group study assessing the efficacy and safety of AUT-00063 in adults with age-related hearing loss (ARHL) and specifically targeting deficits in understanding speech-in-noise.[2]
3. Pilot Study in CI Users (NCT02832128): A pilot, double-blind, placebo-controlled, crossover study exploring potential benefits of AUT-00063 on temporal processing measures in adult post-lingual unilateral cochlear implant (CI) recipients.[2]

These trials represented a significant effort to translate the preclinical rationale into clinical benefit across different patient groups experiencing hearing difficulties potentially linked to impaired temporal processing or central auditory hyperactivity.

4. Clinical Trial Details and Results

The Phase II clinical program for AUT-00063 yielded consistently negative efficacy results across all targeted indications, despite pharmacokinetic data confirming drug uptake.[7]

• QUIET-1 (NCT02315508): This trial randomized 91 participants with subjective tinnitus to receive AUT-00063 (800 mg/day) or placebo for 28 days. The primary endpoint was the change in the Tinnitus Functional Index (TFI). The trial was terminated early for futility, as AUT-00063 showed no significant effect on tinnitus symptoms compared to placebo (1.56 point change in TFI).[2]
• CLARITY-1 (NCT02345031): This study enrolled 78 participants with ARHL and speech-in-noise deficits. The primary endpoint was improvement in the signal-to-noise ratio (SNR) threshold on the Quick Speech in Noise Test (QuickSIN) after 28 days of treatment. The trial failed to meet its primary objective, showing no statistically significant difference between AUT-00063 and placebo on the QuickSIN or secondary hearing performance measures.[2]
• CI Pilot Study (NCT02832128): This crossover study involved 12 adult CI users. It assessed the effects of AUT-00063 on psychophysical measures of temporal processing, including the upper limit of temporal pitch, gap detection, and low-rate discrimination. No significant differences were found between the post-drug and post-placebo conditions on any of the temporal processing measures.[2]

A summary of these key Phase II trials is presented in Table 1.

Table 1: Summary of AUT-00063 Phase II Clinical Trials

CI: Cochlear Implant; SNR: Signal-to-Noise Ratio; TFI: Tinnitus Functional Index.

Data sourced from.2

5. Safety and Tolerability Profile

Despite the lack of demonstrated efficacy in the target indications, AUT-00063 exhibited a generally favorable safety and tolerability profile across the clinical trials conducted. In the Phase IIa QUIET-1 trial for tinnitus, daily administration of 800 mg AUT-00063 for 28 days was reported to be safe and well-tolerated.[7] Similarly, the Phase IIa CLARITY-1 trial in ARHL and the pilot study in CI users did not report significant safety concerns.[4] No treatment-related serious adverse events were highlighted in the available summaries of these trials.[7]

This consistent safety profile across different patient populations and trial designs, even at relatively high doses maintained for several weeks, is noteworthy. It suggests that the failure to achieve efficacy endpoints was unlikely due to dose-limiting toxicity preventing the administration of potentially effective exposures. The confirmation of drug uptake via pharmacokinetic markers in the QUIET-1 trial further supports this, pointing towards a lack of pharmacological effect on the targeted disease mechanisms in humans for these specific conditions, rather than an inability to safely test the drug at relevant concentrations.[7]

6. Development Status and Conclusion

The clinical development of AUT-00063 for hearing loss and tinnitus indications was halted following the consistent failure to demonstrate efficacy in Phase II trials. The QUIET-1 trial (NCT02315508) for tinnitus was terminated early due to futility [7], and both the CLARITY-1 trial (NCT02345031) for ARHL and the pilot study in CI users (NCT02832128) failed to meet their primary endpoints.[4] Consequently, as of August 2019, development for these indications was officially reported as discontinued ("No development reported").[1] The compound remains available for licensing for these indications, signifying Autifony Therapeutics' deprioritization of AUT-00063 for hearing disorders.[1]

The trajectory of AUT-00063 underscores the significant challenges inherent in translating preclinical findings, particularly in the complex field of central auditory processing, into clinically meaningful benefits for patients with hearing disorders. While the preclinical rationale targeting Kv3 channels was strong, based on their role in neuronal firing and observed deficits in relevant animal models [4], the lack of efficacy in human trials raises questions regarding the predictive validity of these specific models for tinnitus and ARHL, or potentially the specific role of Kv3.1 modulation in these human conditions.[7]

Despite the cessation of AUT-00063 development for hearing loss and tinnitus, Autifony Therapeutics has continued to invest in its Kv3 modulator platform. The company has advanced other Kv3 modulators, namely AUT00201 and AUT00206, into clinical trials for different central nervous system indications, including schizophrenia and rare pediatric epilepsies like EPM7.[15] This strategic redirection suggests that while AUT-00063 or the hearing disorder indications proved unsuccessful, the company maintains confidence in the therapeutic potential of modulating Kv3 channels for other neurological conditions. The favorable safety profile established for AUT-00063 across its trials may provide valuable information for the continued development of these related compounds.

In conclusion, AUT-00063, a Kv3.1 channel modulator, represented a novel therapeutic approach for hearing loss and tinnitus based on compelling preclinical rationale. However, rigorous Phase II clinical testing failed to demonstrate efficacy in these indications, leading to the discontinuation of its development for auditory disorders around 2019. While unsuccessful in its initial target areas, the program provided valuable clinical experience and safety data for Kv3 modulators, informing Autifony's ongoing efforts to target this channel class for other CNS diseases.

Works cited

1. AUT 00063 - AdisInsight - Springer, accessed May 9, 2025, https://adisinsight.springer.com/drugs/800038170
2. AUT-00063 - Drug Targets, Indications, Patents - Patsnap Synapse, accessed May 9, 2025, https://synapse.patsnap.com/drug/28414a7c68484223a20f105f49dc6f21
3. Autifony Therapeutics Initiates Phase I Study for Lead Product, AUT00063, for the Treatment of Hearing Loss and Tinnitus and Tops Up Series A Financing with Further 5.5 million Investment, accessed May 9, 2025, https://autifony.com/autifony-therapeutics-initiates-phase-i-study-for-lead-product-aut00063-for-the-treatment-of-hearing-loss-and-tinnitus-and-tops-up-series-a-financing-with-further-5-5-million-investment/
4. Evaluation of Possible Effects of a Potassium Channel Modulator on ..., accessed May 9, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC6249161/
5. Effect of Kv3 channel modulators on auditory temporal resolution in ..., accessed May 9, 2025, https://pubmed.ncbi.nlm.nih.gov/33348192/
6. Clinical proof of concept trial of a Kv3 modulator for the treatment of tinnitus - UKRI gateway, accessed May 9, 2025, https://gtr.ukri.org/projects?ref=101873
7. A balanced randomised placebo controlled blinded phase IIa multi-centre study to investigate the efficacy and safety of AUT00063 versus placebo in subjective tinnitus: The QUIET-1 trial - PubMed, accessed May 9, 2025, https://pubmed.ncbi.nlm.nih.gov/30939361/
8. Voltage-gated potassium channels as a potential therapeutic target for the treatment of neurological and psychiatric disorders - Frontiers, accessed May 9, 2025, https://www.frontiersin.org/journals/cellular-neuroscience/articles/10.3389/fncel.2024.1449151/full
9. BACKGROUND CLARITY-1 STUDY DESIGN EFFICACY ENDPOINTS RESULTS SUMMARY - Technology Networks, accessed May 9, 2025, https://cdn.technologynetworks.com/ep/pdfs/clarity-1-trial-results-and-implications-for-future-audiology-related-pharmaceutical-trials.pdf
10. A Novel Modulator of Kv3 Potassium Channels Regulates the Firing of Parvalbumin-Positive Cortical Interneurons - ResearchGate, accessed May 9, 2025, https://www.researchgate.net/publication/278791293_A_Novel_Modulator_of_Kv3_Potassium_Channels_Regulates_the_Firing_of_Parvalbumin-Positive_Cortical_Interneurons
11. Evaluating Possible Improvement in Tinnitus Severity - ClinConnect, accessed May 9, 2025, https://clinconnect.io/trials/NCT02315508
12. Biomedical Catalyst – Clinical proof of concept trial of a Kv3 modulator for the treatment of tinnitus - UKRI gateway, accessed May 9, 2025, https://gtr.ukri.org/projects?ref=MC_PC_14094
13. Evaluating Possible Improvement in Tinnitus Severity After 28 Days Dosing of the Study Drug AUT00063 Compared to Placebo (QUIET-1) - ngram, accessed May 9, 2025, https://www.ngram.com/trials/NCT02315508
14. Autifony Announces Results from Completed CLARITY-1, Phase IIa Trial of AUT00063 in Age-related Hearing Loss, accessed May 9, 2025, https://autifony.com/autifony-announces-results-from-completed-clarity-1-phase-iia-trial-of-aut00063-in-age-related-hearing-loss/
15. News & Events – Autifony Therapeutics, accessed May 9, 2025, https://autifony.com/news-events/